Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. - Bentley, Amy R; Sung, Yun J; Brown, Michael R; Winkler, Thomas W; Kraja, Aldi T; Ntalla, Ioanna; Schwander, Karen; Chasman, Daniel I; Lim, Elise; Deng, Xuan; Guo, Xiuqing; Liu, Jingmin; et al. (Nat Genet, 2019)
The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

{A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure - Sung, Y. J.; de Las Fuentes, L.; Winkler, T. W.; Chasman, D. I.; Bentley, A. R.; Kraja, A. T.; Ntalla, I.; Warren, H. R.; Guo, X.; Schwander, K.; Manning, A. K.; Brown, M. R.; et al. (Hum. Mol. Genet., 2019)
Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 Ã— 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. - Noordam, Raymond; Bos, Maxime M; Wang, Heming; Winkler, Thomas W; Bentley, Amy R; Kilpeläinen, Tuomas O; de Vries, Paul S; Sung, Yun Ju; Schwander, Karen; Cade, Brian E; Manning, Alisa; Aschard, Hugues; et al. (Nat Commun, 2019)
Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. - Kilpeläinen, Tuomas O; Bentley, Amy R; Noordam, Raymond; Sung, Yun Ju; Schwander, Karen; Winkler, Thomas W; Jakupović, Hermina; Chasman, Daniel I; Manning, Alisa; Ntalla, Ioanna; Aschard, Hugues; Brown, Michael R; et al. (Nat Commun, 2019)
Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
Keywords: Adolescent; Adult; African Continental Ancestry Group; Aged; Aged, 80 and over; Asian Continental Ancestry Group; Brazil; Calcium-Binding Proteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; European Continental Ancestry Group; Exercise; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Hispanic Americans; Humans; LIM-Homeodomain Proteins; Lipid Metabolism; Lipids; Male; Membrane Proteins; Microtubule-Associated Proteins; Middle Aged; Muscle Proteins; Nerve Tissue Proteins; Transcription Factors; Triglycerides; Young Adult

Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. - Pollack, Samuela; Igo, Robert P; Jensen, Richard A; Christiansen, Mark; Li, Xiaohui; Cheng, Ching-Yu; Ng, Maggie C Y; Smith, Albert V; Rossin, Elizabeth J; Segrè, Ayellet V; Davoudi, Samaneh; Tan, Gavin S; et al. (Diabetes, 2019)
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 × 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 × 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

{New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders - Evangelou, E.; Gao, H.; Chu, C.; Ntritsos, G.; Blakeley, P.; Butts, A. R.; Pazoki, R.; Suzuki, H.; Koskeridis, F.; Yiorkas, A. M.; Karaman, I.; Elliott, J.; et al. (Nat Hum Behav, 2019)
Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study. - Jordan, Daniel M; Choi, Hyon K; Verbanck, Marie; Topless, Ruth; Won, Hong-Hee; Nadkarni, Girish; Merriman, Tony R; Do, Ron (PLoS Med, 2019)
BACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR). METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study. CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.
Keywords: Adult; Age Factors; Female; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Male; Mendelian Randomization Analysis; Renal Insufficiency, Chronic; Sex Factors; Uric Acid; Young Adult

NT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure. - Whitman, Isaac R; Vittinghoff, Eric; deFilippi, Christopher R; Gottdiener, John S; Alonso, Alvaro; Psaty, Bruce M; Heckbert, Susan R; Hoogeveen, Ron C; Arking, Dan E; Selvin, Elizabeth; Chen, Lin Y; Dewland, Thomas A; et al. (J Am Heart Assoc, 2019)
Background Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40% higher than blacks; 95% CI , 29-53; ARIC : 39% higher; 95% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2%; 95% CI , 23.2-69.2%; ARIC : 24.6%; 95% CI , 14.8-39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed.

{Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal DPP10-Pulmonary Function Association - Xu, J.; Gaddis, N. C.; Bartz, T. M.; Hou, R.; Manichaikul, A. W.; Pankratz, N.; Smith, A. V.; Sun, F.; Terzikhan, N.; Markunas, C. A.; Patchen, B. K.; Schu, M.; et al. (Am J Respir Crit Care Med, 2019)
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.\ To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.\ Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs.\ DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; βSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; βSNP×DHA interaction = 36.2 ml).\ We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. - Floyd, James S; Bloch, Katarzyna M; Brody, Jennifer A; Maroteau, Cyrielle; Siddiqui, Moneeza K; Gregory, Richard; Carr, Daniel F; Molokhia, Mariam; Liu, Xiaoming; Bis, Joshua C; Ahmed, Ammar; Liu, Xuan; et al. (PLoS One, 2019)
AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

{Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis - Merino, J.; Guasch-Ferr?, M.; Ellervik, C.; Dashti, H. S.; Sharp, S. J.; Wu, P.; Overvad, K.; Sarnowski, C.; Kuokkanen, M.; Lemaitre, R. N.; Justice, A. E.; Ericson, U.; et al. (BMJ, 2019)
{To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.\ Individual participant data meta-analysis.\ Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators.\ Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score.\ Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75

A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. - Zhang, Xiaoling; Zhu, Congcong; Beecham, Gary; Vardarajan, Badri N; Ma, Yiyi; Lancour, Daniel; Farrell, John J; Chung, Jaeyoon; Mayeux, Richard; Haines, Jonathan L; Schellenberg, Gerard D; Pericak-Vance, Margaret A; et al. (Alzheimers Dement, 2019)
INTRODUCTION: The genetic architecture of Alzheimer's disease (AD) is only partially understood. METHODS: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. RESULTS: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10). DISCUSSION: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.

{Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium - Inker, L. A.; Grams, M. E.; Levey, A. S.; Coresh, J.; Cirillo, M.; Collins, J. F.; Gansevoort, R. T.; Gutierrez, O. M.; Hamano, T.; Heine, G. H.; Ishikawa, S.; Jee, S. H.; et al. (Am J Kidney Dis, 2019)
Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.\ Cross-sectional individual participant-level analyses in a global consortium.\ 17 CKD and 38 general population and high-risk cohorts.\ Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.\ Data were obtained and analyzed between July 2015 and January 2018.\ We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.\ The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).\ Variations in study era, health care delivery system, typical diet, and laboratory assays.\ Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. - Liang, Jingjing; Cade, Brian E; He, Karen Y; Wang, Heming; Lee, Jiwon; Sofer, Tamar; Williams, Stephanie; Li, Ruitong; Chen, Han; Gottlieb, Daniel J; Evans, Daniel S; Guo, Xiuqing; et al. (Am J Hum Genet, 2019)
Average arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.

Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study. - Smit, Roelof A J; Trompet, Stella; Leong, Aaron; Goodarzi, Mark O; Postmus, Iris; Warren, Helen; Theusch, Elizabeth; Barnes, Michael R; Arsenault, Benoit J; Li, Xiaohui; Feng, QiPing; Chasman, Daniel I; et al. (Pharmacogenomics J, 2019)
It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, n = 40,914) and DIAGRAM (n = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (r = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.

Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight. - Ebbert, Mark T W; Jensen, Tanner D; Jansen-West, Karen; Sens, Jonathon P; Reddy, Joseph S; Ridge, Perry G; Kauwe, John S K; Belzil, Veronique; Pregent, Luc; Carrasquillo, Minerva M; Keene, Dirk; Larson, Eric; et al. (Genome Biol, 2019)
BACKGROUND: The human genome contains "dark" gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions. RESULTS: Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer's Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer's disease gene, found in disease cases but not in controls. CONCLUSIONS: While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer's disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.
Keywords: Genetic Predisposition to Disease; Genome, Human; Humans; Mutation

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. - Tin, Adrienne; Marten, Jonathan; Halperin Kuhns, Victoria L; Li, Yong; Wuttke, Matthias; Kirsten, Holger; Sieber, Karsten B; Qiu, Chengxiang; Gorski, Mathias; Yu, Zhi; Giri, Ayush; Sveinbjornsson, Gardar; et al. (Nat Genet, 2019)
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. - Giri, Ayush; Hellwege, Jacklyn N; Keaton, Jacob M; Park, Jihwan; Qiu, Chengxiang; Warren, Helen R; Torstenson, Eric S; Kovesdy, Csaba P; Sun, Yan V; Wilson, Otis D; Robinson-Cohen, Cassianne; Roumie, Christianne L; et al. (Nat Genet, 2019)
In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

{Variants Associated with the Ankle Brachial Index Differ by Hispanic/Latino Ethnic Group: a genome-wide association study in the Hispanic Community Health Study/Study of Latinos - Sofer, T.; Emery, L.; Jain, D.; Ellis, A. M.; Laurie, C. C.; Allison, M. A.; Lee, J.; Kurniansyah, N.; Kerr, K. F.; Gonz?lez, H. M.; Tarraf, W.; Criqui, M. H.; et al. (Sci Rep, 2019)
Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 Ã— 10-5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10-7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 Ã— 10-4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.

{Androgens In Men Study (AIMS): protocol for meta-analyses of individual participant data investigating associations of androgens with health outcomes in men - Yeap, B. B.; Marriott, R. J.; Adams, R. J.; Antonio, L.; Ballantyne, C. M.; Bhasin, S.; Cawthon, P. M.; Couper, D. J.; Dobs, A. S.; Flicker, L.; Karlsson, M.; Martin, S. A.; et al. (BMJ Open, 2020)
This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men.\ Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses.\ Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities.\ CRD42019139668.

Association of Genetic Variation With Keratoconus. - McComish, Bennet J; Sahebjada, Srujana; Bykhovskaya, Yelena; Willoughby, Colin E; Richardson, Andrea J; Tenen, Abi; Charlesworth, Jac C; Macgregor, Stuart; Mitchell, Paul; Lucas, Sionne E M; Mills, Richard A; Mackey, David A; et al. (JAMA Ophthalmol, 2020)
Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. Objective: To identify genetic susceptibility regions for keratoconus in the human genome. Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. Main Outcomes and Measures: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8). Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.
Keywords: Adult; Female; Fuchs' Endothelial Dystrophy; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Keratoconus; Lipase; Logistic Models; Male; Middle Aged; Polymorphism, Single Nucleotide

Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies. - Arbeev, Konstantin G; Verhulst, Simon; Steenstrup, Troels; Kark, Jeremy D; Bagley, Olivia; Kooperberg, Charles; Reiner, Alexander P; Hwang, Shih-Jen; Levy, Daniel; Fitzpatrick, Annette L; Christensen, Kaare; Yashin, Anatoliy I; et al. (JAMA Netw Open, 2020)
Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span. Objective: To examine whether LTL is associated with the life span of contemporary humans. Design, Setting, and Participants: This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019. Main Outcomes and Measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees. Results: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77). Conclusions and Relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

Association of Nonobstructive Chronic Bronchitis With Respiratory Health Outcomes in Adults. - Balte, Pallavi P; Chaves, Paulo H M; Couper, David J; Enright, Paul; Jacobs, David R; Kalhan, Ravi; Kronmal, Richard A; Loehr, Laura R; London, Stephanie J; Newman, Anne B; O'Connor, George T; Schwartz, Joseph E; et al. (JAMA Intern Med, 2020)
Importance: Chronic bronchitis has been associated with cigarette smoking as well as with e-cigarette use among young adults, but the association of chronic bronchitis in persons without airflow obstruction or clinical asthma, described as nonobstructive chronic bronchitis, with respiratory health outcomes remains uncertain. Objective: To assess whether nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes in adult ever smokers and never smokers. Design, Setting, and Participants: This prospective cohort study included 22 325 adults without initial airflow obstruction (defined as the ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity [FVC] of <0.70) or clinical asthma at baseline. The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 9 US general population-based cohorts. Thus present study is based on data from 5 of these cohorts. Participants were enrolled from August 1971 through May 2007 and were followed up through December 2018. Exposures: Nonobstructive chronic bronchitis was defined by questionnaire at baseline as both cough and phlegm for at least 3 months for at least 2 consecutive years. Main Outcomes and Measures: Lung function was measured by prebronchodilator spirometry. Hospitalizations and deaths due to chronic lower respiratory disease and respiratory disease-related mortality were defined by events adjudication and administrative criteria. Models were stratified by smoking status and adjusted for anthropometric, sociodemographic, and smoking-related factors. The comparison group was participants without nonobstructive chronic bronchitis. Results: Among 22 325 adults included in the analysis, mean (SD) age was 53.0 (16.3) years (range, 18.0-95.0 years), 58.2% were female, 65.9% were non-Hispanic white, and 49.6% were ever smokers. Among 11 082 ever smokers with 99 869 person-years of follow-up, participants with nonobstructive chronic bronchitis (300 [2.7%]) had accelerated decreases in FEV1 (4.1 mL/y; 95% CI, 2.1-6.1 mL/y) and FVC (4.7 mL/y; 95% CI, 2.2-7.2 mL/y), increased risks of chronic lower respiratory disease-related hospitalization or mortality (hazard ratio [HR], 2.2; 95% CI, 1.7-2.7), and greater respiratory disease-related (HR, 2.0; 95% CI, 1.1-3.8) and all-cause mortality (HR, 1.5; 95% CI, 1.3-1.8) compared with ever smokers without nonobstructive chronic bronchitis. Among 11 243 never smokers with 120 004 person-years of follow-up, participants with nonobstructive chronic bronchitis (151 [1.3%]) had greater rates of chronic lower respiratory disease-related hospitalization or mortality (HR, 3.1; 95% CI, 2.1-4.5) compared with never smokers without nonobstructive chronic bronchitis. Nonobstructive chronic bronchitis was not associated with FEV1:FVC decline or incident airflow obstruction. The presence of at least 1 of the component symptoms of nonobstructive chronic bronchitis (ie, chronic cough or phlegm), which was common in both ever smokers (11.0%) and never smokers (6.7%), was associated with adverse respiratory health outcomes. Conclusions and Relevance: The findings suggest that nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes, particularly in ever smokers, and may be a high-risk phenotype suitable for risk stratification and targeted therapies.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Bronchitis, Chronic; Female; Humans; Lung; Male; Middle Aged; Prospective Studies; Respiratory Function Tests; Smokers; Smoking; Young Adult

The association of prediagnosis social support with survival after heart failure in the Cardiovascular Health Study. - Kaiser, Paulina; Allen, Norrina; Delaney, Joseph A C; Hirsch, Calvin H; Carnethon, Mercedes; Arnold, Alice M; Odden, Michelle C (Ann Epidemiol, 2020)
PURPOSE: Although social support has been shown to be associated with survival among persons with cardiovascular disease, little research has focused on whether social support, measured before the onset of heart failure, can enhance survival after diagnosis. The objective of this study was to assess the association between prediagnosis social support and postdiagnosis survival among older adults with heart failure. METHODS: We obtained the data from the Cardiovascular Health Study, which included noninstitutionalized adults aged 65 years or older from four sites in the United States with primary enrollment in 1989-1990. We used two measures of social support, the Lubben Social Network Scale and the Interpersonal Support Evaluation List. The analytic data set included 529 participants with a social support measure within two years before diagnosis of heart failure. RESULTS: After adjustment for demographic covariates, cardiovascular risk factors, and general health status, mortality rates were lower among participants in the highest tertile of social network scores (HR 0.74, 95% CI: 0.59, 0.93) and the middle tertile (HR 0.73 [0.58, 0.90]), compared with the lowest tertile. Results with interpersonal support were null. CONCLUSIONS: These findings suggest that prediagnosis structural social support may modestly buffer heart failure patients from mortality.

Associations of body composition with incident dementia in older adults: Cardiovascular Health Study-Cognition Study. - Cui, Chendi; Mackey, Rachel H; Shaaban, C Elizabeth; Kuller, Lewis H; Lopez, Oscar L; Sekikawa, Akira (Alzheimers Dement, 2020)
INTRODUCTION: A body of literature reported associations between late-life general adiposity measures (eg, body mass index) and dementia. Little is known about the association of late-life body composition with dementia risk. METHODS: We determined this association among cognitively normal participants from the Cardiovascular Health Study- Cognition Study. Body composition was assessed by dual-energy x-ray absorptiometry in 1994-1995. Dementia was ascertained at annual follow-up from 1998-1999 to 2013. Associations of body composition with incident dementia were assessed by the Fine-Gray model. RESULT: Among 344 participants (mean age 78, 62.2% women), body composition was significantly different between men and women, despite similar body mass indexes (BMIs). Increased dementia risk was significantly associated with lower lean mass in men and marginally with low appendicular lean mass in women. DISCUSSION: Decreased lean mass was an indicator of increased dementia risk in older adults. Studies should test whether preventing lean mass loss in older adults reduces dementia risk.

Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study. - Tang, Weihong; Stimson, Mary Rachel; Basu, Saonli; Heckbert, Susan R; Cushman, Mary; Pankow, James S; Folsom, Aaron R; Pankratz, Nathan (J Thromb Haemost, 2020)
BACKGROUND: Rare coding mutations underlying deficiencies of antithrombin and proteins C and S contribute to familial venous thromboembolism (VTE). It is uncertain whether rare variants play a role in the etiology of VTE in the general population. OBJECTIVES: We conducted a deep whole-exome sequencing (WES) study to investigate the associations between rare coding variants and the risk of VTE in two population-based prospective cohorts. PATIENTS/METHODS: Whole-exome sequencing was performed in the Longitudinal Investigation of Thromboembolism Etiology (LITE), which combines the Atherosclerosis Risk in Communities (ARIC) study (316 incident VTE events among 3159 African Americans [AAs] and 458 incident VTEs among 7772 European Americans [EAs]) and the Cardiovascular Healthy Study (CHS; 60 incident VTEs among 1751 EAs). We performed gene-based tests of rare variants (allele frequency < 1%, exome-wide significance P < 1.47 × 10 ) separately in each study and ancestry group, and meta-analyzed the results for the EAs in ARIC and CHS. RESULTS: In the meta-analysis of EAs, we identified one gene, PROC, in which the burden of rare, coding variants was significantly associated with increased risk of VTE (HR = 5.42 [3.11, 9.42] for carriers versus non-carriers, P = 2.27 × 10 ). In ARIC EAs, carriers of the PROC rare variants had on average 0.75 standard deviation (SD) lower concentrations of plasma protein C and 0.28 SD higher D-dimer (P < .05) than non-carriers. Adjustment for low protein C status did not eliminate the association of PROC burden with VTE. In AAs, rare coding PROC variants were not associated with VTE. CONCLUSIONS: Rare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample.

{Cerebral small vessel disease genomics and its implications across the lifespan - Sargurupremraj, M.; Suzuki, H.; Jian, X.; Sarnowski, C.; Evans, T. E.; Bis, J. C.; Eiriksdottir, G.; Sakaue, S.; Terzikhan, N.; Habes, M.; Zhao, W.; Armstrong, N. J.; et al. (Nat Commun, 2020)
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5Ã—10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study. - Patel, Ravi B; Delaney, Joseph A; Hu, Mo; Patel, Harnish; Cheng, Jeanette; Gottdiener, John; Kizer, Jorge R; Marcus, Gregory M; Turakhia, Mintu P; Deo, Rajat; Heckbert, Susan R; Psaty, Bruce M; et al. (JCI Insight, 2020)
BACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear. METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF. RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain. CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF. FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH's National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts. - Moll, Matthew; Sakornsakolpat, Phuwanat; Shrine, Nick; Hobbs, Brian D; DeMeo, Dawn L; John, Catherine; Guyatt, Anna L; McGeachie, Michael J; Gharib, Sina A; Obeidat, Ma'en; Lahousse, Lies; Wijnant, Sara R A; et al. (Lancet Respir Med, 2020)
BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. FUNDING: US National Institutes of Health, Wellcome Trust.
Keywords: Adult; Case-Control Studies; Cohort Studies; Female; Forced Expiratory Volume; Genome-Wide Association Study; Humans; Male; Middle Aged; Phenotype; Pulmonary Disease, Chronic Obstructive; Risk Factors; Vital Capacity

Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study. - Rohmann, Jessica L; Longstreth, W T; Cushman, Mary; Fitzpatrick, Annette L; Heckbert, Susan R; Rice, Kenneth; Rosendaal, Frits R; Sitlani, Colleen M; Psaty, Bruce M; Siegerink, Bob (PLoS One, 2020)
OBJECTIVE: To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time. METHODS: Data from the population-based Cardiovascular Health Study (n = 5,888, aged ≥65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function. RESULTS: After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95% CI -0.97 to 0.53, N = 2,306) after confounding adjustment. INTERPRETATION: The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.
Keywords: Aged; Blood Coagulation; Cognition; Cross-Sectional Studies; Factor VIII; Female; Humans; Logistic Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Up-Regulation; White Matter

{Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals - Surendran, P.; Feofanova, E. V.; Lahrouchi, N.; Ntalla, I.; Karthikeyan, S.; Cook, J.; Chen, L.; Mifsud, B.; Yao, C.; Kraja, A. T.; Cartwright, J. H.; Hellwege, J. N.; et al. (Nat Genet, 2020)
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency â‰¤ 0.01) variant BP associations (P < 5 Ã— 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline. - Cornelius, Talea; Schwartz, Joseph E; Balte, Pallavi; Bhatt, Surya P; Cassano, Patricia A; Currow, David; Jacobs, David R; Johnson, Miriam; Kalhan, Ravi; Kronmal, Richard; Loehr, Laura; O'Connor, George T; et al. (Am J Epidemiol, 2020)
The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at ≥3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and -0.24%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r = -0.16) and FVC (r = -0.26) and slower declines in FEV1:FVC ratio (r = 0.11) (all P values < 0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P < 0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.
Keywords: Adult; Aged; Body Mass Index; Cohort Studies; Humans; Linear Models; Lung; Middle Aged; Respiratory Function Tests; Weight Gain

{Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale - Li, X.; Li, Z.; Zhou, H.; Gaynor, S. M.; Liu, Y.; Chen, H.; Sun, R.; Dey, R.; Arnett, D. K.; Aslibekyan, S.; Ballantyne, C. M.; Bielak, L. F.; et al. (Nat Genet, 2020)
Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.

Estrogen, brain structure, and cognition in postmenopausal women. - Boyle, Christina P; Raji, Cyrus A; Erickson, Kirk I; Lopez, Oscar L; Becker, James T; Gach, H Michael; Kuller, Lewis H; Longstreth, William; Carmichael, Owen T; Riedel, Brandalyn C; Thompson, Paul M (Hum Brain Mapp, 2020)
Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.

Examining the causal mediating role of brain pathology on the relationship between diabetes and cognitive impairment: the Cardiovascular Health Study. - Andrews, Ryan M; Shpitser, Ilya; Lopez, Oscar; Longstreth, William T; Chaves, Paulo H M; Kuller, Lewis; Carlson, Michelle C (J R Stat Soc Ser A Stat Soc, 2020)
The paper examines whether leads to incident mild cognitive impairment and dementia through brain hypoperfusion and white matter disease. We performed inverse odds ratio weighted causal mediation analyses to decompose the effect of diabetes on cognitive impairment into direct and indirect effects, and we found that approximately a third of the total effect of diabetes is mediated through vascular-related brain pathology. Our findings lend support for a common aetiological hypothesis regarding incident cognitive impairment, which is that diabetes increases the risk of clinical cognitive impairment in part by impacting the vasculature of the brain.

{Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies - Imamura, F.; Fretts, A. M.; Marklund, M.; Ardisson Korat, A. V.; Yang, W. S.; Lankinen, M.; Qureshi, W.; Helmer, C.; Chen, T. A.; Virtanen, J. K.; Wong, K.; Bassett, J. K.; et al. (PLoS Med, 2020)
De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).\ Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.\ Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. - de Las Fuentes, Lisa; Sung, Yun Ju; Noordam, Raymond; Winkler, Thomas; Feitosa, Mary F; Schwander, Karen; Bentley, Amy R; Brown, Michael R; Guo, Xiuqing; Manning, Alisa; Chasman, Daniel I; Aschard, Hugues; et al. (Mol Psychiatry, 2020)
Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Genetic and regulatory architecture of Alzheimer's disease in the region. - Kulminski, Alexander M; Shu, Leonardo; Loika, Yury; He, Liang; Nazarian, Alireza; Arbeev, Konstantin; Ukraintseva, Svetlana; Yashin, Anatoliy; Culminskaya, Irina (Alzheimers Dement (Amst), 2020)
Introduction: Apolipoprotein E () ε2 and ε4 alleles encoded by rs7412 and rs429358 polymorphisms, respectively, are landmark contra and pro "risk" factors for Alzheimer's disease (AD). Methods: We examined differences in linkage disequilibrium (LD) structures between (1) AD-affected and unaffected subjects and (2) older AD-unaffected and younger subjects in the 19q13.3 region harboring rs7412 and rs429358. Results: AD is associated with sex-nonspecific heterogeneous patterns of decreased and increased LD of rs7412 and rs429358, respectively, with other polymorphisms from five genes in this region in AD-affected subjects. The LD patterns in older AD-unaffected subjects resembled those in younger individuals. Polarization of the ε4- and ε2 allele-related heterogeneous LD clusters differentiated cell types and implicated specific tissues in AD pathogenesis. Discussion: Protection and predisposition to AD is characterized by an interplay of rs7412 and rs429358, with multiple polymorphisms in the 19q13.3 region in a tissue-specific manner, which is not driven by common evolutionary forces.

The genetic architecture of the human cerebral cortex - Grasby, Katrina L.; Jahanshad, Neda; Painter, Jodie N.; Colodro-Conde, Lucía; Bralten, Janita; Hibar, Derrek P.; Lind, Penelope A.; Pizzagalli, Fabrizio; Ching, Christopher R. K.; McMahon, Mary Agnes B.; Shatokhina, Natalia; Zsembik, Leo C. P.; et al. (Science, 2020)

{Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults - Hofer, E.; Roshchupkin, G. V.; Adams, H. H. H.; Knol, M. J.; Lin, H.; Li, S.; Zare, H.; Ahmad, S.; Armstrong, N. J.; Satizabal, C. L.; Bernard, M.; Bis, J. C.; et al. (Nat Commun, 2020)
Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/Î²-catenin, TGF-Î² and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

{Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation - Weng, L. C.; Hall, A. W.; Choi, S. H.; Jurgens, S. J.; Haessler, J.; Bihlmeyer, N. A.; Grarup, N.; Lin, H.; Teumer, A.; Li-Gao, R.; Yao, J.; Guo, X.; et al. (Circ Genom Precis Med, 2020)
Background - The P-wave duration (PWD) is an electrocardiographic (ECG) measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome chip data to examine the associations between common and rare variants with PWD. Methods - Fifteen studies comprising 64,440 individuals (56,943 European, 5,681 African, 1,186 Hispanic, 630 Asian), and 230,000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and SKAT tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF GWAS. Results - We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (e.g., PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions - Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. - Hahn, Julie; Fu, Yi-Ping; Brown, Michael R; Bis, Joshua C; de Vries, Paul S; Feitosa, Mary F; Yanek, Lisa R; Weiss, Stefan; Giulianini, Franco; Smith, Albert Vernon; Guo, Xiuqing; Bartz, Traci M; et al. (PLoS One, 2020)
BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome. METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event. CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
Keywords: Aging; Coronary Artery Disease; Cross-Sectional Studies; Europe; European Continental Ancestry Group; Genetic Loci; Genome-Wide Association Study; Humans; Myocardial Infarction; Polymorphism, Single Nucleotide; Prospective Studies

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. - Yaghootkar, Hanieh; Zhang, Yiying; Spracklen, Cassandra N; Karaderi, Tugce; Huang, Lam Opal; Bradfield, Jonathan; Schurmann, Claudia; Fine, Rebecca S; Preuss, Michael H; Kutalik, Zoltán; Wittemans, Laura Bl; Lu, Yingchang; et al. (Diabetes, 2020)
Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

{Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure - Shah, S.; Henry, A.; Roselli, C.; Lin, H.; Sveinbj?rnsson, G.; Fatemifar, G.; Hedman, ?. K.; Wilk, J. B.; Morley, M. P.; Chaffin, M. D.; Helgadottir, A.; Verweij, N.; et al. (Nat Commun, 2020)
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

{Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke - Keene, K. L.; Hyacinth, H. I.; Bis, J. C.; Kittner, S. J.; Mitchell, B. D.; Cheng, Y. C.; Pare, G.; Chong, M.; O'Donnell, M.; Meschia, J. F.; Chen, W. M.; Sale, M. M.; et al. (Stroke, 2020)
Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans.\ The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts.\ In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci.\ These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

{An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms - Wildisen, L.; Del Giovane, C.; Moutzouri, E.; Beglinger, S.; Syrogiannouli, L.; Collet, T. H.; Cappola, A. R.; ?svold, B. O.; Bakker, S. J. L.; Yeap, B. B.; Almeida, O. P.; Ceresini, G.; et al. (Sci Rep, 2020)
{In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck's Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (Â± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval = - 0.17 to 0.76

Inherited causes of clonal haematopoiesis in 97,691 whole genomes. - Bick, Alexander G; Weinstock, Joshua S; Nandakumar, Satish K; Fulco, Charles P; Bao, Erik L; Zekavat, Seyedeh M; Szeto, Mindy D; Liao, Xiaotian; Leventhal, Matthew J; Nasser, Joseph; Chang, Kyle; Laurie, Cecelia; et al. (Nature, 2020)
Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes? - Sharma, Shilpa; Katz, Ronit; Bullen, Alexander L; Chaves, Paulo H M; de Leeuw, Peter W; Kroon, Abraham A; Houben, Alfons J H M; Shlipak, Michael G; Ix, Joachim H (J Clin Endocrinol Metab, 2020)
CONTEXT: Higher fibroblast growth factor-23 (FGF23) concentrations are associated with heart failure and mortality in diverse populations, but the strengths of associations differ markedly depending up on which assay is used. OBJECTIVE: We sought to evaluate whether iron deficiency, inflammation, or kidney function account for differences in the strengths of associations between these 2 FGF23 assays with clinical outcomes. DESIGN: Case cohort study from the Cardiovascular Health Study. SETTING: A total of 844 community-dwelling individuals aged 65 years or older with and without chronic kidney disease were followed for 10 years. OUTCOMES: Outcomes included death, incident heart failure (HF), and incident myocardial infarction (MI). Exposure was baseline intact and C-terminal FGF23. Using modified Cox models, adjusting sequentially we tested whether observed associations of each assay with outcomes were attenuated by iron status, inflammation, kidney function, or their combinations. RESULTS: FGF23 measured by either assay was associated with mortality in unadjusted analysis (intact FGF23 hazard ratio [HR] per 2-fold higher 1.45; 95% CI, 1.25-1.68; C-terminal FGF23 HR 1.38; 95% CI, 1.26-1.50). Adjustment for kidney function completely attenuated associations of intact FGF23 with mortality (HR 1.00; 95% CI, 0.85-1.17), but had much less influence on the association of C-terminal FGF23, for which results remained significant after adjustment (HR 1.15; 95% CI, 1.04-1.28). Attenuation was much less with adjustment for iron status or inflammation. Results were similar for the HF end point. Neither C-terminal or intact FGF23 was associated with MI risk. CONCLUSIONS: The relationship of FGF23 with clinical end points is markedly different depending on the type of FGF23 assay used. The associations of biologically active FGF23 with clinical end points may be confounded by kidney disease, and thus much weaker than previously thought.

Level and change in N-terminal pro B-type Natriuretic Peptide and kidney function and survival to age 90. - Häberle, Astrid D; Biggs, Mary L; Cushman, Mary; Psaty, Bruce M; Newman, Anne B; Shlipak, Michael G; Gottdiener, John; Wu, Chenkai; Gardin, Julius M; Bansal, Nisha; Odden, Michelle C (J Gerontol A Biol Sci Med Sci, 2020)
BACKGROUND: Many traditional cardiovascular risk factors do not predict survival to very old age. Studies have shown associations of estimated glomerular filtration rate (eGFR) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with cardiovascular disease and mortality in older populations. This study aimed to evaluate the associations of the level and change in eGFR and NT-pro-BNP with longevity to age 90 years. METHODS: The population included participants (n=3,645) in the Cardiovascular Health Study, aged between 67-75 at baseline. The main exposures were eGFR, calculated with the Berlin Initiative Study equation (BIS2), and NT-pro-BNP, and the main outcome was survival to age 90. Mixed models were used to estimate level and change of the main exposures. RESULTS: There was an association between baseline level and change of both eGFR and NT-pro-BNP and survival to 90, and this association persisted after adjustment for covariates. Each 10 ml/min per 1.73 m2 higher eGFR level was associated with an adjusted odds ratio (OR) of 1.23 (95% CI: 1.13, 1.34) of survival to 90, and a 0.5 ml/min/ 1.73 m2 slower decline in eGFR was associated with an OR of 1.51 (95% CI: 1.31, 1.74). A 2-fold higher level of NT-pro-BNP level had an adjusted OR of 0.67 (95% CI: 0.61, 0.73), and a 1.05-fold increase per year in NT-pro-BNP had an OR of 0.53 (95% CI: 0.43, 0.65) for survival to age 90. CONCLUSION: eGFR and NT-pro-BNP appear to be important risk factors for longevity to age 90.

Long-term cognitive decline and mortality after carotid endarterectomy. - Thirumala, Parthasarathy D; Reddy, Rajiv P; Lopez, Oscar L; Chang, Yue-Fang; Becker, James T; Kuller, Lewis H (Clin Neurol Neurosurg, 2020)
OBJECTIVES: To date no studies have evaluated long term cognitive decline after carotid endarterectomy (CEA). We evaluated whether participants who had CEA were at increased risk of cognitive decline over participants who didn't undergo CEA. PATIENTS AND METHODS: The patients in the study were participants in the Cardiovascular Health Study (CHS), a study of 5201 men and women over the age of 65 who were recruited from four communities (Pittsburgh, Pennsylvania; Sacramento, California; Winston-Salem, North Carolina; Hagerstown, Maryland) in 1988-89. The outcomes measured were 1) Decline in 3MSE and digit symbol substitution test (DSST) scores after CEA compared to before CEA. 2) All-cause mortality in CHS cohort among participants who did and did not have CEA. RESULTS: CEA patients had significantly greater annual decrease in the DSST scores -2.43 (SD 4.21) compared to those who did not have a CEA -1.1 (SD 2.57) (p < 0.001) but this was not seen in the 3MSE scores. CEA patients had increased the risk of decline in DSST (OR 2.41, 95 % CI 1.49, 3.88) and 3MSE (OR 2.17, 95 % CI 1.35, 3.48) scores after adjusting for age, gender, race and educational status. CEA was associated with all-cause mortality in the long term with a HR of 2.72 (95 % CI 2.22, 3.34) after adjusting for covariates. Participants with lower baseline 3MSE scores HR 1.39 (1.27, 1.51), lower DSST scores <34 HR 1.69(1.54, 1.85) were more likely deceased. CONCLUSIONS: CEA patients are at increased risk of lower scores on 3MSE and DSST testing in the long term. Mortality in the CHS cohort was higher in participants who underwent CEA. Further, lower 3MSE and DSST scores increased the risk of mortality.

Lung function decline in former smokers and low-intensity current smokers: a secondary data analysis of the NHLBI Pooled Cohorts Study. - Oelsner, Elizabeth C; Balte, Pallavi P; Bhatt, Surya P; Cassano, Patricia A; Couper, David; Folsom, Aaron R; Freedman, Neal D; Jacobs, David R; Kalhan, Ravi; Mathew, Amanda R; Kronmal, Richard A; Loehr, Laura R; et al. (Lancet Respir Med, 2020)
BACKGROUND: Former smokers now outnumber current smokers in many developed countries, and current smokers are smoking fewer cigarettes per day. Some data suggest that lung function decline normalises with smoking cessation; however, mechanistic studies suggest that lung function decline could continue. We hypothesised that former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers, including among those without prevalent lung disease. METHODS: We used data on six US population-based cohorts included in the NHLBI Pooled Cohort Study. We restricted the sample to participants with valid spirometry at two or more exams. Two cohorts recruited younger adults (≥17 years), two recruited middle-aged and older adults (≥45 years), and two recruited only elderly adults (≥65 years) with examinations done between 1983 and 2014. FEV decline in sustained former smokers and current smokers was compared to that of never-smokers by use of mixed models adjusted for sociodemographic and anthropometric factors. Differential FEV decline was also evaluated according to duration of smoking cessation and cumulative (number of pack-years) and current (number of cigarettes per day) cigarette consumption. FINDINGS: 25 352 participants (ages 17-93 years) completed 70 228 valid spirometry exams. Over a median follow-up of 7 years (IQR 3-20), FEV decline at the median age (57 years) was 31·01 mL per year (95% CI 30·66-31·37) in sustained never-smokers, 34·97 mL per year (34·36-35·57) in former smokers, and 39·92 mL per year (38·92-40·92) in current smokers. With adjustment, former smokers showed an accelerated FEV decline of 1·82 mL per year (95% CI 1·24-2·40) compared to never-smokers, which was approximately 20% of the effect estimate for current smokers (9·21 mL per year; 95% CI 8·35-10·08). Compared to never-smokers, accelerated FEV decline was observed in former smokers for decades after smoking cessation and in current smokers with low cumulative cigarette consumption (<10 pack-years). With respect to current cigarette consumption, the effect estimate for FEV decline in current smokers consuming less than five cigarettes per day (7·65 mL per year; 95% CI 6·21-9·09) was 68% of that in current smokers consuming 30 or more cigarettes per day (11·24 mL per year; 9·86-12·62), and around five times greater than in former smokers (1·57 mL per year; 1·00-2·14). Among participants without prevalent lung disease, associations were attenuated but were consistent with the main results. INTERPRETATION: Former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers. These results suggest that all levels of smoking exposure are likely to be associated with lasting and progressive lung damage. FUNDING: National Institutes of Health, National Heart Lung and Blood Institute, and US Environmental Protection Agency.
Keywords: Adult; Aged; Case-Control Studies; Ex-Smokers; Female; Follow-Up Studies; Humans; Lung; Male; Middle Aged; National Heart, Lung, and Blood Institute (U.S.); Non-Smokers; Respiratory Physiological Phenomena; Smokers; Smoking; Spirometry; United States; Young Adult

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood. - Zheng, Yan; Huang, Tao; Wang, Tiange; Mei, Zhendong; Sun, Zhonghan; Zhang, Tao; Ellervik, Christina; Chai, Jin-Fang; Sim, Xueling; van Dam, Rob M; Tai, E-Shyong; Koh, Woon-Puay; et al. (Eur J Epidemiol, 2020)
Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. - Gorski, Mathias; Jung, Bettina; Li, Yong; Matias-Garcia, Pamela R; Wuttke, Matthias; Coassin, Stefan; Thio, Chris H L; Kleber, Marcus E; Winkler, Thomas W; Wanner, Veronika; Chai, Jin-Fang; Chu, Audrey Y; et al. (Kidney Int, 2020)
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Metabolites Associated with Walking Ability Among the Oldest Old from the CHS All Stars Study. - Marron, Megan M; Wendell, Stacy G; Boudreau, Robert M; Clish, Clary B; Santanasto, Adam J; Tseng, George C; Zmuda, Joseph M; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2020)
BACKGROUND: Low walking ability is highly prevalent with advancing age and predicts major health outcomes. Metabolomics may help to better characterize differences in walking ability among older adults, providing insight into potentially altered molecular processes underlying age-related decline in functioning. We sought to identify metabolites and metabolic pathways associated with high versus low walking ability among 120 participants ages 79-95 from the CHS All Stars study. METHODS: Using a nested case-control design, 60 randomly selected participants with low walking ability were matched one-to-one on age, gender, race, and fasting time with 60 participants with high walking ability. High versus low walking ability was defined as being in the best versus worst tertiles for both gait speed (≥0.9 vs <0.7 m/s) and the Walking Ability Index (7-9 vs 0-1). Using liquid chromatography-mass spectrometry, 569 metabolites were identified in overnight-fasting plasma. RESULTS: Ninety-six metabolites were associated with walking ability, where 24% were triacylglycerols. Triacylglycerols that were higher among those with high walking ability consisted mostly of polyunsaturated fatty acids, whereas triacylglycerols that were lower among those with high walking ability consisted mostly of saturated or monounsaturated fatty acids. Body composition partly explained associations between some metabolites and walking ability. Proline and arginine metabolism was a top pathway associated with walking ability. CONCLUSION: These results may partly reflect pathways of modifiable risk factors, including excess dietary lipids and lack of physical activity, contributing to obesity and further alterations in metabolic pathways that lead to age-related decline in walking ability in this older adult cohort.
Keywords: Aged; Aged, 80 and over; Case-Control Studies; Female; Geriatric Assessment; Humans; Male; Metabolomics; Risk Factors; Walking; Walking Speed

{Mitochondrial DNA copy number and incident atrial fibrillation - Zhao, D.; Bartz, T. M.; Sotoodehnia, N.; Post, W. S.; Heckbert, S. R.; Alonso, A.; Longchamps, R. J.; Castellani, C. A.; Hong, Y. S.; Rotter, J. I.; Lin, H. J.; O'Rourke, B.; et al. (BMC Med, 2020)
Mechanistic studies suggest that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown.\ We conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study (CHS). mtDNA-CN from the peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA and from multiplexed real-time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates.\ The median follow-up time was 21.4 years in ARIC, 12.9 years in MESA, and 11.0 years in CHS, during which 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups.\ Mitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management of atrial fibrillation risk.

Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs. - Castellani, Christina A; Longchamps, Ryan J; Sumpter, Jason A; Newcomb, Charles E; Lane, John A; Grove, Megan L; Bressler, Jan; Brody, Jennifer A; Floyd, James S; Bartz, Traci M; Taylor, Kent D; Wang, Penglong; et al. (Genome Med, 2020)
BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10), as well as the TFAM knockout methylation (P = 4.41 × 10) and expression (P = 4.30 × 10) studies. CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. - Ntalla, Ioanna; Weng, Lu-Chen; Cartwright, James H; Hall, Amelia Weber; Sveinbjornsson, Gardar; Tucker, Nathan R; Choi, Seung Hoan; Chaffin, Mark D; Roselli, Carolina; Barnes, Michael R; Mifsud, Borbala; Warren, Helen R; et al. (Nat Commun, 2020)
The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Patterns of Cardiovascular Risk Factors in Old Age and Survival and Health Status at 90. - Odden, Michelle C; Rawlings, Andreea M; Arnold, Alice M; Cushman, Mary; Biggs, Mary L; Psaty, Bruce M; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2020)
BACKGROUND: The population age 90 years and older is the fastest growing segment of the U.S. population. Only recently is it possible to study the factors that portend survival to this age. METHODS: Among participants of the Cardiovascular Health Study, we studied the association of repeated measures of cardiovascular risk factors measured over 15-23 years of follow-up and not only survival to 90 years of age, but also healthy aging outcomes among the population who reached age 90. We included participants aged 67-75 years at baseline (n = 3,613/5,888) to control for birth cohort effects, and followed participants until death or age 90 (median follow-up = 14.7 years). RESULTS: Higher systolic blood pressure was associated with a lower likelihood of survival to age 90, although this association was attenuated at older ages (p-value for interaction <.001) and crossed the null for measurements taken in participants' 80's. Higher levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and body mass index (BMI) were associated with greater longevity. Among the survivors to age 90, those with worse cardiovascular profile (high blood pressure, LDL cholesterol, glucose, and BMI; low HDL cholesterol) had lower likelihood of remaining free of cardiovascular disease, cognitive impairment, and disability. CONCLUSION: In summary, we observed paradoxical associations between some cardiovascular risk factors and survival to old age; whereas, among those who survive to very old age, these risk factors were associated with higher risk of adverse health outcomes.

Performance of the Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Body Mass Index. - Khera, Rohan; Pandey, Ambarish; Ayers, Colby R; Carnethon, Mercedes R; Greenland, Philip; Ndumele, Chiadi E; Nambi, Vijay; Seliger, Stephen L; Chaves, Paulo H M; Safford, Monika M; Cushman, Mary; Xanthakis, Vanessa; et al. (JAMA Netw Open, 2020)
Importance: Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown. Objective: To assess performance of the PCE across clinical BMI categories. Design, Setting, and Participants: This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020. Exposures: Participant BMI category: underweight (<18.5), normal weight (18.5 to <25), overweight (25 to <30), mild obesity (30 to <35), and moderate to severe obesity (≥35). Main Outcomes and Measures: Discrimination (Harrell C statistic) and calibration (Nam-D'Agostino χ2 goodness-of-fit test) of the PCE across BMI categories. Improvement in discrimination and net reclassification with addition of BMI, waist circumference, and high-sensitivity C-reactive protein (hsCRP) to the PCE. Results: Among 37 311 participants (mean [SD] age, 58.6 [11.8] years; 21 897 [58.7%] women), 380 604 person-years of follow-up were conducted. Mean (SD) baseline BMI was 29.0 (6.2), and 360 individuals (1.0%) were in the underweight category, 9937 individuals (26.6%) were in the normal weight category, 13 601 individuals (36.4%) were in the overweight category, 7783 individuals (20.9%) were in the mild obesity category, and 5630 individuals (15.1%) were in the moderate to severe obesity category. Median (interquartile range [IQR]) 10-year estimated ASCVD risk was 7.1% (2.5%-15.4%), and 3709 individuals (9.9%) developed ASCVD over a median (IQR) 10.8 [8.5-12.6] years. The PCE overestimated ASCVD risk in the overall cohort (estimated/observed [E/O] risk ratio, 1.22; 95% CI, 1.18-1.26) and across all BMI categories except the underweight category. Calibration was better near the clinical decision threshold in all BMI groups but worse among individuals with moderate or severe obesity (E/O risk ratio, 1.36; 95% CI, 1.25-1.47) and among those with the highest estimated ASCVD risk ≥20%. The PCE C statistic overall was 0.760 (95% CI, 0.753-0.767), with lower discrimination in the moderate or severe obesity group (C statistic, 0.742; 95% CI, 0.721-0.763) compared with the normal-range BMI group (C statistic, 0.785; 95% CI, 0.772-0.798). Waist circumference (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.03-1.11) and hsCRP (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.05-1.09), but not BMI, were associated with increased ASCVD risk when added to the PCE. However, these factors did not improve model performance (C statistic, 0.760; 95% CI, 0.753-0.767) with or without added metrics. Conclusions and Relevance: These findings suggest that the PCE had acceptable model discrimination and were well calibrated at clinical decision thresholds but overestimated risk of ASCVD for individuals in overweight and obese categories, particularly individuals with high estimated risk. Incorporation of the usual clinical measures of obesity did not improve risk estimation of the PCE. Future research is needed to determine whether incorporation of alternative high-risk obesity markers (eg, weight trajectory or measures of visceral or ectopic fat) into the PCE may improve risk prediction.
Keywords: Adult; Aged; Body Mass Index; Cardiovascular Diseases; Cohort Studies; Correlation of Data; Female; Humans; Longitudinal Studies; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors

The Polygenic and Monogenic Basis of Blood Traits and Diseases. - Vuckovic, Dragana; Bao, Erik L; Akbari, Parsa; Lareau, Caleb A; Mousas, Abdou; Jiang, Tao; Chen, Ming-Huei; Raffield, Laura M; Tardaguila, Manuel; Huffman, Jennifer E; Ritchie, Scott C; Megy, Karyn; et al. (Cell, 2020)
Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Pre-diabetes, diabetes and predictors of incident angina among older women and men in the Cardiovascular Health Study. - Mathenge, Njambi; Fan, Wenjun; Wong, Nathan D; Hirsch, Calvin; Delaney, Chris Joseph; Amsterdam, Ezra A; Koch, Bruce; Calara, Rico; Gardin, Julius M (Diab Vasc Dis Res, 2020)
Diabetes mellitus and angina pectoris are important conditions in older persons. The utility of pre-diabetes mellitus, diabetes mellitus and other risk factors as predictors of incident angina pectoris among older adults has not been characterized. We examined incident angina pectoris rates by sex and diabetes mellitus status in 4511 adults aged ⩾65 years without coronary heart disease at baseline from the Cardiovascular Health Study. Cox regression examined predictors of incident angina pectoris, including pre-diabetes mellitus or diabetes mellitus adjusted for sociodemographic characteristics and other risk factors, over 12.2 ± 6.9 years of follow-up. Overall, 39.1% of participants had pre-diabetes mellitus, 14.0% had diabetes mellitus and 532 (11.8%) had incident angina pectoris. Incident angina pectoris rates per 1000 person-years in those with neither condition, pre-diabetes mellitus, and diabetes mellitus were 7.9, 9.0 and 12.3 in women and 10.3, 11.2 and 14.5 in men, respectively. Pre-diabetes mellitus and diabetes mellitus were not independently associated with incident AP; however, key predictors of AP were male sex, low-density lipoprotein-cholesterol, triglycerides, systolic blood pressure, antihypertensive medication and difficulty performing at least one instrumental activity of daily living (all  < 0.05 to  < 0.01). In our cohort of older adult participants, while the incidence of AP is greater in those with diabetes mellitus, neither diabetes mellitus nor pre-diabetes mellitus independently predicted incident angina pectoris.
Keywords: Age Factors; Aged; Angina Pectoris; Diabetes Mellitus; Female; Humans; Incidence; Male; Prediabetic State; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; Sex Factors; Time Factors; United States

Putative Cut-Points in Sarcopenia Components and Incident Adverse Health Outcomes: An SDOC Analysis. - Cawthon, Peggy M; Manini, Todd; Patel, Sheena M; Newman, Anne; Travison, Thomas; Kiel, Douglas P; Santanasto, Adam J; Ensrud, Kristine E; Xue, Qian-Li; Shardell, Michelle; Duchowny, Kate; Erlandson, Kristine M; et al. (J Am Geriatr Soc, 2020)
OBJECTIVES: Analyses performed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) identified cut-points in several metrics of grip strength for consideration in a definition of sarcopenia. We describe the associations between the SDOC-identified metrics of low grip strength (absolute or standardized to body size/composition); low dual-energy x-ray absorptiometry (DXA) lean mass as previously defined in the literature (appendicular lean mass [ALM]/ht ); and slowness (walking speed <.8 m/s) with subsequent adverse outcomes (falls, hip fractures, mobility limitation, and mortality). DESIGN: Individual-level, sex-stratified pooled analysis. We calculated odds ratios (ORs) or hazard ratios (HRs) for incident falls, mobility limitation, hip fractures, and mortality. Follow-up time ranged from 1 year for falls to 8.8 ± 2.3 years for mortality. SETTING: Eight prospective observational cohort studies. PARTICIPANTS: A total of 13,421 community-dwelling men and 4,828 community-dwelling women. MEASUREMENTS Grip strength by hand dynamometry, gait speed, and lean mass by DXA. RESULTS: Low grip strength (absolute or standardized to body size/composition) was associated with incident outcomes, usually independently of slowness, in both men and women. ORs and HRs generally ranged from 1.2 to 3.0 for those below vs above the cut-point. DXA lean mass was not consistently associated with these outcomes. When considered together, those who had both muscle weakness by absolute grip strength (<35.5 kg in men and <20 kg in women) and slowness were consistently more likely to have a fall, hip fracture, mobility limitation, or die than those without either slowness or muscle weakness. CONCLUSION: Older men and women with both muscle weakness and slowness have a higher likelihood of adverse health outcomes. These results support the inclusion of grip strength and walking speed as components in a summary definition of sarcopenia. J Am Geriatr Soc 68:1429-1437, 2020.

Relation of Biomarkers of Cardiac Injury, Stress, and Fibrosis With Cardiac Mechanics in Patients ≥ 65 Years of Age. - Gottdiener, John S; Seliger, Stephen; DeFilippi, Christopher; Christenson, Robert; Baldridge, Abigail S; Kizer, Jorge R; Psaty, Bruce M; Shah, Sanjiv J (Am J Cardiol, 2020)
High sensitivity cardiac troponin T (hscTnT), soluble ST2 (sST2), N-terminal B-type natriuretic peptide (NT-proBNP), and galectin-3 are biomarkers of cardiac injury, stress, myocardial stretch, and fibrosis. Elevated levels are associated with poor outcomes. However, their association with cardiac mechanics in older persons is unknown. Associations between these biomarkers and cardiac mechanics derived from speckle tracking echocardiography, including left ventricular longitudinal strain (LVLS), early diastolic strain, and left atrial reservoir strain (LARS) were evaluated using standardized beta coefficients () in a cross sectional analysis with cardiac biomarkers in older patients without cardiovascular disease, low ejection fraction, or wall motion abnormalities. Biomarker associations with strain were attenuated by demographics and risk factors. In adjusted models, LVLS was associated with continuous measures of hscTnT (β-0.06, p = 0.020), sST2 (β -0.05, p = 0.024) and NT-proBNP (β -0.06, p = 0.007). "High" levels (i.e., greater than prognostic cutpoint) of hscTnT (>13 ng/ml), sST2 (>35 ng/ml), and NT-proBNP (>190 pg/ml) were also associated with worse LVLS. In risk factor adjusted models, LARS was associated with hscTnT (β -0.08, p = 0.003) and NT-proBNP (β-0.18, p <0.0001). High hscTnT (>13 ng/ml) and high NT-proBNP (>190 pg/ml) were also both associated with worse LARS. Gal-3 was not associated with any strain measure. In conclusion, in persons ≥ 65 years of age, without cardiovascular disease, low ejection fraction, or wall motion abnormalities, hscTnT, sST2, and NT-proBNP are associated with worse LVLS. HscTnT and NT-proBNP are associated with worse LARS. In conclusion, these subclinical increases in blood biomarkers, and their associations with subtle diastolic and systolic dysfunction, may represent pre-clinical heart failure.

Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels. - Wang, Zhe; Chen, Han; Bartz, Traci M; Bielak, Lawrence F; Chasman, Daniel I; Feitosa, Mary F; Franceschini, Nora; Guo, Xiuqing; Lim, Elise; Noordam, Raymond; Richard, Melissa A; Wang, Heming; et al. (Circ Genom Precis Med, 2020)
BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in . CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure. - Suthahar, Navin; Lau, Emily S; Blaha, Michael J; Paniagua, Samantha M; Larson, Martin G; Psaty, Bruce M; Benjamin, Emelia J; Allison, Matthew A; Bartz, Traci M; Januzzi, James L; Levy, Daniel; Meems, Laura M G; et al. (J Am Coll Cardiol, 2020)
BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear. OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF. METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio. RESULTS: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001). CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.

A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber and reduced kidney function. - Lye, Weng Kit; Paterson, Euan; Patterson, Christopher C; Maxwell, Alexander P; Binte Mohammed Abdul, Riswana Banu; Tai, E Shyong; Cheng, Ching Yu; Kayama, Takamasa; Yamashita, Hidetoshi; Sarnak, Mark; Shlipak, Michael; Matsushita, Kunihiro; et al. (Kidney Int, 2020)
Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 μm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2 % of 33,222 and 11.3 % of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95- 1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations. - Chen, Ming-Huei; Raffield, Laura M; Mousas, Abdou; Sakaue, Saori; Huffman, Jennifer E; Moscati, Arden; Trivedi, Bhavi; Jiang, Tao; Akbari, Parsa; Vuckovic, Dragana; Bao, Erik L; Zhong, Xue; et al. (Cell, 2020)
Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium - Wolters, Frank J; Chibnik, L B; Waziry, Reem; Anderson, Roy (Neurology, 2020)

Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality. - Ma, Jiantao; Rebholz, Casey M; Braun, Kim V E; Reynolds, Lindsay M; Aslibekyan, Stella; Xia, Rui; Biligowda, Niranjan G; Huan, Tianxiao; Liu, Chunyu; Mendelson, Michael M; Joehanes, Roby; Hu, Emily A; et al. (Circ Genom Precis Med, 2020)
BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied. METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10). CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants. - Zhao, Xutong; Qiao, Dandi; Yang, Chaojie; Kasela, Silva; Kim, Wonji; Ma, Yanlin; Shrine, Nick; Batini, Chiara; Sofer, Tamar; Taliun, Sarah A Gagliano; Sakornsakolpat, Phuwanat; Balte, Pallavi P; et al. (Nat Commun, 2020)
Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
Keywords: Adult; African Americans; Aged; Aged, 80 and over; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Calcium-Binding Proteins; Feasibility Studies; Female; Follow-Up Studies; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Intracellular Signaling Peptides and Proteins; Lung; Male; Middle Aged; Polymorphism, Single Nucleotide; Protein Inhibitors of Activated STAT; Pulmonary Disease, Chronic Obstructive; Respiratory Physiological Phenomena; Small Ubiquitin-Related Modifier Proteins; Whole Genome Sequencing

{Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation - Goumidi, L.; Thibord, F.; Wiggins, K. L.; Li-Gao, R.; Brown, M. R.; van Hylckama Vlieg, A.; Souto, J. C.; Soria, J. M.; Ibrahim-Kosta, M.; Saut, N.; Daian, D.; Olaso, R.; et al. (Blood, 2021)
10.1182/blood.2020008997Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1 and B haplotypes are associated with an ∼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

Association Between Intracerebral Hemorrhage and Subsequent Arterial Ischemic Events in Participants From 4 Population-Based Cohort Studies. - Murthy, Santosh B; Zhang, Cenai; Diaz, Ivan; Levitan, Emily B; Koton, Silvia; Bartz, Traci M; DeRosa, Janet T; Strobino, Kevin; Colantonio, Lisandro D; Iadecola, Costantino; Safford, Monika M; Howard, Virginia J; et al. (JAMA Neurol, 2021)
Importance: Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown. Objective: To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction. Design, Setting, and Participants: An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020. Exposure: Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria. Main Outcomes and Measures: The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications. Results: Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1). Conclusions and Relevance: This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults. - Wan, Emily S; Balte, Pallavi; Schwartz, Joseph E; Bhatt, Surya P; Cassano, Patricia A; Couper, David; Daviglus, Martha L; Dransfield, Mark T; Gharib, Sina A; Jacobs, David R; Kalhan, Ravi; London, Stephanie J; et al. (JAMA, 2021)
Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]). Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.
Keywords: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Female; Forced Expiratory Volume; Humans; Lung; Lung Diseases; Male; Middle Aged; Prevalence; Retrospective Studies; Spirometry; United States; Vital Capacity

Association of low-frequency and rare coding variants with information processing speed. - Bressler, Jan; Davies, Gail; Smith, Albert V; Saba, Yasaman; Bis, Joshua C; Jian, Xueqiu; Hayward, Caroline; Yanek, Lisa; Smith, Jennifer A; Mirza, Saira S; Wang, Ruiqi; Adams, Hieab H H; et al. (Transl Psychiatry, 2021)
Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
Keywords: Adult; Aging; Cognition; Genome-Wide Association Study; Geroscience; Humans; Polymorphism, Single Nucleotide; Ubiquitin-Protein Ligases

Association of Midlife Cardiovascular Risk Factors With the Risk of Heart Failure Subtypes Later in Life. - Cohen, Laura P; Vittinghoff, Eric; Pletcher, Mark J; Allen, Norrina B; Shah, Sanjiv J; Wilkins, John T; Chang, Patricia P; Ndumele, Chiadi E; Newman, Anne B; Ives, Diane; Maurer, Mathew S; Oelsner, Elizabeth C; et al. (J Card Fail, 2021)
BACKGROUND: Independent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied. METHODS: We pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF. RESULTS: A total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF. CONCLUSIONS: Midlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.

Association of mitochondrial DNA copy number with cardiometabolic diseases. - Liu, Xue; Longchamps, Ryan J; Wiggins, Kerri L; Raffield, Laura M; Bielak, Lawrence F; Zhao, Wei; Pitsillides, Achilleas; Blackwell, Thomas W; Yao, Jie; Guo, Xiuqing; Kurniansyah, Nuzulul; Thyagarajan, Bharat; et al. (Cell Genom, 2021)
Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 × 10) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 × 10), hypertension ( = 2.8 × 10), diabetes ( = 3.6 × 10), and hyperlipidemia ( = 6.3 × 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

Associations of hemoglobin and change in hemoglobin with risk of incident hip fracture in older men and women: the cardiovascular health study. - Valderrábano, R J; Bůžková, P; Chang, P-Y; Zakai, N A; Fink, H A; Robbins, J A; Wu, J Y; Lee, J S (Osteoporos Int, 2021)
In a multi-site longitudinal cohort study, decreasing hemoglobin was associated with increased hip fracture risk in men. Anemia was associated with hip fracture in men and in African American women. Decreasing hemoglobin may be a marker of progressing bone fragility, making its serial measurement useful for fracture risk stratification. INTRODUCTION: Hematopoiesis and bone health are interdependent. Anemia has been associated with risk of fracture in humans. To further elucidate this relationship, we hypothesized that decreasing hemoglobin could indicate defective hematopoiesis and would also predict fracture risk. METHODS: We performed a prospective analysis from study baseline (1992) of the Cardiovascular Health Study, a multi-site longitudinal cohort study. A total of 4670 men and women, ages >65 years, who were able to consent and not institutionalized or wheelchair bound, had hemoglobin (Hb) measured in 1992. For 4006 subjects, Hb change from 1989 to 1992 was annualized and divided into sex-specific quartiles. Incident hip fractures were verified against Medicare claims data during a median follow-up of 11.8 years. RESULTS: Nested Cox proportional-hazard models estimated association of hip fracture with anemia (men Hb <13 g/dL, women Hb <12 g/dL) and separately, greatest Hb decrease (versus others). Anemia was associated with increased hip fracture risk in all men (HR 1.59; 95% CI 1.01-2.50) and African American women (HR 3.21; 95% CI 1.07-9.63). In men, an annualized Hb loss of >0.36 g/dL/year was associated with a higher risk of hip fracture (HR 1.67; 95% CI 1.10-2.54), which was lessened by anemia at the start of fracture follow-up (HR 1.53; 95% CI 0.99-2.39). CONCLUSIONS: Decreasing Hb may be an early marker for subsequent hip fracture risk in men, which may be less informative once an anemia threshold is crossed. Only African American women with anemia had increased hip fracture risk, suggesting a race difference in this relationship.

BinomiRare: A robust test for association of a rare genetic variant with a binary outcome for mixed models and any case-control proportion. - Sofer, Tamar; Lee, Jiwon; Kurniansyah, Nuzulul; Jain, Deepti; Laurie, Cecelia A; Gogarten, Stephanie M; Conomos, Matthew P; Heavner, Ben; Hu, Yao; Kooperberg, Charles; Haessler, Jeffrey; Vasan, Ramachandran S; et al. (HGG Adv, 2021)
Whole-genome sequencing (WGS) and whole-exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g., family or household) when testing genetic associations. However, no existing tests of the association of a rare variant with a binary outcome in the presence of correlated data control the type 1 error where there are (1) few individuals harboring the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing a framework for testing rare variant association with a binary trait in individuals harboring at least one risk allele. In this framework, we estimate outcome probabilities under the null hypothesis and then use them, within the individuals with at least one risk allele, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small-vessel disease (SVD) stroke, short sleep, and venous thromboembolism (VTE), in whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program.

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. - Harris, William S; Tintle, Nathan L; Imamura, Fumiaki; Qian, Frank; Korat, Andres V Ardisson; Marklund, Matti; Djoussé, Luc; Bassett, Julie K; Carmichael, Pierre-Hugues; Chen, Yun-Yu; Hirakawa, Yoichiro; Küpers, Leanne K; et al. (Nat Commun, 2021)
The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
Keywords: Aged; Aged, 80 and over; Cause of Death; Fatty Acids, Omega-3; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mortality, Premature; Prospective Studies; Protective Factors; Risk Factors

Cardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study. - Stein, Phyllis K; Bůzková, Petra; Fink, Howard A; Robbins, John A; Mukamal, Kenneth J; Cauley, Jane A; Carbone, Laura; Elam, Rachel; McMillan, David W; Valderrabano, Rodrigo; Barzilay, Joshua I (Arch Osteoporos, 2021)
Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants. PURPOSE: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans. METHODS: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI). RESULTS: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men. CONCLUSIONS: In older women, increased heart rate variation is associated with hip fracture risk.
Keywords: Aged; Autonomic Nervous System; Female; Heart Rate; Hip Fractures; Humans; Osteoporosis; Proportional Hazards Models

Cardiovascular damage phenotypes and all-cause and CVD mortality in older adults. - Miller, Lindsay M; Wu, Chenkai; Hirsch, Calvin H; Lopez, Oscar L; Cushman, Mary; Odden, Michelle C (Ann Epidemiol, 2021)
PURPOSE: The association between CVD risk factors and mortality is well established, however, current tools for addressing subgroups have focused on the overall burden of disease. The identification of risky combinations of characteristics may lead to a better understanding of physiologic pathways that underlie morbidity and mortality in older adults. METHODS: Participants included 5067 older adults from the Cardiovascular Health Study, followed for up to 6 years. Using latent class analysis (LCA), we created CV damage phenotypes based on probabilities of abnormal brain infarctions, major echocardiogram abnormalities, N-terminal probrain natriuretic peptide, troponin T, interleukin-6, c reactive-protein, galectin-3, cystatin C. We assigned class descriptions based on the probability of having an abnormality among risk factors, such that a healthy phenotype would have low probabilities in all risk factors. Participants were assigned to phenotypes based on the maximum probability of membership. We used Cox-proportional hazards regression to evaluate the association between the categorical CV damage phenotype and all-cause and CVD-mortality. RESULTS: The analysis yielded 5 CV damage phenotypes consistent with the following descriptions: healthy (59%), cardio-renal (11%), cardiac (15%), multisystem morbidity (6%), and inflammatory (9%). All four phenotypes were statistically associated with a greater risk of all-cause mortality when compared with the healthy phenotype. The multisystem morbidity phenotype had the greatest risk of all-cause death (HR: 4.02; 95% CI: 3.44, 4.70), and CVD-mortality (HR: 4.90, 95% CI: 3.95, 6.06). CONCLUSIONS: Five CV damage phenotypes emerged from CVD risk factor measures. CV damage across multiple systems confers a greater mortality risk compared to damage in any single domain.

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. - Natarajan, Pradeep; Pampana, Akhil; Graham, Sarah E; Ruotsalainen, Sanni E; Perry, James A; de Vries, Paul S; Broome, Jai G; Pirruccello, James P; Honigberg, Michael C; Aragam, Krishna; Wolford, Brooke; Brody, Jennifer A; et al. (Nat Commun, 2021)
Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Cognitive decline in older adults with epilepsy: The Cardiovascular Health Study. - Choi, Hyunmi; Thacker, Evan L; Longstreth, William T; Elkind, Mitchell S V; Boehme, Amelia K (Epilepsia, 2021)
OBJECTIVE: Cognitive decline is a major concern for older adults with epilepsy. Whether and how much faster older adults with epilepsy experience cognitive decline beyond expected age-related cognitive change remain unclear. We sought to estimate and compare rates of cognitive decline in older adults with and without epilepsy. METHODS: The Cardiovascular Health Study is a population-based longitudinal cohort study of 5888 US adults aged 65+. Cognitive function was assessed annually with Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). We used linear mixed models to estimate average rates of decline in 3MS and DSST scores by epilepsy status (prevalent, incident, or no epilepsy), adjusted for risk factors associated with cognitive decline. RESULTS: The rate of decline in 3MS was significantly faster in prevalent epilepsy (P < .001) and after incident epilepsy (P = .002) compared with no epilepsy. Prevalent epilepsy and apolipoprotein E gene (APOE) ε4 (ApoE4) had a synergistic interaction, whereby prevalent epilepsy and ApoE4 together were associated with 1.51 points faster annual decline in 3MS than would be expected if prevalent epilepsy and ApoE4 did not interact (P < .001). Older adults with prevalent epilepsy had a significantly lower initial DSST score and faster rate of decline compared to those with no epilepsy (P < .001). SIGNIFICANCE: Faster decline in global cognitive ability seen in this study validates concerns of patients. ApoE4 allele status was an effect modifier of the relationship between cognitive decline and prevalent epilepsy. Further research is warranted to explore biological mechanisms and possible interventions to mitigate cognitive decline.

Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults. - Owens, David S; Bartz, Traci M; Bůzková, Petra; Massera, Daniele; Biggs, Mary L; Carlson, Selma D; Psaty, Bruce M; Sotoodehnia, Nona; Gottdiener, John S; Kizer, Jorge R (Heart, 2021)
OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up. METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods. RESULTS: The cohort comprised 5795 participants (age 73±6, 42.2% male, 14.3% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69% (probable/definite) to 4.67% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88% to 3.71%. Of incident cases, about 85% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95% CI 0.23 to 0.81]). CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. - Goodrich, Julia K; Singer-Berk, Moriel; Son, Rachel; Sveden, Abigail; Wood, Jordan; England, Eleina; Cole, Joanne B; Weisburd, Ben; Watts, Nick; Caulkins, Lizz; Dornbos, Peter; Koesterer, Ryan; et al. (Nat Commun, 2021)
Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
Keywords: Adult; Biological Variation, Population; Biomarkers; Diabetes Mellitus, Type 2; Dyslipidemias; Exome; Genetic Predisposition to Disease; Genotype; Humans; Multifactorial Inheritance; Penetrance; Risk Assessment

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. - Graff, Mariaelisa; Justice, Anne E; Young, Kristin L; Marouli, Eirini; Zhang, Xinruo; Fine, Rebecca S; Lim, Elise; Buchanan, Victoria; Rand, Kristin; Feitosa, Mary F; Wojczynski, Mary K; Yanek, Lisa R; et al. (Am J Hum Genet, 2021)
Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: A pooling project of US prospective cohorts. - Djoussé, Luc; Zhou, Guohai; McClelland, Robyn L; Ma, Nanxun; Zhou, Xia; Kabagambe, Edmond K; Talegawkar, Sameera A; Judd, Suzanne E; Biggs, Mary L; Fitzpatrick, Annette L; Clark, Cheryl R; Gagnon, David R; et al. (Clin Nutr, 2021)
BACKGROUND AND AIMS: Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults. DESIGN: We used prospective cohort design to complete time-to-event analyses. METHODS: We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n = 103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks. RESULTS: Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of ≥2 eggs per week was associated with elevated risk [27% elevated risk of T2D comparing 7+ eggs/week with none (95% CI: 16%-37%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30% higher risk of CHD (95% CI: 3%-56%) restricted to older adults consuming 5-6 eggs/week. CONCLUSIONS: Our data showed an elevated risk of T2D with egg consumption of ≥2 eggs per week but not with <2 eggs/week. While there was no overall association of egg consumption with CHD risk, the elevated CHD observed with consumption of 5-6 eggs/week in older cohorts merits further investigation.
Keywords: Adult; Aged; Cohort Studies; Coronary Disease; Diabetes Mellitus, Type 2; Diet; Eggs; Humans; Middle Aged; Prospective Studies; Risk Factors; United States

{Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption - Karabegović, I.; Portilla-Fernandez, E.; Li, Y.; Ma, J.; Maas, S. C. E.; Sun, D.; Hu, E. A.; Kühnel, B.; Zhang, Y.; Ambatipudi, S.; Fiorito, G.; Huang, J.; et al. (Nat Commun, 2021)
10.1038/s41467-021-22752-6Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.

Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. - Tin, Adrienne; Schlosser, Pascal; Matias-Garcia, Pamela R; Thio, Chris H L; Joehanes, Roby; Liu, Hongbo; Yu, Zhi; Weihs, Antoine; Hoppmann, Anselm; Grundner-Culemann, Franziska; Min, Josine L; Kuhns, Victoria L Halperin; et al. (Nat Commun, 2021)
Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
Keywords: Amino Acid Transport System y+; Cohort Studies; CpG Islands; DNA Methylation; Epigenome; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Glucose Transport Proteins, Facilitative; Gout; Humans; Male; Uric Acid

Estimating Systolic Blood Pressure Intervention Trial Participant Posttrial Survival Using Pooled Epidemiologic Cohort Data. - Bellows, Brandon K; Zhang, Yiyi; Zhang, Zugui; Lloyd-Jones, Donald M; Bress, Adam P; King, Jordan B; Kolm, Paul; Cushman, William C; Johnson, Karen C; Tamariz, Leonardo; Oelsner, Elizabeth C; Shea, Steven; et al. (J Am Heart Assoc, 2021)
Background Intensive systolic blood pressure treatment (<120 mm Hg) in SPRINT (Systolic Blood Pressure Intervention Trial) improved survival compared with standard treatment (<140 mm Hg) over a median follow-up of 3.3 years. We projected life expectancy after observed follow-up in SPRINT using SPRINT-eligible participants in the NHLBI-PCS (National Heart, Lung, and Blood Institute Pooled Cohorts Study). Methods and Results We used propensity scores to weight SPRINT-eligible NHLBI-PCS participants to resemble SPRINT participants. In SPRINT participants, we estimated in-trial survival (<4 years) using a time-based flexible parametric survival model. In SPRINT-eligible NHLBI-PCS participants, we estimated posttrial survival (≥4 years) using an age-based flexible parametric survival model and applied the formula to SPRINT participants to predict posttrial survival. We projected overall life expectancy for each SPRINT participant and compared it to parametric regression (eg, Gompertz) projections based on SPRINT data alone. We included 8584 SPRINT and 10 593 SPRINT-eligible NHLBI-PCS participants. After propensity weighting, mean (SD) age was 67.9 (9.4) and 68.2 (8.8) years, and 35.5% and 37.6% were women in SPRINT and NHLBI-PCS, respectively. Using the NHLBI-PCS-based method, projected mean life expectancy from randomization was 21.0 (7.4) years with intensive and 19.1 (7.2) years with standard treatment. Using the Gompertz regression, life expectancy was 11.2 (2.3) years with intensive and 10.5 (2.2) years with standard treatment. Conclusions Combining SPRINT and NHLBI-PCS observed data likely offers a more realistic estimate of life expectancy than parametrically extrapolating SPRINT data alone. These results offer insight into the potential long-term effectiveness of intensive SBP goals.

FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer. - Thibord, Florian; Song, Ci; Pattee, Jack; Rodriguez, Benjamin A T; Chen, Ming-Huei; O'Donnell, Christopher J; Kleber, Marcus E; Delgado, Graciela E; Guo, Xiuqing; Yao, Jie; Taylor, Kent D; Ozel, Ayse Bilge; et al. (J Thromb Haemost, 2021)
BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer. OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach. METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing. RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels. CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.

Genetic insights into biological mechanisms governing human ovarian ageing. - Ruth, Katherine S; Day, Felix R; Hussain, Jazib; Martínez-Marchal, Ana; Aiken, Catherine E; Azad, Ajuna; Thompson, Deborah J; Knoblochova, Lucie; Abe, Hironori; Tarry-Adkins, Jane L; Gonzalez, Javier Martin; Fontanillas, Pierre; et al. (Nature, 2021)
Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

{Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci - Ahluwalia, T. S.; Prins, B. P.; Abdollahi, M.; Armstrong, N. J.; Aslibekyan, S.; Bain, L.; Jefferis, B.; Baumert, J.; Beekman, M.; Ben-Shlomo, Y.; Bis, J. C.; Mitchell, B. D.; et al. (Hum Mol Genet, 2021)
Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

{Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women - Jones, G.; Trajanoska, K.; Santanasto, A. J.; Stringa, N.; Kuo, C. L.; Atkins, J. L.; Lewis, J. R.; Duong, T.; Hong, S.; Biggs, M. L.; Luan, J.; Sarnowski, C.; et al. (Nat Commun, 2021)
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

{The genomics of heart failure: design and rationale of the HERMES consortium - Lumbers, R. T.; Shah, S.; Lin, H.; Czuba, T.; Henry, A.; Swerdlow, D. I.; Malarstig, A.; Andersson, C.; Verweij, N.; Holmes, M. V.; Ärnlöv, J.; Svensson, P.; et al. (ESC Heart Fail, 2021)
The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.\ under an additive genetic model.\ HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Hemostatic factor levels and cognitive decline in older adults: The Cardiovascular Health Study. - Harrington, Laura B; Ehlert, Alexa N; Thacker, Evan L; Jenny, Nancy S; Lopez, Oscar; Cushman, Mary; Fitzpatrick, Annette; Mukamal, Kenneth J; Jensen, Majken K (J Thromb Haemost, 2021)
BACKGROUND: Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear. OBJECTIVE: To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during ≥8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults. METHODS: We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors. RESULTS: Of 20 factors evaluated individually, only higher levels of plasmin-α -antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP β = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI β = -0.55, 95% CI: -0.90 to -0.19; FXc β = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE. CONCLUSIONS: Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.

Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program. - Sarnowski, Chloe; Chen, Han; Biggs, Mary L; Wassertheil-Smoller, Sylvia; Bressler, Jan; Irvin, Marguerite R; Ryan, Kathleen A; Karasik, David; Arnett, Donna K; Cupples, L Adrienne; Fardo, David W; Gogarten, Stephanie M; et al. (PLoS One, 2021)
Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

Identification of putative causal loci in whole-genome sequencing data via knockoff statistics. - He, Zihuai; Liu, Linxi; Wang, Chen; Le Guen, Yann; Lee, Justin; Gogarten, Stephanie; Lu, Fred; Montgomery, Stephen; Tang, Hua; Silverman, Edwin K; Cho, Michael H; Greicius, Michael; et al. (Nat Commun, 2021)
The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.
Keywords: Algorithms; Causality; Computer Simulation; Data Interpretation, Statistical; Datasets as Topic; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Markov Chains; Models, Genetic; Polymorphism, Single Nucleotide; Reproducibility of Results; Whole Genome Sequencing

Meta-analyses identify DNA methylation associated with kidney function and damage. - Schlosser, Pascal; Tin, Adrienne; Matias-Garcia, Pamela R; Thio, Chris H L; Joehanes, Roby; Liu, Hongbo; Weihs, Antoine; Yu, Zhi; Hoppmann, Anselm; Grundner-Culemann, Franziska; Min, Josine L; Adeyemo, Adebowale A; et al. (Nat Commun, 2021)
Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
Keywords: Adult; Aged; CpG Islands; DNA Methylation; Female; Glomerular Filtration Rate; Humans; Interferon Regulatory Factors; Kidney; Kidney Function Tests; LIM Domain Proteins; Male; Membrane Proteins; Middle Aged; Renal Insufficiency, Chronic; Transcription Factors

Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. - Sun, Daokun; Richard, Melissa; Musani, Solomon K; Sung, Yun Ju; Winkler, Thomas W; Schwander, Karen; Chai, Jin Fang; Guo, Xiuqing; Kilpeläinen, Tuomas O; Vojinovic, Dina; Aschard, Hugues; Bartz, Traci M; et al. (HGG Adv, 2021)
Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. - Wang, Heming; Noordam, Raymond; Cade, Brian E; Schwander, Karen; Winkler, Thomas W; Lee, Jiwon; Sung, Yun Ju; Bentley, Amy R; Manning, Alisa K; Aschard, Hugues; Kilpeläinen, Tuomas O; Ilkov, Marjan; et al. (Mol Psychiatry, 2021)
Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

{A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids - Jhun, M. A.; Mendelson, M.; Wilson, R.; Gondalia, R.; Joehanes, R.; Salfati, E.; Zhao, X.; Braun, K. V. E.; Do, A. N.; Hedman, Å. K.; Zhang, T.; Carnero-Montoro, E.; et al. (Nat Commun, 2021)
10.1038/s41467-021-23899-yHere we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.

Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes. - Lu, Yingchang; Dimitrov, Latchezar; Chen, Shyh-Huei; Bielak, Lawrence F; Bis, Joshua C; Feitosa, Mary F; Lu, Lingyi; Kavousi, Maryam; Raffield, Laura M; Smith, Albert V; Wang, Lihua; Weiss, Stefan; et al. (Circ Genom Precis Med, 2021)
BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT). CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing. - Beauchamp, Ellen M; Leventhal, Matthew; Bernard, Elsa; Hoppe, Emma R; Todisco, Gabriele; Creignou, Maria; Gallì, Anna; Castellano, Cecilia A; McConkey, Marie; Tarun, Akansha; Wong, Waihay; Schenone, Monica; et al. (Blood Cancer Discov, 2021)
Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, , as well as in , , and . We also identified these mutations at low frequency in myelodysplastic syndrome patients. edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage and increased genome-wide intron retention. mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies - Qian, F.; Ardisson Korat, A. V.; Imamura, F.; Marklund, M.; Tintle, N.; Virtanen, J. K.; Zhou, X.; Bassett, J. K.; Lai, H.; Hirakawa, Y.; Chien, K. L.; Wood, A. C.; et al. (Diabetes Care, 2021)
-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.\ For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis.\ 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses.\ Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.

Ophthalmic conditions associated with dementia risk: The Cardiovascular Health Study. - Hwang, Phillip H; Longstreth, Will T; Thielke, Stephen M; Francis, Courtney E; Carone, Marco; Kuller, Lewis H; Fitzpatrick, Annette L (Alzheimers Dement, 2021)
INTRODUCTION: Ophthalmic conditions and dementia appear to overlap and may share common pathways, but research has not differentiated dementia subtypes. METHODS: Diagnoses of cataracts, age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma were based on medical histories and International Classification of Diseases, Ninth Revision (ICD-9) codes for 3375 participants from the Cardiovascular Health Study. Dementia, including Alzheimer's disease (AD) and vascular dementia (VaD), was classified using standardized research criteria. RESULTS: Cataracts were associated with AD (hazard ratio [HR] = 1.34; 95% confidence interval [CI] = 1.01-1.80) and VaD/mixed dementia (HR = 1.41; 95% CI = 1.02-1.95). AMD was associated with AD only (HR = 1.87; 95% CI = 1.13-3.09), whereas DR was associated with VaD/mixed dementia only (HR = 2.63; 95% CI = 1.10-6.27). DISCUSSION: Differential associations between specific ophthalmic conditions and dementia subtypes may elucidate pathophysiologic pathways. Lack of association between glaucoma and dementia was most surprising from these analyses.

Performance of the American Heart Association/American College of Cardiology Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Self-reported Physical Activity Levels. - Pandey, Ambarish; Mehta, Anurag; Paluch, Amanda; Ning, Hongyan; Carnethon, Mercedes R; Allen, Norrina B; Michos, Erin D; Berry, Jarett D; Lloyd-Jones, Donald M; Wilkins, John T (JAMA Cardiol, 2021)
Importance: The American Heart Association/American College of Cardiology pooled cohort equations (PCEs) are used for predicting 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Pooled cohort equation risk prediction capabilities across self-reported leisure-time physical activity (LTPA) levels and the change in model performance with addition of LTPA to the PCE are unclear. Objective: To evaluate PCE risk prediction performance across self-reported LTPA levels and the change in model performance by adding LTPA to the existing PCE model. Design, Setting, and Participants: Individual-level pooling of data from 3 longitudinal cohort studies-Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, and Cardiovascular Health Study-was performed. A total of 18 824 participants were stratified into 4 groups based on self-reported LTPA levels: inactive (0 metabolic equivalent of task [MET]-min/wk), less than guideline-recommended (<500 MET-min/wk), guideline-recommended (500-1000 MET-min/week), and greater than guideline-recommended (>1000 MET-min/wk). Pooled cohort equation risk discrimination was studied using the C statistic and reclassification capabilities were studied using the Greenwood Nam-D'Agostino χ2 goodness-of-fit test. Change in risk discrimination and reclassification on adding LTPA to PCEs was evaluated using change in C statistic, integrated discrimination index, and categorical net reclassification index. Main Outcomes and Measures: Adjudicated ASCVD events during 10-year follow-up. Results: Among 18 824 participants studied, 10 302 were women (54.7%); mean (SD) age was 57.6 (8.2) years. A total of 5868 participants (31.2%) were inactive, 3849 (20.4%) had less than guideline-recommended LTPA, 3372 (17.9%) had guideline-recommended LTPA, and 5735 (30.5%) had greater than guideline-recommended LTPA level. Higher LTPA levels were associated with a lower risk of ASCVD after adjustment for risk factors (hazard ratio [HR] per 1-SD higher LTPA, 0.91; 95% CI, 0.86-0.96). Across LTPA groups, PCE risk discrimination (C statistic, 0.76-0.78) and risk calibration (all χ2﻿ P > .10) was similar. Addition of LTPA to the PCE model resulted in no significant change in the C statistic (0.0005; 95% CI, -0.0004 to 0.0015; P = .28) and categorical net reclassification index (-0.003; 95% CI, -0.010 to 0.010; P = .95), but a minimal improvement in the integrated discrimination index (0.0008; 95% CI, 0.0002-0.0013; P = .005) was observed. Similar results were noted when cohort-specific coefficients were used for creating the baseline model. Conclusions and Relevance: Higher self-reported LTPA levels appear to be associated with lower ASCVD risk and increasing LTPA promotes cardiovascular wellness. These findings suggest the American Heart Association/American College of Cardiology PCEs are accurate at estimating the probability of 10-year ASCVD risk regardless of LTPA level. The addition of self-reported LTPA to PCEs does not appear to be associated with improvement in risk prediction model performance.

The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction. - Trompet, Stella; Postmus, Iris; Warren, Helen R; Noordam, Raymond; Smit, Roelof A J; Theusch, Elizabeth; Li, Xiaohui; Arsenault, Benoit; Chasman, Daniel I; Hitman, Graham A; Munroe, Patricia B; Rotter, Jerome I; et al. (Front Pharmacol, 2021)
The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with -values <5.0 × 10 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. In stage-1 meta-analysis (eight studies, = 10,769, 4,212 cases), we observed no genome-wide significant results ( < 5.0 × 10). A total of 144 genetic variants were followed-up in the second stage (three studies, = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.

{The power of genetic diversity in genome-wide association studies of lipids - Graham, S. E.; Clarke, S. L.; Wu, K. H.; Kanoni, S.; Zajac, G. J. M.; Ramdas, S.; Surakka, I.; Ntalla, I.; Vedantam, S.; Winkler, T. W.; Locke, A. E.; Marouli, E.; et al. (Nature, 2021)
application of polygenic scores in clinical practice.

{Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function - Yang, T.; Jackson, V. E.; Smith, A. V.; Chen, H.; Bartz, T. M.; Sitlani, C. M.; Psaty, B. M.; Gharib, S. A.; O'Connor, G. T.; Dupuis, J.; Xu, J.; Lohman, K.; et al. (Sci Rep, 2021)
. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

{Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis - Choi, S. H.; Jurgens, S. J.; Haggerty, C. M.; Hall, A. W.; Halford, J. L.; Morrill, V. N.; Weng, L. C.; Lagerman, B.; Mirshahi, T.; Pettinger, M.; Guo, X.; Lin, H. J.; et al. (Circ Genom Precis Med, 2021)
Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.\ Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).\ ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.\ Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. - Taliun, Daniel; Harris, Daniel N; Kessler, Michael D; Carlson, Jedidiah; Szpiech, Zachary A; Torres, Raul; Taliun, Sarah A Gagliano; Corvelo, André; Gogarten, Stephanie M; Kang, Hyun Min; Pitsillides, Achilleas N; LeFaive, Jonathon; et al. (Nature, 2021)
The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Serum non-esterified fatty acid levels and hip fracture risk: The Cardiovascular Health Study. - Barzilay, J I; Bůžková, P; Djoussé, L; Ix, J; Kizer, J; Cauley, J; Matthan, N; Lichtenstein, A H; Mukamal, K J (Osteoporos Int, 2021)
Among elderly participants from the Cardiovascular Health Study, we found that non-esterified trans fatty acid levels had a significant prospective association with hip fracture risk. Other non-esterified fatty acid classes were not associated with hip fracture risk. INTRODUCTION: Serum non-esterified fatty acids (NEFAs) are bioactive metabolic intermediates that can be taken up by bone tissue. Their associations with hip fracture risk have not been previously examined. METHODS: Thirty-five individual NEFAs in five classes (saturated [SFA], mono-un-saturated [MUFA], poly-unsaturated n-6 and n-3 [PUFA], and trans-FA) were measured in Cardiovascular Health Study participants (n = 2139, mean age 77.8 years) without known diabetes. The multivariable associations of NEFA levels with hip fracture risk were evaluated in Cox hazards models. RESULTS: We documented 303 incident hip fractures during 11.1 years of follow-up. Among the five NEFA classes, total trans FA levels were positively associated with higher hip fracture risk (HR 1.17 [95% CI, 1.04, 1.31; p = 0.01] per one standard deviation higher level). The SFA lignoceric acid (24:0) was positively associated with higher risk (HR 1.09 [1.04, 1.1]; p < 0.001), while behenic (22:0) and docosatetraenoic (22:4 n6) acids were associated with lower risk (HR 0.76 [0.61, 0.94]; p = 0.01; 0.84 [0.70, 1.00]; p = 0.05, respectively). CONCLUSION: Total plasma trans NEFA levels are related to hip fracture risk, suggesting an unrecognized benefit of their systematic removal from food. Novel associations of individual NEFAs with hip fracture risk require confirmation in other cohort studies.

{Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability - Lagou, V.; Mägi, R.; Hottenga, J. J.; Grallert, H.; Perry, J. R. B.; Bouatia-Naji, N.; Marullo, L.; Rybin, D.; Jansen, R.; Min, J. L.; Dimas, A. S.; Ulrich, A.; et al. (Nat Commun, 2021)
Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

{Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability - Lagou, V.; M?gi, R.; Hottenga, J. J.; Grallert, H.; Perry, J. R. B.; Bouatia-Naji, N.; Marullo, L.; Rybin, D.; Jansen, R.; Min, J. L.; Dimas, A. S.; Ulrich, A.; et al. (Nat Commun, 2021)
Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

Statins and cognitive decline in the Cardiovascular Health Study: A comparison of different analytical approaches. - Zeki Al Hazzouri, Adina; Jawadekar, Neal; Grasset, Leslie; Kaiser, Paulina; Kezios, Katrina; Calonico, Sebastian; Glymour, M Maria; Hirsch, Calvin; Arnold, Alice M; Varadhan, Ravi; Opoodden, Michelle C (J Gerontol A Biol Sci Med Sci, 2021)
BACKGROUND: Despite their well-established benefits for the prevention of cardiovascular disease, robust evidence on the effects of statins on cognition is largely inconclusive. We apply various study designs and analytical approaches to mimic randomized controlled trial (RCT) effects from observational data. METHODS: We used observational data from 5,580 participants enrolled in the Cardiovascular Health Study from 1989/90 to 1999/2000. We conceptualized the cohort as an overlapping sequence of non-randomized trials. We compared multiple selection (eligible population, prevalent users, new-users) and analytic approaches (multivariable adjustment, inverse probability treatment weights, propensity score matching) to evaluate the association between statin use and 5-year change in global cognitive function, assessed using the Modified Mini-Mental State (3MS) examination. RESULTS: When comparing prevalent users to non-users (N=2,772), statin use was associated with slower cognitive decline over 5 years (adjusted annual change in 3MSE = 0.34 points/year; 95% CI:0.05;0.63). Compared to prevalent user design, estimates from new user designs (e.g. comparing eligible statin initiators to non-initiators) were attenuated showing either null or negative association, though not significant. For example, in a propensity score-matched sample of statin-eligible individuals (N=454), annual 3MS change comparing statin initiators to non-initiators was -0.21 points/year (95% CI:-0.81;0.39). CONCLUSIONS: The association of statin use and cognitive decline is attenuated towards the null when using rigorous analytical approaches that more closely mimic RCTs. Point estimates, even within the same study, may vary depending on the analytical methods used. Further studies that leverage natural or quasi experiments around statin use are needed to replicate our findings.

Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations. - Haslam, Danielle E; Peloso, Gina M; Guirette, Melanie; Imamura, Fumiaki; Bartz, Traci M; Pitsillides, Achilleas N; Wang, Carol A; Li-Gao, Ruifang; Westra, Jason M; Pitkänen, Niina; Young, Kristin L; Graff, Mariaelisa; et al. (Circ Genom Precis Med, 2021)
BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia. METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005). CONCLUSIONS: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. - Yu, Bing; Roberts, Mary B; Raffield, Laura M; Zekavat, Seyedeh Maryam; Nguyen, Ngoc Quynh H; Biggs, Mary L; Brown, Michael R; Griffin, Gabriel; Desai, Pinkal; Correa, Adolfo; Morrison, Alanna C; Shah, Amil M; et al. (J Am Coll Cardiol, 2021)
BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF. METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.
Keywords: Aged; Clonal Hematopoiesis; Correlation of Data; Demography; DNA-Binding Proteins; Female; Heart Failure; Humans; Janus Kinase 2; Male; Middle Aged; Mutation; Proportional Hazards Models; Proto-Oncogene Proteins; Repressor Proteins; Risk Factors; Stroke Volume; Ventricular Dysfunction, Left; Whole Exome Sequencing

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. - Stilp, Adrienne M; Emery, Leslie S; Broome, Jai G; Buth, Erin J; Khan, Alyna T; Laurie, Cecelia A; Wang, Fei Fei; Wong, Quenna; Chen, Dongquan; D'Augustine, Catherine M; Heard-Costa, Nancy L; Hohensee, Chancellor R; et al. (Am J Epidemiol, 2021)
Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

{The trans-ancestral genomic architecture of glycemic traits - Chen, J.; Spracklen, C. N.; Marenne, G.; Varshney, A.; Corbin, L. J.; Luan, J.; Willems, S. M.; Wu, Y.; Zhang, X.; Horikoshi, M.; Boutin, T. S.; Mägi, R.; et al. (Nat Genet, 2021)
10.1038/s41588-021-00852-9Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

What Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium. - Cawthon, Peggy M; Patel, Sheena M; Kritchevsky, Stephen B; Newman, Anne B; Santanasto, Adam; Kiel, Douglas P; Travison, Thomas G; Lane, Nancy; Cummings, Steven R; Orwoll, Eric S; Duchowny, Kate A; Kwok, Timothy; et al. (J Gerontol A Biol Sci Med Sci, 2021)
BACKGROUND: Cut-points to define slow walking speed have largely been derived from expert opinion. METHODS: Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not. RESULTS: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants. CONCLUSIONS: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.
Keywords: Aged; Female; Gait; Humans; Independent Living; Male; Mobility Limitation; Sarcopenia; Walking; Walking Speed

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium. - Lin, Bridget M; Grinde, Kelsey E; Brody, Jennifer A; Breeze, Charles E; Raffield, Laura M; Mychaleckyj, Josyf C; Thornton, Timothy A; Perry, James A; Baier, Leslie J; de Las Fuentes, Lisa; Guo, Xiuqing; Heavner, Benjamin D; et al. (EBioMedicine, 2021)
BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative. - Little, Amarise; Hu, Yao; Sun, Quan; Jain, Deepti; Broome, Jai; Chen, Ming-Huei; Thibord, Florian; McHugh, Caitlin; Surendran, Praveen; Blackwell, Thomas W; Brody, Jennifer A; Bhan, Arunoday; et al. (Hum Mol Genet, 2021)
Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program. - Cade, Brian E; Lee, Jiwon; Sofer, Tamar; Wang, Heming; Zhang, Man; Chen, Han; Gharib, Sina A; Gottlieb, Daniel J; Guo, Xiuqing; Lane, Jacqueline M; Liang, Jingjing; Lin, Xihong; et al. (Genome Med, 2021)
BACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. - Hu, Yao; Stilp, Adrienne M; McHugh, Caitlin P; Rao, Shuquan; Jain, Deepti; Zheng, Xiuwen; Lane, John; Méric de Bellefon, Sébastian; Raffield, Laura M; Chen, Ming-Huei; Yanek, Lisa R; Wheeler, Marsha; et al. (Am J Hum Genet, 2021)
Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
Keywords: Adult; Aged; Chromosomes, Human, Pair 16; Datasets as Topic; Erythrocytes; Female; Gene Editing; Genetic Variation; Genome-Wide Association Study; HEK293 Cells; Humans; Male; Middle Aged; National Heart, Lung, and Blood Institute (U.S.); Phenotype; Quality Control; Reproducibility of Results; United States

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program. - Mikhaylova, Anna V; McHugh, Caitlin P; Polfus, Linda M; Raffield, Laura M; Boorgula, Meher Preethi; Blackwell, Thomas W; Brody, Jennifer A; Broome, Jai; Chami, Nathalie; Chen, Ming-Huei; Conomos, Matthew P; Cox, Corey; et al. (Am J Hum Genet, 2021)
Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
Keywords: Asthma; Biomarkers; Dermatitis, Atopic; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Leukocytes; National Heart, Lung, and Blood Institute (U.S.); Phenotype; Polymorphism, Single Nucleotide; Prognosis; Proteome; Pulmonary Disease, Chronic Obstructive; Quantitative Trait Loci; United Kingdom; United States; Whole Genome Sequencing

Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. - Wainschtein, Pierrick; Jain, Deepti; Zheng, Zhili; Cupples, L Adrienne; Shadyab, Aladdin H; McKnight, Barbara; Shoemaker, Benjamin M; Mitchell, Braxton D; Psaty, Bruce M; Kooperberg, Charles; Liu, Ching-Ti; Albert, Christine M; et al. (Nat Genet, 2022)
Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

The Association of Lipids and Lipoproteins with Hip Fracture Risk the Cardiovascular Health Study. - Barzilay, Joshua I; Bůzková, Petra; Kuller, Lewis H; Cauley, Jane A; Fink, Howard A; Sheets, Kerry; Robbins, John A; Carbone, Laura D; Elam, Rachel E; Mukamal, Kenneth J (Am J Med, 2022)
BACKGROUND: It is uncertain if lipids or lipoproteins are associated with osteoporotic fractures. In this study, incident hip fracture risk according to conventional lipid levels and lipoprotein levels and sizes was examined. METHODS: We followed 5832 participants aged ≥65 years from the Cardiovascular Health Study for hip fracture for a mean of 13.5 (SD 5.7) years. Standard enzymatic methods were used to determine lipid levels (HDL-c, LDL-c, triglycerides). Nuclear magnetic resonance spectroscopy was used to measure lipoprotein fractions (VLDL-P, LDL-P, HDL-P) in a subset of 1849 participants. RESULTS: We documented 755 incident hip fractures among women (1.19 fractures per 100 participant years [95% CI, 1.04, 1.35]) and 197 among men (0.67 fractures per 100 participant years [95% CI, 0.41, 1.10]) over an average follow-up. HDL-c and LDL-c levels had statistically significant non-linear U-shaped relationships with hip fracture risk (HDL-c, p=0.009; LDL-c, p=0.02). Triglyceride levels were not significantly associated with hip fracture risk. In fully adjusted conjoint models, higher VLDL-P concentration [HR per 1-standard (SD) increment 1.47 (1.13, 1.91)] and size [HR per 1-SD increment 1.24 [1.05, 1.46]) and higher HDL-P size (HR per 1-SD increment 1.81 [1.25, 2.62]) were all associated with higher hip fracture risk. CONCLUSIONS: Lipids and lipoproteins are associated with hip fracture risk in older adults. The associations are complex. Mechanistic studies are needed to understand these findings.

An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns - Jin, B.; Capra, J. A.; Benchek, P.; Wheeler, N.; Naj, A. C.; Hamilton-Nelson, K. L.; Farrell, J. J.; Leung, Y. Y.; Kunkle, B.; Vadarajan, B.; Schellenberg, G. D.; Mayeux, R.; et al. (Genome Res, 2022)
is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.

Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study. - Durda, Peter; Raffield, Laura M; Lange, Ethan M; Olson, Nels C; Jenny, Nancy Swords; Cushman, Mary; Deichgraeber, Pia; Grarup, Niels; Jonsson, Anna; Hansen, Torben; Mychaleckyj, Josyf C; Psaty, Bruce M; et al. (J Am Heart Assoc, 2022)
Background Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near (top result rs62165726, =3.3×10),19 variants near chromosome 17 gene (rs55714927, =1.5×10), and 18 variants near chromosome 11 gene . These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 =7.1×10) in the region, and 3 variants (rs115391969 =4.3×10) near the chromosome 16 gene Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.
Keywords: Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Asialoglycoprotein Receptor; Biomarkers; Cardiovascular Diseases; Female; Genome-Wide Association Study; Heart Failure; Humans; Longitudinal Studies; Male

Clonal Hematopoiesis Is Associated With Higher Risk of Stroke. - Bhattacharya, Romit; Zekavat, Seyedeh M; Haessler, Jeffrey; Fornage, Myriam; Raffield, Laura; Uddin, Md Mesbah; Bick, Alexander G; Niroula, Abhishek; Yu, Bing; Gibson, Christopher; Griffin, Gabriel; Morrison, Alanna C; et al. (Stroke, 2022)
BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (, , and ) with any stroke, ischemic stroke, and hemorrhagic stroke. RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, showed the strongest association with total stroke and ischemic stroke, whereas and were each associated with increased risk of hemorrhagic stroke. CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

{Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease - Uddin, M. D. M.; Nguyen, N. Q. H.; Yu, B.; Brody, J. A.; Pampana, A.; Nakao, T.; Fornage, M.; Bressler, J.; Sotoodehnia, N.; Weinstock, J. S.; Honigberg, M. C.; Nachun, D.; et al. (Nat Commun, 2022)
Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Correlations between complex human phenotypes vary by genetic background, gender, and environment. - Elgart, Michael; Goodman, Matthew O; Isasi, Carmen; Chen, Han; Morrison, Alanna C; de Vries, Paul S; Xu, Huichun; Manichaikul, Ani W; Guo, Xiuqing; Franceschini, Nora; Psaty, Bruce M; Rich, Stephen S; et al. (Cell Rep Med, 2022)
We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.
Keywords: Female; Genetic Background; Humans; Male; Phenotype

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. - Thibord, Florian; Klarin, Derek; Brody, Jennifer A; Chen, Ming-Huei; Levin, Michael G; Chasman, Daniel I; Goode, Ellen L; Hveem, Kristian; Teder-Laving, Maris; Martinez-Perez, Angel; Aïssi, Dylan; Daian-Bacq, Delphine; et al. (Circulation, 2022)
BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.
Keywords: Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Thrombosis; Venous Thromboembolism

Diabetes Status Modifies the Association Between Different Measures of Obesity and Heart Failure Risk Among Older Adults: A Pooled Analysis of Community-Based NHLBI Cohorts. - Patel, Kershaw V; Segar, Matthew W; Lavie, Carl J; Kondamudi, Nitin; Neeland, Ian J; Almandoz, Jaime P; Martin, Corby K; Carbone, Salvatore; Butler, Javed; Powell-Wiley, Tiffany M; Pandey, Ambarish (Circulation, 2022)
BACKGROUND: Obesity and diabetes are associated with a higher risk of heart failure (HF). The interrelationships between different measures of adiposity-overall obesity, central obesity, fat mass (FM)-and diabetes status for HF risk are not well-established. METHODS: Participant-level data from the ARIC study (Atherosclerosis Risk in Communities; visit 5) and the CHS (Cardiovascular Health Study; visit 1) cohorts were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center, harmonized, and pooled for the present analysis, excluding individuals with prevalent HF. FM was estimated in all participants using established anthropometric prediction equations additionally validated using the bioelectrical impedance-based FM in the ARIC subgroup. Incident HF events on follow-up were captured across both cohorts using similar adjudication methods. Multivariable-adjusted Fine-Gray models were created to evaluate the associations of body mass index (BMI), waist circumference (WC), and FM with risk of HF in the overall cohort as well as among those with versus without diabetes at baseline. The population attributable risk of overall obesity (BMI≥30 kg/m), abdominal obesity (WC>88 and 102 cm in women and men, respectively), and high FM (above sex-specific median) for incident HF was evaluated among participants with and without diabetes. RESULTS: The study included 10 387 participants (52.9% ARIC; 25.1% diabetes; median age, 74 years). The correlation between predicted and bioelectrical impedance-based FM was high (=0.90; n=5038). During a 5-year follow-up, 447 participants developed HF (4.3%). Higher levels of each adiposity measure were significantly associated with higher HF risk (hazard ratio [95% CI] per 1 SD higher BMI=1.15 [1.05, 1.27], WC=1.22 [1.10, 1.36]; FM=1.13 [1.02, 1.25]). A significant interaction was noted between diabetes status and measures of BMI ( interaction=0.04) and WC ( interaction=0.004) for the risk of HF. In stratified analysis, higher measures of each adiposity parameter were significantly associated with higher HF risk in individuals with diabetes (hazard ratio [95% CI] per 1 SD higher BMI=1.29 [1.14-1.47]; WC=1.48 [1.29-1.70]; FM=1.25 [1.09-1.43]) but not those without diabetes, including participants with prediabetes and euglycemia. The population attributable risk percentage of overall obesity, abdominal obesity, and high FM for incident HF was higher among participants with diabetes (12.8%, 29.9%, and 13.7%, respectively) versus those without diabetes (≤1% for each). CONCLUSIONS: Higher BMI, WC, and FM are strongly associated with greater risk of HF among older adults, particularly among those with prevalent diabetes.
Keywords: Aged; Cohort Studies; Diabetes Mellitus; Female; Heart Failure; Humans; Male; National Heart, Lung, and Blood Institute (U.S.); Obesity; Risk Factors; United States

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. - Winkler, Thomas W; Rasheed, Humaira; Teumer, Alexander; Gorski, Mathias; Rowan, Bryce X; Stanzick, Kira J; Thomas, Laurent F; Tin, Adrienne; Hoppmann, Anselm; Chu, Audrey Y; Tayo, Bamidele; Thio, Chris H L; et al. (Commun Biol, 2022)
Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
Keywords: Creatinine; Diabetes Mellitus; Diabetic Nephropathies; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney

{DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases - Wielscher, M.; Mandaviya, P. R.; Kuehnel, B.; Joehanes, R.; Mustafa, R.; Robinson, O.; Zhang, Y.; Bodinier, B.; Walton, E.; Mishra, P. P.; Schlosser, P.; Wilson, R.; et al. (Nat Commun, 2022)
We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes. - Halford, Jennifer L; Morrill, Valerie N; Choi, Seung Hoan; Jurgens, Sean J; Melloni, Giorgio; Marston, Nicholas A; Weng, Lu-Chen; Nauffal, Victor; Hall, Amelia W; Gunn, Sophia; Austin-Tse, Christina A; Pirruccello, James P; et al. (Nat Commun, 2022)
Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.
Keywords: Disease Susceptibility; Endophenotypes; Humans; Long QT Syndrome; Virulence

Epilepsy, Vascular Risk Factors, and Cognitive Decline in Older Adults: The Cardiovascular Health Study. - Choi, Hyunmi; Elkind, Mitchell S V; Longstreth, W T; Boehme, Amelia K; Hafen, Rebekah; Hoyt, Emma J; Thacker, Evan L (Neurology, 2022)
BACKGROUND AND OBJECTIVES: Recent studies have shown that global cognitive ability tends to decline faster over time in older adults (≥65 years) with epilepsy compared with older adults without epilepsy. Scarce data exist about the role of vascular risk factors (VRFs) on cognitive course in epilepsy. We assessed whether the associations of individual VRFs with cognitive trajectory differed depending on the presence of prevalent epilepsy. METHODS: The Cardiovascular Health Study is a population-based longitudinal cohort study of 5,888 US adults aged ≥65 years. Cognitive function was assessed annually with modified Mini-Mental State Examination (3MS; global cognitive ability) and Digit Symbol Substitution Test (DSST; information processing speed). We used linear mixed models to estimate the individual and joint associations of epilepsy and VRFs with cognitive decline by modeling epilepsy × VRF interactions one by one, each adjusted for all other VRFs considered, including demographics, health behaviors, clinical characteristics, and comorbid diagnoses. From these models, we estimated excess mean cognitive decline due to interaction of epilepsy with each VRF. RESULTS: We observed excess mean decline in global cognitive ability (3MS) due to interactions of epilepsy with hypertension (6.6 points greater mean 8-year decline than expected if no interaction; 95% CI 1.3-12.0) and with abstaining from alcohol (5.8 points greater than expected; 95% CI 0.3-11.3). We also observed excess mean decline in information processing speed (DSST) due to interactions of epilepsy with prior stroke (18.1 points greater mean 9-year decline than expected; 95% CI 7.6-28.5), with abstaining from alcohol (6.1 points greater than expected; 95% CI 2.5-9.8), and with higher triglyceride levels (2.4 points greater than expected per SD; 95% CI 0.4-4.3). DISCUSSION: Associations of some VRFs with cognitive decline in older adults are stronger in the presence of epilepsy, suggesting a need for greater attention to vascular protection for preserving brain health in older adults with epilepsy.
Keywords: Aged; Cognition; Cognitive Dysfunction; Epilepsy; Humans; Longitudinal Studies; Neuropsychological Tests; Risk Factors

eSCAN: scan regulatory regions for aggregate association testing using whole-genome sequencing data. - Yang, Yingxi; Sun, Quan; Huang, Le; Broome, Jai G; Correa, Adolfo; Reiner, Alexander; Raffield, Laura M; Yang, Yuchen; Li, Yun (Brief Bioinform, 2022)
Multiple statistical methods for aggregate association testing have been developed for whole-genome sequencing (WGS) data. Many aggregate variants in a given genomic window and ignore existing knowledge to define test regions, resulting in many identified regions not clearly linked to genes, and thus, limiting biological understanding. Functional information from new technologies (such as Hi-C and its derivatives), which can help link enhancers to their effector genes, can be leveraged to predefine variant sets for aggregate testing in WGS data. Here, we propose the eSCAN (scan the enhancers) method for genome-wide assessment of enhancer regions in sequencing studies, combining the advantages of dynamic window selection in SCANG (SCAN the Genome), a previously developed method, with the advantages of incorporating putative regulatory regions from annotation. eSCAN, by searching in putative enhancers, increases statistical power and aids mechanistic interpretation, as demonstrated by extensive simulation studies. We also apply eSCAN for blood cell traits using NHLBI Trans-Omics for Precision Medicine WGS data. Results from real data analysis show that eSCAN is able to capture more significant signals, and these signals are of shorter length (indicating higher resolution fine-mapping capability) and drive association of larger regions detected by other methods.
Keywords: Genome; Genome-Wide Association Study; Genomics; Regulatory Sequences, Nucleic Acid; Whole Genome Sequencing

Fishing for health: Neighborhood variation in fish intake, fish quality and association with stroke risk among older adults in the Cardiovascular Health Study. - Liang, Li-Jung; Casillas, Alejandra; Longstreth, W T; PhanVo, Lynn; Vassar, Stefanie D; Brown, Arleen F (Nutr Metab Cardiovasc Dis, 2022)
BACKGROUND AND AIMS: Fish consumption has been associated with better health outcomes. Dietary patterns may vary substantially by neighborhood of residence. However, it is unclear if the benefits of a healthy diet are equivalent in different communities. This study examines associations of fish consumption with stroke incidence and stroke risk factors, and whether these differ by neighborhood socioeconomic status (NSES). METHODS AND RESULTS: We studied 4007 participants in the Cardiovascular Health Study who were 65 years or older and recruited between 1989 and 1990 from 4 US communities. Outcomes included fish consumption type (bakes/broiled vs. fried) and frequency, stroke incidence, and stroke risk factors. Multilevel regressions models were used to estimate fish consumption associations with clinical outcomes. Lower NSES was associated with higher consumption of fried fish (aOR = 1.47, 95% CI: 1.10-1.98) and lower consumption of non-fried fish (0.64, 0.47-0.86). Frequent fried fish (11.9 vs. 9.2 person-years for at least once weekly vs. less than once a month, respectively) and less frequent non-fried fish (17.7 vs. 9.6 person-years for less than once a month vs. at least once weekly, respectively) were independently associated with an increased risk of stroke (p-values < 0.05). However, among those with similar levels of healthy fish consumption, residents with low NSES had less benefit on stroke risk reduction, compared with high NSES. CONCLUSION: Fish consumption type and frequency both impact stroke risk. Benefits of healthy fish consumption differ by neighborhood socioeconomic status.

A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. - Li, Zilin; Li, Xihao; Zhou, Hufeng; Gaynor, Sheila M; Selvaraj, Margaret Sunitha; Arapoglou, Theodore; Quick, Corbin; Liu, Yaowu; Chen, Han; Sun, Ryan; Dey, Rounak; Arnett, Donna K; et al. (Nat Methods, 2022)
Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.
Keywords: Genetic Variation; Genome; Genome-Wide Association Study; Humans; Phenotype; Whole Genome Sequencing

{Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy - Sobrin, L.; Susarla, G.; Stanwyck, L.; Rouhana, J. M.; Li, A.; Pollack, S.; Igo, R. P.; Jensen, R. A.; Li, X.; Ng, M. C. Y.; Smith, A. V.; Kuo, J. Z.; et al. (Am J Ophthalmol, 2022)
{To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses.\ .05.\ .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment

{Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate - Mishra, A.; Duplaà, C.; Vojinovic, D.; Suzuki, H.; Sargurupremraj, M.; Zilhao, N. R.; Li, S.; Bartz, T. M.; Jian, X.; Zhao, W.; Hofer, E.; Wittfeld, K.; et al. (Brain, 2022)
Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

{Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways - Young, W. J.; Lahrouchi, N.; Isaacs, A.; Duong, T.; Foco, L.; Ahmed, F.; Brody, J. A.; Salman, R.; Noordam, R.; Benjamins, J. W.; Haessler, J.; Lyytikäinen, L. P.; et al. (Nat Commun, 2022)
250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

{Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study - Portilla-Fernandez, E.; Klarin, D.; Hwang, S. J.; Biggs, M. L.; Bis, J. C.; Weiss, S.; Rospleszcz, S.; Natarajan, P.; Hoffmann, U.; Rogers, I. S.; Truong, Q. A.; lker, U.; et al. (Hum Mol Genet, 2022)
0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. - Gorski, Mathias; Rasheed, Humaira; Teumer, Alexander; Thomas, Laurent F; Graham, Sarah E; Sveinbjornsson, Gardar; Winkler, Thomas W; Günther, Felix; Stark, Klaus J; Chai, Jin-Fang; Tayo, Bamidele O; Wuttke, Matthias; et al. (Kidney Int, 2022)
Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

Genome-wide analyses identify as a susceptibility locus for premature atrial contraction frequency. - Thériault, Sébastien; Imboden, Medea; Biggs, Mary L; Austin, Thomas R; Aeschbacher, Stefanie; Schaffner, Emmanuel; Brody, Jennifer A; Bartz, Traci M; Risch, Martin; Grossmann, Kirsten; Lin, Henry J; Soliman, Elsayed Z; et al. (iScience, 2022)
Premature atrial contractions (PACs) are frequently observed on electrocardiograms and are associated with increased risks of atrial fibrillation (AF), stroke, and mortality. In this study, we aimed to identify genetic susceptibility loci for PAC frequency. We performed a genome-wide association study meta-analysis with PAC frequency obtained from ambulatory cardiac monitoring in 4,831 individuals of European ancestry. We identified a genome-wide significant locus at the gene. The lead variant, rs7373862, located in an intron of , was associated with an increase of 0.12 [95% CI 0.08-0.16] standard deviations of the normalized PAC frequency per risk allele. Among genetic variants previously associated with AF, there was a significant enrichment in concordance of effect for PAC frequency (n = 73/106, p = 5.1 × 10). However, several AF risk loci, including , were not associated with PAC frequency. These findings suggest the existence of both shared and distinct genetic mechanisms for PAC frequency and AF.

{Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation - Longchamps, R. J.; Yang, S. Y.; Castellani, C. A.; Shi, W.; Lane, J.; Grove, M. L.; Bartz, T. M.; Sarnowski, C.; Liu, C.; Burrows, K.; Guyatt, A. L.; Gaunt, T. R.; et al. (Hum Genet, 2022)
).

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. - Lahti, Jari; Tuominen, Samuli; Yang, Qiong; Pergola, Giulio; Ahmad, Shahzad; Amin, Najaf; Armstrong, Nicola J; Beiser, Alexa; Bey, Katharina; Bis, Joshua C; Boerwinkle, Eric; Bressler, Jan; et al. (Mol Psychiatry, 2022)
Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

{Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases - Li, Y.; Cheng, Y.; Consolato, F.; Schiano, G.; Chong, M. R.; Pietzner, M.; Nguyen, N. Q. H.; Scherer, N.; Biggs, M. L.; Kleber, M. E.; Haug, S.; Göçmen, B.; et al. (JCI Insight, 2022)
Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.

Glucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study. - Garg, Parveen K; Biggs, Mary L; Kizer, Jorge R; Shah, Sanjiv J; Psaty, Bruce; Carnethon, Mercedes; Gottdiener, John S; Siscovick, David; Mukamal, Kenneth J (Cardiovasc Diabetol, 2022)
OBJECTIVE: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population. METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics. RESULTS: Mean age for the 2433 included participants was 72.0 years, 33.6% were male, and 3.7% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95% confidence interval = 0.03-0.33). CONCLUSION: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.
Keywords: Aged; Cross-Sectional Studies; Female; Glucose; Humans; Insulin Resistance; Male; Ventricular Dysfunction, Left; Ventricular Function, Left

{Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis - Kanoni, S.; Graham, S. E.; Wang, Y.; Surakka, I.; Ramdas, S.; Zhu, X.; Clarke, S. L.; Bhatti, K. F.; Vedantam, S.; Winkler, T. W.; Locke, A. E.; Marouli, E.; et al. (Genome Biol, 2022)
Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.\ 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.\ Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. - Kelly, Tanika N; Sun, Xiao; He, Karen Y; Brown, Michael R; Taliun, Sarah A Gagliano; Hellwege, Jacklyn N; Irvin, Marguerite R; Mi, Xuenan; Brody, Jennifer A; Franceschini, Nora; Guo, Xiuqing; Hwang, Shih-Jen; et al. (Hypertension, 2022)
BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively). DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

Integrative analysis of clinical and epigenetic biomarkers of mortality. - Huan, Tianxiao; Nguyen, Steve; Colicino, Elena; Ochoa-Rosales, Carolina; Hill, W David; Brody, Jennifer A; Soerensen, Mette; Zhang, Yan; Baldassari, Antoine; Elhadad, Mohamed Ahmed; Toshiko, Tanaka; Zheng, Yinan; et al. (Aging Cell, 2022)
DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P  = 4.1 × 10 ) and negatively associated with longevity (Beta = -1.9, P  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.
Keywords: Biomarkers; Cardiovascular Diseases; DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Male; Neoplasms

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. - Tcheandjieu, Catherine; Zhu, Xiang; Hilliard, Austin T; Clarke, Shoa L; Napolioni, Valerio; Ma, Shining; Lee, Kyung Min; Fang, Huaying; Chen, Fei; Lu, Yingchang; Tsao, Noah L; Raghavan, Sridharan; et al. (Nat Med, 2022)
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
Keywords: Coronary Artery Disease; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Risk Factors

Longitudinal Changes in Hearing and Visual Impairments and Risk of Dementia in Older Adults in the United States. - Hwang, Phillip H; Longstreth, W T; Thielke, Stephen M; Francis, Courtney E; Carone, Marco; Kuller, Lewis H; Fitzpatrick, Annette L (JAMA Netw Open, 2022)
Importance: Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known. Objective: To evaluate whether DSI is associated with incident dementia in older adults. Design, Setting, and Participants: This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020. Exposures: Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits. Main Outcomes and Measures: All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria. Results: A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2%] women; 455 [15.5%] African American or Black; 2472 [85.5%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95% CI, 1.66-2.06; P < .001), AD (HR, 3.67; 95% CI, 2.04-6.60; P < .001) but not VaD (HR, 2.03; 95% CI, 1.00-4.09; P = .05). Conclusions and Relevance: In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.
Keywords: Aged; Alzheimer Disease; Cohort Studies; Female; Hearing; Hearing Loss; Humans; Male; Medicare; Prospective Studies; United States; Vision Disorders

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study. - Eckhardt, Christina M; Balte, Pallavi P; Barr, Robert Graham; Bertoni, Alain G; Bhatt, Surya P; Cuttica, Michael; Cassano, Patricia A; Chaves, Paolo; Couper, David; Jacobs, David R; Kalhan, Ravi; Kronmal, Richard; et al. (Eur Heart J, 2022)
AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.
Keywords: Adult; Heart Failure; Hospitalization; Humans; Lung; National Heart, Lung, and Blood Institute (U.S.); Prognosis; Risk Factors; Stroke Volume; United States

Monogenic and Polygenic Contributions to QTc Prolongation in the Population. - Nauffal, Victor; Morrill, Valerie N; Jurgens, Sean J; Choi, Seung Hoan; Hall, Amelia W; Weng, Lu-Chen; Halford, Jennifer L; Austin-Tse, Christina; Haggerty, Christopher M; Harris, Stephanie L; Wong, Eugene K; Alonso, Alvaro; et al. (Circulation, 2022)
Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95% CI 1.3 -1.5; p-value=1.1×10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. - Mahajan, Anubha; Spracklen, Cassandra N; Zhang, Weihua; Ng, Maggie C Y; Petty, Lauren E; Kitajima, Hidetoshi; Yu, Grace Z; Rüeger, Sina; Speidel, Leo; Kim, Young Jin; Horikoshi, Momoko; Mercader, Josep M; et al. (Nat Genet, 2022)
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
Keywords: Diabetes Mellitus, Type 2; Ethnicity; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Risk Factors

A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. - Kurniansyah, Nuzulul; Goodman, Matthew O; Kelly, Tanika N; Elfassy, Tali; Wiggins, Kerri L; Bis, Joshua C; Guo, Xiuqing; Palmas, Walter; Taylor, Kent D; Lin, Henry J; Haessler, Jeffrey; Gao, Yan; et al. (Nat Commun, 2022)
In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.
Keywords: Adult; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Hypertension; Multifactorial Inheritance; Prevalence; Risk Factors

Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease. - Liu, Jiahao; Nair, Viji; Zhao, Yi-Yang; Chang, Dong-Yuan; Limonte, Christine; Bansal, Nisha; Fermin, Damian; Eichinger, Felix; Tanner, Emily C; Bellovich, Keith A; Steigerwalt, Susan; Bhat, Zeenat; et al. (Diabetes, 2022)
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.
Keywords: Angiopoietin-1; Angiopoietin-2; Angiopoietins; Biomarkers; Cohort Studies; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Endothelial Cells; Humans; Kidney Failure, Chronic; Receptor, TIE-2; Signal Transduction

New insights into the genetic etiology of Alzheimer's disease and related dementias. - Bellenguez, Céline; Küçükali, Fahri; Jansen, Iris E; Kleineidam, Luca; Moreno-Grau, Sonia; Amin, Najaf; Naj, Adam C; Campos-Martin, Rafael; Grenier-Boley, Benjamin; Andrade, Victor; Holmans, Peter A; Boland, Anne; et al. (Nat Genet, 2022)
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
Keywords: Alzheimer Disease; Cognitive Dysfunction; Genome-Wide Association Study; Humans; tau Proteins

Non-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations. - Elgart, Michael; Lyons, Genevieve; Romero-Brufau, Santiago; Kurniansyah, Nuzulul; Brody, Jennifer A; Guo, Xiuqing; Lin, Henry J; Raffield, Laura; Gao, Yan; Chen, Han; de Vries, Paul; Lloyd-Jones, Donald M; et al. (Commun Biol, 2022)
Polygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22% for height, 27% for HDL cholesterol, 43% for body mass index, 50% for sleep duration, 58% for systolic blood pressure, 64% for total cholesterol, 66% for triglycerides, 77% for LDL cholesterol, and 100% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.
Keywords: Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Machine Learning; Multifactorial Inheritance; Polymorphism, Single Nucleotide

{Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol - Wu, P.; Moon, J. Y.; Daghlas, I.; Franco, G.; Porneala, B. C.; Ahmadizar, F.; Richardson, T. G.; Isaksen, J. L.; Hindy, G.; Yao, J.; Sitlani, C. M.; Raffield, L. M.; et al. (Diabetes Care, 2022)
LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.\ We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.\ A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).\ These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program. - Hu, Xiaowei; Qiao, Dandi; Kim, Wonji; Moll, Matthew; Balte, Pallavi P; Lange, Leslie A; Bartz, Traci M; Kumar, Rajesh; Li, Xingnan; Yu, Bing; Cade, Brian E; Laurie, Cecelia A; et al. (Am J Hum Genet, 2022)
While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

Pooled Cohort Probability Score for Subclinical Airflow Obstruction. - Bhatt, Surya P; Balte, Pallavi P; Schwartz, Joseph E; Jaeger, Byron C; Cassano, Patricia A; Chaves, Paulo H; Couper, David; Jacobs, David R; Kalhan, Ravi; Kaplan, Robert; Lloyd-Jones, Donald; Newman, Anne B; et al. (Ann Am Thorac Soc, 2022)
Early detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Of 33,546 participants (mean age 52 yr, 54% female, 44% non-Hispanic White), 4,424 (13.2%) had prevalent SAO. The incidence of respiratory events ( = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15%, 3.2 would need to undergo spirometry to detect one case of SAO. Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.
Keywords: Adult; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Nutrition Surveys; Pulmonary Disease, Chronic Obstructive; Risk Factors; Spirometry; Vital Capacity

Prospective study of breakfast frequency and timing and the risk of incident type 2 diabetes in community-dwelling older adults: The Cardiovascular Health Study. - Carew, Allie S; Mekary, Rania A; Kirkland, Susan; Theou, Olga; Siddiqi, Ferhan; Urquhart, Robin; George, Michelle; Blanchard, Chris; Biggs, Mary L; Djoussé, Luc; Mukamal, Kenneth J; Cahill, Leah E (Am J Clin Nutr, 2022)
BACKGROUND: No evidence-based recommendations regarding optimal breakfast frequency and timing and type 2 diabetes mellitus (T2DM) exist for older adults due to limited studies. OBJECTIVE: We sought to prospectively assess relationships between breakfast frequency and timing and T2DM risk among older adults and determine whether these depended on gender or cardiometabolic risk factors. METHODS: Weekly breakfast frequency and usual daily breakfast time were assessed by questionnaire at baseline in 3,747 older adults (aged ≥65 years) from the Cardiovascular Health Study (CHS) who were free of cancer and T2DM and followed for 17.6 years. Multivariable-adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from Cox proportional hazards models were used to quantify associations with T2DM. RESULTS: Most CHS participants (median age: 74 years; interquartile range: 71, 78) consumed breakfast daily (85.5%), and 73% had their first daily eating occasion between 07:00-09:00 hours, which were associated with higher socioeconomic status, factors that are indicative of a healthier lifestyle, and lower levels of cardiometabolic risk indicators at baseline. During follow-up, 547 T2DM cases were documented. No strong evidence was observed between breakfast frequency and risk of T2DM. Compared to participants whose breakfast timing (first eating occasion of the day) was 07:00-09:00, those who broke fast after 09:00 had an aHR for T2DM of 0.71 (95% CI: 0.51, 0.99). This association was present in participants with impaired fasting glucose at baseline (0.61; 0.39, 0.95) but not in those without (0.83; 0.50, 1.38)). No associations between eating frequency or timing and T2DM were observed within other pre-specified subgroups. CONCLUSIONS: Eating breakfast daily was not associated with either higher or lower risk of T2DM in this cohort of older adults, while a later (after 09:00) daily first eating occasion time was associated with lower T2DM risk in participants with impaired fasting glucose at baseline.

Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing. - Austin, Thomas R; McHugh, Caitlin P; Brody, Jennifer A; Bis, Joshua C; Sitlani, Colleen M; Bartz, Traci M; Biggs, Mary L; Bansal, Nisha; Bůzková, Petra; Carr, Steven A; deFilippi, Christopher R; Elkind, Mitchell S V; et al. (Eur J Epidemiol, 2022)
BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology. METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations. CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

PUFA ω-3 and ω-6 biomarkers and sleep: a pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE). - Murphy, Rachel A; Tintle, Nathan; Harris, William S; Darvishian, Maryam; Marklund, Matti; Virtanen, Jyrki K; Hantunen, Sari; de Mello, Vanessa D; Tuomilehto, Jaakko; Lindström, Jaana; Bolt, Matthew A; Brouwer, Ingeborg A; et al. (Am J Clin Nutr, 2022)
BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters. OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium. METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis. RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified. CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.
Keywords: Biomarkers; Cohort Studies; Cross-Sectional Studies; Fatty Acids; Fatty Acids, Omega-3; Humans; Outcome Assessment, Health Care; Sleep

Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. - Hindy, George; Dornbos, Peter; Chaffin, Mark D; Liu, Dajiang J; Wang, Minxian; Selvaraj, Margaret Sunitha; Zhang, David; Park, Joseph; Aguilar-Salinas, Carlos A; Antonacci-Fulton, Lucinda; Ardissino, Diego; Arnett, Donna K; et al. (Am J Hum Genet, 2022)
Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
Keywords: Alleles; Blood Glucose; Case-Control Studies; Computational Biology; Databases, Genetic; Diabetes Mellitus, Type 2; Exome; Genetic Predisposition to Disease; Genetic Variation; Genetics, Population; Genome-Wide Association Study; Humans; Lipid Metabolism; Lipids; Liver; Molecular Sequence Annotation; Multifactorial Inheritance; Open Reading Frames; Phenotype; Polymorphism, Single Nucleotide

Rare genetic variants explain missing heritability in smoking. - Jang, Seon-Kyeong; Evans, Luke; Fialkowski, Allison; Arnett, Donna K; Ashley-Koch, Allison E; Barnes, Kathleen C; Becker, Diane M; Bis, Joshua C; Blangero, John; Bleecker, Eugene R; Boorgula, Meher Preethi; Bowden, Donald W; et al. (Nat Hum Behav, 2022)
Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

{Replication study of AD-associated rare variants - Neupane, A.; Lenny, B.; Budde, J. P.; Wang, F.; Norton, J.; Morris, J. C.; Cruchaga, C.; Fernández, M. V. (Alzheimers Dement, 2022)

{A saturated map of common genetic variants associated with human height - Yengo, L.; Vedantam, S.; Marouli, E.; Sidorenko, J.; Bartell, E.; Sakaue, S.; Graff, M.; Eliasen, A. U.; Jiang, Y.; Raghavan, S.; Miao, J.; Arias, J. D.; et al. (Nature, 2022)
) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults. - Gao, Hans; Patel, Sheena; Fohtung, Raymond B; Cawthon, Peggy M; Newman, Anne B; Cauley, Jane A; Carbone, Laura; Chaves, Paulo H M; Stein, Phyllis K; Civitelli, Roberto; Kizer, Jorge R (J Am Geriatr Soc, 2022)
BACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent. METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC. RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm decrement [95% CI = 1.23-1.62]), and showed the same to be true for White men (HR = 1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men. CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

Stroke genetics informs drug discovery and risk prediction across ancestries. - Mishra, Aniket; Malik, Rainer; Hachiya, Tsuyoshi; Jürgenson, Tuuli; Namba, Shinichi; Posner, Daniel C; Kamanu, Frederick K; Koido, Masaru; Le Grand, Quentin; Shi, Mingyang; He, Yunye; Georgakis, Marios K; et al. (Nature, 2022)
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. - Liang, Jingjing; Wang, Heming; Cade, Brian E; Kurniansyah, Nuzulul; He, Karen Y; Lee, Jiwon; Sands, Scott A; Brody, Jennifer; Chen, Han; Gottlieb, Daniel J; Evans, Daniel S; Guo, Xiuqing; et al. (Am J Respir Crit Care Med, 2022)
INTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes. METHODS: Leveraging high depth genomic sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleve-land Family Study (CFS) followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. RESULTS: Linkage analysis in CFS identified a suggestive linkage peak on chromosome 7q31 (LOD=2.31). Gene-based analysis identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (p=7.4×10-8). These non-coding variants together significantly contributed to the linkage evidence (p<10-3). Follow-up anal-ysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (p=0.024) and higher minimum overnight oxygen saturation (p=0.007). CONCLUSION: Rare variants in CAV1, a membrane scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

{Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes: Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE) - Lai, H. T. M.; Imamura, F.; Korat, A. V. A.; Murphy, R. A.; Tintle, N.; Bassett, J. K.; Chen, J.; ger, J.; Chien, K. L.; Senn, M.; Wood, A. C.; Forouhi, N. G.; et al. (Diabetes Care, 2022)
Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.\ 18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.\ 0.1).\ Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.

Trimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study. - Elam, Rachel E; Bůzková, Petra; Barzilay, Joshua I; Wang, Zeneng; Nemet, Ina; Budoff, Matthew J; Cauley, Jane A; Fink, Howard A; Lee, Yujin; Robbins, John A; Wang, Meng; Hazen, Stanley L; et al. (Bone, 2022)
CONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain. OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults. DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study. PARTICIPANTS: 5019 U.S. adults aged ≥65 years. EXPOSURE: Plasma TMAO. MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n = 1400). RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26 years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95% CI] of 0.42 g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P < 0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI ≥ 25) (HR [95% CI]:1.17[1.05,1.31]), but not normal or underweight. CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.
Keywords: Absorptiometry, Photon; Aged; Bone Density; Female; Hip Fractures; Humans; Male; Methylamines; Risk Factors

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. - Wang, Zhe; Choi, Shing Wan; Chami, Nathalie; Boerwinkle, Eric; Fornage, Myriam; Redline, Susan; Bis, Joshua C; Brody, Jennifer A; Psaty, Bruce M; Kim, Wonji; McDonald, Merry-Lynn N; Regan, Elizabeth A; et al. (Front Endocrinol (Lausanne), 2022)
Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.
Keywords: Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Obesity; Whole Genome Sequencing

Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. - Pankratz, Nathan; Wei, Peng; Brody, Jennifer A; Chen, Ming-Huei; Vries, Paul S; Huffman, Jennifer E; Stimson, Mary Rachel; Auer, Paul L; Boerwinkle, Eric; Cushman, Mary; Maat, Moniek P M; Folsom, Aaron R; et al. (Hum Mol Genet, 2022)
Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. - DiCorpo, Daniel; Gaynor, Sheila M; Russell, Emily M; Westerman, Kenneth E; Raffield, Laura M; Majarian, Timothy D; Wu, Peitao; Sarnowski, Chloe; Highland, Heather M; Jackson, Anne; Hasbani, Natalie R; de Vries, Paul S; et al. (Commun Biol, 2022)
The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.
Keywords: Diabetes Mellitus, Type 2; Fasting; Glucose; Humans; Insulin; National Heart, Lung, and Blood Institute (U.S.); Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Precision Medicine; Receptors, Immunologic; United States

Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. - Wheeler, Marsha M; Stilp, Adrienne M; Rao, Shuquan; Halldorsson, Bjarni V; Beyter, Doruk; Wen, Jia; Mihkaylova, Anna V; McHugh, Caitlin P; Lane, John; Jiang, Min-Zhi; Raffield, Laura M; Jun, Goo; et al. (Nat Commun, 2022)
Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
Keywords: Blood Cells; Genome-Wide Association Study; Humans; Whole Genome Sequencing

Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. - Pan, Yang; Sun, Xiao; Mi, Xuenan; Huang, Zhijie; Hsu, Yenchih; Hixson, James E; Munzy, Donna; Metcalf, Ginger; Franceschini, Nora; Tin, Adrienne; Köttgen, Anna; Francis, Michael; et al. (Hum Mol Genet, 2022)
Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

{Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project - Hu, Y.; Haessler, J. W.; Manansala, R.; Wiggins, K. L.; Moscati, A.; Beiser, A.; Heard-Costa, N. L.; Sarnowski, C.; Raffield, L. M.; Chung, J.; Marini, S.; Anderson, C. D.; et al. (Stroke, 2022)
Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).\ Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis.\ .\ We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. - Weinstock, Joshua S; Gopakumar, Jayakrishnan; Burugula, Bala Bharathi; Uddin, Md Mesbah; Jahn, Nikolaus; Belk, Julia A; Bouzid, Hind; Daniel, Bence; Miao, Zhuang; Ly, Nghi; Mack, Taralynn M; Luna, Sofia E; et al. (Nature, 2023)
Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
Keywords: Alleles; Animals; Clonal Hematopoiesis; Genome-Wide Association Study; Hematopoiesis; Hematopoietic Stem Cells; Humans; Mice; Mutation; Promoter Regions, Genetic

Age-Related Factors Associated with Hip Fracture Risk. - Bůzková, Petra; Cauley, Jane A; Fink, Howard A; Robbins, John A; Mukamal, Kenneth J; Barzilay, Joshua I (Endocr Pract, 2023)
OBJECTIVES: Advancing age is a powerful risk factor for hip fracture. The biological mechanisms through which aging impacts hip fracture risk have not been well studied. METHODS: Biological factors associated with "advancing age" that help to explain how aging is associated with hip fracture risk are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults ages >65 years with 25 years of follow up. RESULTS: Five age-related factors were found to be significantly associated with hip fracture risk: (1) microvascular disease of the kidney (albuminuria and / or elevated urine albumin to creatinine ratio) and of the brain (abnormal white matter disease on brain MRI); (2) increased serum levels of carboxymethyl-lysine (CML), an advanced glycation end-product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased trans-fatty acid levels in the blood. Each of these factors was associated with a 10-25%. increased risk of fracture. These associations were independent of traditional risk factors for hip fracture. CONCLUSION: Several factors associated with older age help to explain how "aging" may be associated with hip fracture risk. These same factors may also explain the high risk for mortality following hip fracture.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels. - Ji, Yuekai; Temprano-Sagrera, Gerard; Holle, Lori A; Bebo, Allison; Brody, Jennifer A; Le, Ngoc-Quynh; Kangro, Kadri; Brown, Michael R; Martinez-Perez, Angel; Sitlani, Colleen M; Suchon, Pierre; Kleber, Marcus E; et al. (Arterioscler Thromb Vasc Biol, 2023)
BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (, , and ) and 1 with PS levels (-). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (), 1 with PC (), and 1 with PS (). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of , , and genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
Keywords: Anticoagulants; Antithrombin III; Antithrombins; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Protein C; Protein S; Transcriptome

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk. - Liu, Xue; Sun, Xianbang; Zhang, Yuankai; Jiang, Wenqing; Lai, Meng; Wiggins, Kerri L; Raffield, Laura M; Bielak, Lawrence F; Zhao, Wei; Pitsillides, Achilleas; Haessler, Jeffrey; Zheng, Yinan; et al. (J Am Heart Assoc, 2023)
Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study. - Sheets, Kerry M; Bůzková, Petra; Chen, Zhao; Carbone, Laura D; Cauley, Jane A; Barzilay, Joshua I; Starks, Jamie L; Miller, Lindsay M; Fink, Howard A (Osteoporos Int, 2023)
UNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture. INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture. METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive). RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90). CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.
Keywords: Aged; Brain Infarction; Frailty; Hip Fractures; Humans; Prospective Studies; Risk Factors; White Matter

Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study. - Elam, Rachel E; Bůzková, Petra; Delaney, Joseph A C; Fink, Howard A; Barzilay, Joshua I; Carbone, Laura D; Saha, Rick; Robbins, John A; Mukamal, Kenneth J; Valderrábano, Rodrigo J; Psaty, Bruce M; Tracy, Russell P; et al. (Calcif Tissue Int, 2023)
In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. - Zhang, Yuankai; Liu, Xue; Wiggins, Kerri L; Kurniansyah, Nuzulul; Guo, Xiuqing; Rodrigue, Amanda L; Zhao, Wei; Yanek, Lisa R; Ratliff, Scott M; Pitsillides, Achilleas; Aguirre Patiño, Juan Sebastian; Sofer, Tamar; et al. (Neurology, 2023)
BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality. RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. - Ong, Kwok Leung; Marklund, Matti; Huang, Liping; Rye, Kerry-Anne; Hui, Nicholas; Pan, Xiong-Fei; Rebholz, Casey M; Kim, Hyunju; Steffen, Lyn M; van Westing, Anniek C; Geleijnse, Johanna M; Hoogeveen, Ellen K; et al. (BMJ, 2023)
OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate. RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline. CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.
Keywords: alpha-Linolenic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Humans; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors

Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease. - Zhang, Yiyi; Dron, Jacqueline S; Bellows, Brandon K; Khera, Amit V; Liu, Junxiu; Balte, Pallavi P; Oelsner, Elizabeth C; Amr, Sami Samir; Lebo, Matthew S; Nagy, Anna; Peloso, Gina M; Natarajan, Pradeep; et al. (Circulation, 2023)
Keywords: Coronary Disease; Genotype; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II

The Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study. - Carbone, Laura; Bůzková, Petra; Fink, Howard A; Robbins, John A; Barzilay, Joshua I; Elam, Rachel E; Isales, Carlos (JBMR Plus, 2023)
Amino acids are the building blocks of proteins, and sufficient protein intake is important for skeletal health. We utilized stored serum from the Cardiovascular Health Study in 1992-1993 to examine the relationship between levels of the essential amino acid tryptophan (trp) and its oxidized and nonoxidized metabolites to risk for incident hip fractures and mortality over 12 years of follow-up. We included 131 persons who sustained a hip fracture during this time period and 131 without a hip fracture over these same 12 years of follow-up; 58% female and 95% White. Weighted multivariable Cox hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher trp or its metabolites exposure. Relative risk regression was used to evaluate the cross-sectional association of trp and its metabolites with frailty. Higher serum levels of trp were significantly associated with lower risk of incident hip fractures (HR = 0.75 per SD of trp (95% CI 0.57-0.99) but were not significantly associated with mortality or frailty status by Freid's frailty index. There were no statistically significant associations between any of the oxidized or nonoxidized products of trp with incident hip fractures ( ≥ 0.64), mortality ( ≥ 0.20), or cross-sectional frailty status ( ≥ 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

{Associations Between Vascular Risk Factor Levels and Cognitive Decline Among Stroke Survivors - Levine, D. A.; Chen, B.; Galecki, A. T.; Gross, A. L.; o, E. M.; Whitney, R. T.; Ploutz-Snyder, R. J.; Giordani, B. J.; Sussman, J. B.; Burke, J. F.; Lazar, R. M.; Howard, V. J.; et al. (JAMA Netw Open, 2023)
Incident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain.\ To evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline.\ Individual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023.\ Time-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels.\ The primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.\ .002) but not executive function or memory declines.\ In this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.

The associations of markers of endothelial dysfunction with hip fracture risk. - Barzilay, Joshua I; Bůzková, Petra; Fink, Howard A; Cauley, Jane A; Carbone, Laura; Elam, Rachel; Robbins, John A; Stein, Phyllis; Sheets, Kerry; Jalal, Diana; Mukamal, Kenneth J (Arch Osteoporos, 2023)
UNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them. PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk. METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group. RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable. CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.
Keywords: Aged; Forearm; Hip Fractures; Humans; Osteoporotic Fractures; Vascular Diseases

Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study. - Mehta, Rupal; Bůzková, Petra; Patel, Harnish; Cheng, Jeanette; Kizer, Jorge R; Gottdiener, John S; Psaty, Bruce; Khan, Sadiya S; Ix, Joachim H; Isakova, Tamara; Shlipak, Michael G; Bansal, Nisha; et al. (Kidney360, 2023)
BACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown. METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e'). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30% decline in eGFR over 7 years. RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e' were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30% decline in eGFR. CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.

Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease. - Georgakis, Marios K; Malik, Rainer; Hasbani, Natalie R; Shakt, Gabrielle; Morrison, Alanna C; Tsao, Noah L; Judy, Renae; Mitchell, Braxton D; Xu, Huichun; Montasser, May E; Do, Ron; Kenny, Eimear E; et al. (medRxiv, 2023)
BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease. METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated. RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95%CI: 0.39-0.96; OR : 0.64 95%CI: 0.34-1.19; OR : 0.64 95%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants. CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders. - Kizer, Jorge R; Patel, Sheena; Ganz, Peter; Newman, Anne B; Bhasin, Shalender; Lee, Se-Jin; Cawthon, Peggy M; LeBrasseur, Nathan; Shah, Sanjiv J; Psaty, Bruce M; Tracy, Russell P; Cummings, Steven R (J Gerontol A Biol Sci Med Sci, 2023)
BACKGROUND: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8. METHODS: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and follistatin-like (FSTL)-3 by immunoassay, in two longitudinal cohorts of older adults. RESULTS: In 2,599 participants (age 75.2±4.3) followed for 10.8±5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks and lower kidney function. CONCLUSIONS: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-βsuperfamily pathways as potential therapeutic targets.