@article {6002, title = {Atrial fibrillation and cognitive decline: a longitudinal cohort study.}, journal = {Neurology}, volume = {81}, year = {2013}, month = {2013 Jul 09}, pages = {119-25}, abstract = {

OBJECTIVE: We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation.

METHODS: We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times.

RESULTS: Analyses included 5,150 participants, of whom 552 (10.7\%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95\% confidence interval [CI]: -7.0, -5.9) for participants without a history of atrial fibrillation, but was -10.3 points (95\% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95\% CI: -5.3, -2.5).

CONCLUSIONS: In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Atrial Fibrillation, Cognition Disorders, Comorbidity, Female, Humans, Incidence, Longitudinal Studies, Luria-Nebraska Neuropsychological Battery, Male, Predictive Value of Tests}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31829a33d1}, author = {Thacker, Evan L and McKnight, Barbara and Psaty, Bruce M and Longstreth, W T and Sitlani, Colleen M and Dublin, Sascha and Arnold, Alice M and Fitzpatrick, Annette L and Gottesman, Rebecca F and Heckbert, Susan R} } @article {6607, title = {The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e109290}, abstract = {

Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP{\texttimes}SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 {\textperiodcentered} 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP{\texttimes}SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

}, keywords = {Cholesterol, HDL, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1932-6203}, doi = {10.1371/journal.pone.0109290}, author = {van Leeuwen, Elisabeth M and Smouter, Fran{\c c}oise A S and Kam-Thong, Tony and Karbalai, Nazanin and Smith, Albert V and Harris, Tamara B and Launer, Lenore J and Sitlani, Colleen M and Li, Guo and Brody, Jennifer A and Bis, Joshua C and White, Charles C and Jaiswal, Alok and Oostra, Ben A and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Boerwinkle, Eric and Ballantyne, Christie M and Gudnason, Vilmundur and Psaty, Bruce M and Cupples, L Adrienne and Jarvelin, Marjo-Riitta and Ripatti, Samuli and Isaacs, Aaron and M{\"u}ller-Myhsok, Bertram and Karssen, Lennart C and van Duijn, Cornelia M} } @article {6325, title = {Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest.}, journal = {Heart Rhythm}, volume = {11}, year = {2014}, month = {2014 Mar}, pages = {471-7}, abstract = {

BACKGROUND: There is limited information on genetic factors associated with sudden cardiac arrest (SCA).

OBJECTIVE: To assess the association of common variation in genes in fatty acid pathways with SCA risk.

METHODS: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases.

RESULTS: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36\%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13\% lower SCA risk (95\% confidence interval -21\% to -5\%) in the discovery phase and 9\% lower SCA risk (95\% confidence interval -16\% to -1\%) in the replication phase.

CONCLUSIONS: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.

}, keywords = {1-Acylglycerophosphocholine O-Acyltransferase, Aged, Algorithms, Alleles, Case-Control Studies, Death, Sudden, Cardiac, Fatty Acids, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2014.01.008}, author = {Lemaitre, Rozenn N and Johnson, Catherine O and Hesselson, Stephanie and Sotoodehnia, Nona and Sotoodhenia, Nona and McKnight, Barbara and Sitlani, Colleen M and Rea, Thomas D and King, Irena B and Kwok, Pui-Yan and Mak, Angel and Li, Guo and Brody, Jennifer and Larson, Eric and Mozaffarian, Dariush and Psaty, Bruce M and Huertas-Vazquez, Adriana and Tardif, Jean-Claude and Albert, Christine M and Lyytik{\"a}inen, Leo-Pekka and Arking, Dan E and K{\"a}{\"a}b, Stefan and Huikuri, Heikki V and Krijthe, Bouwe P and Eijgelsheim, Mark and Wang, Ying A and Reinier, Kyndaron and Lehtim{\"a}ki, Terho and Pulit, Sara L and Brugada, Ramon and M{\"u}ller-Nurasyid, Martina and Newton-Cheh, Chris H and Karhunen, Pekka J and Stricker, Bruno H and Goyette, Philippe and Rotter, Jerome I and Chugh, Sumeet S and Chakravarti, Aravinda and Jouven, Xavier and Siscovick, David S} } @article {6583, title = {Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {365-73}, abstract = {

BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.

METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1\%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute{\textquoteright}s Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3{\texttimes}10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25{\texttimes}10(-4) and P=5.2{\texttimes}10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82{\texttimes}10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35{\texttimes}10(-7) and P=2.69{\texttimes}10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67{\texttimes}10(-5)).

CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Conduction System, Heart Diseases, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000098}, author = {Magnani, Jared W and Brody, Jennifer A and Prins, Bram P and Arking, Dan E and Lin, Honghuang and Yin, Xiaoyan and Liu, Ching-Ti and Morrison, Alanna C and Zhang, Feng and Spector, Tim D and Alonso, Alvaro and Bis, Joshua C and Heckbert, Susan R and Lumley, Thomas and Sitlani, Colleen M and Cupples, L Adrienne and Lubitz, Steven A and Soliman, Elsayed Z and Pulit, Sara L and Newton-Cheh, Christopher and O{\textquoteright}Donnell, Christopher J and Ellinor, Patrick T and Benjamin, Emelia J and Muzny, Donna M and Gibbs, Richard A and Santibanez, Jireh and Taylor, Herman A and Rotter, Jerome I and Lange, Leslie A and Psaty, Bruce M and Jackson, Rebecca and Rich, Stephen S and Boerwinkle, Eric and Jamshidi, Yalda and Sotoodehnia, Nona} } @article {6578, title = {Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {335-43}, abstract = {

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with >=1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency >=1\%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Research Design, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000350}, author = {Lin, Honghuang and Wang, Min and Brody, Jennifer A and Bis, Joshua C and Dupuis, Jos{\'e}e and Lumley, Thomas and McKnight, Barbara and Rice, Kenneth M and Sitlani, Colleen M and Reid, Jeffrey G and Bressler, Jan and Liu, Xiaoming and Davis, Brian C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Kovar, Christie L and Dinh, Huyen and Wu, Yuanqing and Newsham, Irene and Chen, Han and Broka, Andi and DeStefano, Anita L and Gupta, Mayetri and Lunetta, Kathryn L and Liu, Ching-Ti and White, Charles C and Xing, Chuanhua and Zhou, Yanhua and Benjamin, Emelia J and Schnabel, Renate B and Heckbert, Susan R and Psaty, Bruce M and Muzny, Donna M and Cupples, L Adrienne and Morrison, Alanna C and Boerwinkle, Eric} } @article {6602, title = {Generalized estimating equations for genome-wide association studies using longitudinal phenotype data.}, journal = {Stat Med}, volume = {34}, year = {2015}, month = {2015 Jan 15}, pages = {118-30}, abstract = {

Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.

}, keywords = {Aged, Aging, Cardiovascular Diseases, Cohort Studies, Computer Simulation, Cross-Sectional Studies, Epidemiologic Research Design, Gene-Environment Interaction, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Longitudinal Studies, Meta-Analysis as Topic, Models, Genetic, Pharmacogenetics, Risk Assessment, United States}, issn = {1097-0258}, doi = {10.1002/sim.6323}, author = {Sitlani, Colleen M and Rice, Kenneth M and Lumley, Thomas and McKnight, Barbara and Cupples, L Adrienne and Avery, Christy L and Noordam, Raymond and Stricker, Bruno H C and Whitsel, Eric A and Psaty, Bruce M} } @article {6663, title = {Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 May}, pages = {1047-54}, abstract = {

BACKGROUND: Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes.

OBJECTIVE: By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes.

DESIGN: A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes.

RESULTS: Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47\% lower risk of diabetes (95\% CI: 23\%, 63\%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33\% (95\% CI: 6\%, 53\%; P-trend: 0.02) and 37\% (95\% CI: 11\%, 55\%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32\% lower risk for fourth vs. first quartile; P-trend: 0.04).

CONCLUSIONS: These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cross-Sectional Studies, Diabetes Mellitus, Diet, Eicosanoic Acids, Fatty Acids, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Incidence, Male, Observational Studies as Topic, Palmitic Acid, Phospholipids, Prospective Studies, Risk Factors, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.114.101857}, author = {Lemaitre, Rozenn N and Fretts, Amanda M and Sitlani, Colleen M and Biggs, Mary L and Mukamal, Kenneth and King, Irena B and Song, Xiaoling and Djouss{\'e}, Luc and Siscovick, David S and McKnight, Barbara and Sotoodehnia, Nona and Kizer, Jorge R and Mozaffarian, Dariush} } @article {6561, title = {Variation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults.}, journal = {Heart}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {132-8}, abstract = {

OBJECTIVE: Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults.

METHODS: 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively.

RESULTS: 262 subjects had an incident MI event (13\%) and 1326 died (67\%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95\% CI 1.05 to 1.20) and variation (HR 1.08; 95\% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex.

CONCLUSIONS: Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Electrocardiography, Female, Follow-Up Studies, Heart Rate, Humans, Incidence, Linear Models, Male, Myocardial Infarction, Outcome Assessment (Health Care), Prognosis, Proportional Hazards Models, Prospective Studies, Rest, Risk Factors, Time, Washington}, issn = {1468-201X}, doi = {10.1136/heartjnl-2014-306046}, author = {Floyd, James S and Sitlani, Colleen M and Wiggins, Kerri L and Wallace, Erin and Suchy-Dicey, Astrid and Abbasi, Siddique A and Carnethon, Mercedes R and Siscovick, David S and Sotoodehnia, Nona and Heckbert, Susan R and McKnight, Barbara and Rice, Kenneth M and Psaty, Bruce M} } @article {7135, title = {Global Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies.}, journal = {Circulation}, volume = {133}, year = {2016}, month = {2016 Jun 7}, pages = {2222-34}, abstract = {

BACKGROUND: Asymptomatic individuals account for the majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and noninvasive SCD risk stratification tools is necessary.

METHODS AND RESULTS: Participants from the Atherosclerosis Risk in Communities study and Cardiovascular Health Study (n=20 177; age, 59.3{\textpm}10.1 years; age range, 44-100 years; 56\% female; 77\% white) were followed up for 14.0 years (median). Five ECG markers of global electric heterogeneity (GEH; sum absolute QRST integral, spatial QRST angle, spatial ventricular gradient [SVG] magnitude, SVG elevation, and SVG azimuth) were measured on standard 12-lead ECGs. Cox proportional hazards and competing risks models evaluated associations between GEH electrocardiographic parameters and SCD. An SCD competing risks score was derived from demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1000 person-years. After multivariable adjustment, baseline GEH parameters and large increases in GEH parameters over time were independently associated with SCD. Final SCD risk scores included age, sex, race, diabetes mellitus, hypertension, coronary heart disease, stroke, and GEH parameters as continuous variables. When GEH parameters were added to clinical/demographic factors, the C statistic increased from 0.777 to 0.790 (P=0.008), the risk score classified 10-year SCD risk as high (>5\%) in 7.2\% of participants, 10\% of SCD victims were appropriately reclassified into a high-risk category, and only 1.4\% of SCD victims were inappropriately reclassified from high to intermediate risk. The net reclassification index was 18.3\%.

CONCLUSIONS: Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. The addition of GEH parameters to clinical characteristics improves SCD risk prediction.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.116.021306}, author = {Waks, Jonathan W and Sitlani, Colleen M and Soliman, Elsayed Z and Kabir, Muammar and Ghafoori, Elyar and Biggs, Mary L and Henrikson, Charles A and Sotoodehnia, Nona and Biering-S{\o}rensen, Tor and Agarwal, Sunil K and Siscovick, David S and Post, Wendy S and Solomon, Scott D and Buxton, Alfred E and Josephson, Mark E and Tereshchenko, Larisa G} } @article {7002, title = {Incident Atrial Fibrillation and Disability-Free Survival in the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Apr}, pages = {838-43}, abstract = {

OBJECTIVES: To assess the associations between incident atrial fibrillation (AF) and disability-free survival and risk of disability.

DESIGN: Prospective cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older and enrolled in fee-for-service Medicare followed between 1991 and 2009 (MN = 4,046). Individuals with prevalent AF, activity of daily living (ADL) disability, or a history of stroke or heart failure at baseline were excluded.

MEASUREMENTS: Incident AF was identified according to annual study electrocardiogram, hospital discharge diagnosis, or Medicare claims. Disability-free survival was defined as survival free of ADL disability (any difficulty or inability in bathing, dressing, eating, using the toilet, walking around the home, or getting out of a bed or chair). ADLs were assessed at annual study visits or in a telephone interview. Association between incident AF and disability-free survival or risk of disability was estimated using Cox proportional hazards models.

RESULTS: Over an average of 7.0 years of follow-up, 660 individuals (16.3\%) developed incident AF, and 3,112 (77\%) became disabled or died. Incident AF was associated with shorter disability-free survival (hazard ratio (HR) for death or ADL disability = 1.71, 95\% confidence interval (CI) = 1.55-1.90) and a higher risk of ADL disability (HR = 1.36, 95\% CI = 1.18-1.58) than in individuals with no history of AF. This association persisted after adjustment for interim stroke and heart failure.

CONCLUSION: These results suggest that AF is a risk factor for shorter functional longevity in older adults, independent of other risk factors and comorbid conditions.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Atrial Fibrillation, Disability Evaluation, Electrocardiography, Female, Geriatric Assessment, Humans, Incidence, Longevity, Longitudinal Studies, Male, Medicare, Prevalence, Prospective Studies, Survival Rate, United States}, issn = {1532-5415}, doi = {10.1111/jgs.14037}, author = {Wallace, Erin R and Siscovick, David S and Sitlani, Colleen M and Dublin, Sascha and Mitchell, Pamela H and Odden, Michelle C and Hirsch, Calvin H and Thielke, Stephen and Heckbert, Susan R} } @article {7553, title = {Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Oct 27}, pages = {1560-1563}, issn = {1546-1718}, doi = {10.1038/ng.3968}, author = {Brody, Jennifer A and Morrison, Alanna C and Bis, Joshua C and O{\textquoteright}Connell, Jeffrey R and Brown, Michael R and Huffman, Jennifer E and Ames, Darren C and Carroll, Andrew and Conomos, Matthew P and Gabriel, Stacey and Gibbs, Richard A and Gogarten, Stephanie M and Gupta, Namrata and Jaquish, Cashell E and Johnson, Andrew D and Lewis, Joshua P and Liu, Xiaoming and Manning, Alisa K and Papanicolaou, George J and Pitsillides, Achilleas N and Rice, Kenneth M and Salerno, William and Sitlani, Colleen M and Smith, Nicholas L and Heckbert, Susan R and Laurie, Cathy C and Mitchell, Braxton D and Vasan, Ramachandran S and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Boerwinkle, Eric and Psaty, Bruce M and Cupples, L Adrienne} } @article {7353, title = {A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.}, journal = {J Med Genet}, volume = {54}, year = {2017}, month = {2017 May}, pages = {313-323}, abstract = {

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-104112}, author = {Noordam, Raymond and Sitlani, Colleen M and Avery, Christy L and Stewart, James D and Gogarten, Stephanie M and Wiggins, Kerri L and Trompet, Stella and Warren, Helen R and Sun, Fangui and Evans, Daniel S and Li, Xiaohui and Li, Jin and Smith, Albert V and Bis, Joshua C and Brody, Jennifer A and Busch, Evan L and Caulfield, Mark J and Chen, Yii-der I and Cummings, Steven R and Cupples, L Adrienne and Duan, Qing and Franco, Oscar H and M{\'e}ndez-Gir{\'a}ldez, R{\'a}ul and Harris, Tamara B and Heckbert, Susan R and van Heemst, Diana and Hofman, Albert and Floyd, James S and Kors, Jan A and Launer, Lenore J and Li, Yun and Li-Gao, Ruifang and Lange, Leslie A and Lin, Henry J and de Mutsert, Ren{\'e}e and Napier, Melanie D and Newton-Cheh, Christopher and Poulter, Neil and Reiner, Alexander P and Rice, Kenneth M and Roach, Jeffrey and Rodriguez, Carlos J and Rosendaal, Frits R and Sattar, Naveed and Sever, Peter and Seyerle, Amanda A and Slagboom, P Eline and Soliman, Elsayed Z and Sotoodehnia, Nona and Stott, David J and St{\"u}rmer, Til and Taylor, Kent D and Thornton, Timothy A and Uitterlinden, Andr{\'e} G and Wilhelmsen, Kirk C and Wilson, James G and Gudnason, Vilmundur and Jukema, J Wouter and Laurie, Cathy C and Liu, Yongmei and Mook-Kanamori, Dennis O and Munroe, Patricia B and Rotter, Jerome I and Vasan, Ramachandran S and Psaty, Bruce M and Stricker, Bruno H and Whitsel, Eric A} } @article {7448, title = {PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, pages = {e001632}, abstract = {

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.

METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3\%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1\%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95\% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95\% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95\% CI, 0.28-0.92) in blacks and 0.82 (95\% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95\% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95\% CI, 0.80-1.41 in whites).

CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001632}, author = {Kent, Shia T and Rosenson, Robert S and Avery, Christy L and Chen, Yii-der I and Correa, Adolfo and Cummings, Steven R and Cupples, L Adrienne and Cushman, Mary and Evans, Daniel S and Gudnason, Vilmundur and Harris, Tamara B and Howard, George and Irvin, Marguerite R and Judd, Suzanne E and Jukema, J Wouter and Lange, Leslie and Levitan, Emily B and Li, Xiaohui and Liu, Yongmei and Post, Wendy S and Postmus, Iris and Psaty, Bruce M and Rotter, Jerome I and Safford, Monika M and Sitlani, Colleen M and Smith, Albert V and Stewart, James D and Trompet, Stella and Sun, Fangui and Vasan, Ramachandran S and Woolley, J Michael and Whitsel, Eric A and Wiggins, Kerri L and Wilson, James G and Muntner, Paul} } @article {7919, title = {Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {7}, year = {2018}, month = {2018 Nov 06}, pages = {e010019}, abstract = {

Background Circulating very-long-chain saturated fatty acids ( VLSFAs ) are integrated biomarkers of diet and metabolism that may point to new risk pathways and potential targets for heart failure ( HF ) prevention. The associations of VLSFA to HF in humans are not known. Methods and Results Using a cohort study design, we studied the associations of serially measured plasma phospholipid VLSFA with incident HF in the Cardiovascular Health Study. We investigated the associations of time-varying levels of the 3 major circulating VLSFAs , lignoceric acid (24:0), behenic acid (22:0), and arachidic acid (20:0), with the risk of incident HF using Cox regression. During 45030 person-years among 4249 participants, we identified 1304 cases of incident HF , including 489 with preserved and 310 with reduced ejection fraction. Adjusting for major HF risk factors and other circulating fatty acids, higher levels of each VLSFAs were associated with lower risk of incident HF ( P trend<=0.0007 each). The hazard ratio comparing the highest quintile to the lowest quintile was 0.67 (95\% confidence interval, 0.55-0.81) for 24:0, 0.72 (95\% confidence interval, 0.60-0.87) for 22:0 and 0.72 (95\% confidence interval, 0.59-0.88) for 20:0. The associations were similar in subgroups defined by sex, age, body mass index, coronary heart disease, and diabetes mellitus. Among those with ejection fraction data, the associations appeared similar for those with preserved and with reduced ejection fraction. Conclusions Higher levels of circulating VLSFAs are associated with lower risk of incident HF in older adults. These novel associations should prompt further research on the role of VLSFA in HF , including relevant new risk pathways. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00005133.

}, issn = {2047-9980}, doi = {10.1161/JAHA.118.010019}, author = {Lemaitre, Rozenn N and McKnight, Barbara and Sotoodehnia, Nona and Fretts, Amanda M and Qureshi, Waqas T and Song, Xiaoling and King, Irena B and Sitlani, Colleen M and Siscovick, David S and Psaty, Bruce M and Mozaffarian, Dariush} } @article {7801, title = {Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 May}, pages = {e002037}, abstract = {

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.

RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2{\texttimes}10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9{\texttimes}10) and (=1.1{\texttimes}10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.

CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.002037}, author = {Lin, Honghuang and van Setten, Jessica and Smith, Albert V and Bihlmeyer, Nathan A and Warren, Helen R and Brody, Jennifer A and Radmanesh, Farid and Hall, Leanne and Grarup, Niels and M{\"u}ller-Nurasyid, Martina and Boutin, Thibaud and Verweij, Niek and Lin, Henry J and Li-Gao, Ruifang and van den Berg, Marten E and Marten, Jonathan and Weiss, Stefan and Prins, Bram P and Haessler, Jeffrey and Lyytik{\"a}inen, Leo-Pekka and Mei, Hao and Harris, Tamara B and Launer, Lenore J and Li, Man and Alonso, Alvaro and Soliman, Elsayed Z and Connell, John M and Huang, Paul L and Weng, Lu-Chen and Jameson, Heather S and Hucker, William and Hanley, Alan and Tucker, Nathan R and Chen, Yii-Der Ida and Bis, Joshua C and Rice, Kenneth M and Sitlani, Colleen M and Kors, Jan A and Xie, Zhijun and Wen, Chengping and Magnani, Jared W and Nelson, Christopher P and Kanters, J{\o}rgen K and Sinner, Moritz F and Strauch, Konstantin and Peters, Annette and Waldenberger, Melanie and Meitinger, Thomas and Bork-Jensen, Jette and Pedersen, Oluf and Linneberg, Allan and Rudan, Igor and de Boer, Rudolf A and van der Meer, Peter and Yao, Jie and Guo, Xiuqing and Taylor, Kent D and Sotoodehnia, Nona and Rotter, Jerome I and Mook-Kanamori, Dennis O and Trompet, Stella and Rivadeneira, Fernando and Uitterlinden, Andre and Eijgelsheim, Mark and Padmanabhan, Sandosh and Smith, Blair H and V{\"o}lzke, Henry and Felix, Stephan B and Homuth, Georg and V{\"o}lker, Uwe and Mangino, Massimo and Spector, Timothy D and Bots, Michiel L and Perez, Marco and K{\"a}h{\"o}nen, Mika and Raitakari, Olli T and Gudnason, Vilmundur and Arking, Dan E and Munroe, Patricia B and Psaty, Bruce M and van Duijn, Cornelia M and Benjamin, Emelia J and Rosand, Jonathan and Samani, Nilesh J and Hansen, Torben and K{\"a}{\"a}b, Stefan and Polasek, Ozren and van der Harst, Pim and Heckbert, Susan R and Jukema, J Wouter and Stricker, Bruno H and Hayward, Caroline and D{\"o}rr, Marcus and Jamshidi, Yalda and Asselbergs, Folkert W and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Wilson, James G and Ellinor, Patrick T and Lubitz, Steven A and Isaacs, Aaron} } @article {7802, title = {Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 May}, pages = {e001663}, abstract = {

BACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.

METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.

RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52{\texttimes}10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2{\texttimes}10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( >=0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2{\textpm}3.3\%, =0.03, and I962V+V1073A, 22.4{\textpm}0.8\%, =0.0004 versus wild-type 11.7{\textpm}1.6\%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4{\textpm}1.2\%, =0.03).

CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.116.001663}, author = {Macri, Vincenzo and Brody, Jennifer A and Arking, Dan E and Hucker, William J and Yin, Xiaoyan and Lin, Honghuang and Mills, Robert W and Sinner, Moritz F and Lubitz, Steven A and Liu, Ching-Ti and Morrison, Alanna C and Alonso, Alvaro and Li, Ning and Fedorov, Vadim V and Janssen, Paul M and Bis, Joshua C and Heckbert, Susan R and Dolmatova, Elena V and Lumley, Thomas and Sitlani, Colleen M and Cupples, L Adrienne and Pulit, Sara L and Newton-Cheh, Christopher and Barnard, John and Smith, Jonathan D and Van Wagoner, David R and Chung, Mina K and Vlahakes, Gus J and O{\textquoteright}Donnell, Christopher J and Rotter, Jerome I and Margulies, Kenneth B and Morley, Michael P and Cappola, Thomas P and Benjamin, Emelia J and Muzny, Donna and Gibbs, Richard A and Jackson, Rebecca D and Magnani, Jared W and Herndon, Caroline N and Rich, Stephen S and Psaty, Bruce M and Milan, David J and Boerwinkle, Eric and Mohler, Peter J and Sotoodehnia, Nona and Ellinor, Patrick T} } @article {7669, title = {Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy.}, journal = {Sci Rep}, volume = {8}, year = {2018}, month = {2018 Apr 04}, pages = {5675}, abstract = {

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically~identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 {\texttimes} 10) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 {\texttimes} 10) and multi-trait analysis (P = 2.9 {\texttimes} 10) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

}, issn = {2045-2322}, doi = {10.1038/s41598-018-23843-z}, author = {Napier, Melanie D and Franceschini, Nora and Gondalia, Rahul and Stewart, James D and M{\'e}ndez-Gir{\'a}ldez, R{\'a}ul and Sitlani, Colleen M and Seyerle, Amanda A and Highland, Heather M and Li, Yun and Wilhelmsen, Kirk C and Yan, Song and Duan, Qing and Roach, Jeffrey and Yao, Jie and Guo, Xiuqing and Taylor, Kent D and Heckbert, Susan R and Rotter, Jerome I and North, Kari E and Reiner, Alexander P and Zhang, Zhu-Ming and Tinker, Lesley F and Liao, Duanping and Laurie, Cathy C and Gogarten, Stephanie M and Lin, Henry J and Brody, Jennifer A and Bartz, Traci M and Psaty, Bruce M and Sotoodehnia, Nona and Soliman, Elsayed Z and Avery, Christy L and Whitsel, Eric A} } @article {7672, title = {Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study).}, journal = {J Am Heart Assoc}, volume = {7}, year = {2018}, month = {2018 Apr 05}, abstract = {

BACKGROUND: ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome-wide association study would identify genetic loci related to GEH.

METHODS AND RESULTS: We tested genotyped and imputed variants in black (N=3057) and white (N=10~769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS-T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12-lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome-wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near ) was associated with QRS-T angle (white standardized β+0.16 [95\% CI 0.13-0.19]; =1.5{\texttimes}10), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; =2.1{\texttimes}10), and spatial ventricular gradient magnitude (-0.12 [95\% CI -0.15 to -0.09]; =5.9{\texttimes}10). Altogether, GEH-SNPs explained 1.1\% to 1.6\% of GEH variance. Loci on chromosomes 4 (near ), 5 (), 11 (11p11.2 region cluster), and 7 (near ) are novel ECG phenotype-associated loci. Several loci significantly associated with gene expression in the left ventricle ( locus-with ; locus-with ), and atria ( locus-with expression of a long non-coding RNA and ).

CONCLUSIONS: We identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH-loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

}, issn = {2047-9980}, doi = {10.1161/JAHA.117.008160}, author = {Tereshchenko, Larisa G and Sotoodehnia, Nona and Sitlani, Colleen M and Ashar, Foram N and Kabir, Muammar and Biggs, Mary L and Morley, Michael P and Waks, Jonathan W and Soliman, Elsayed Z and Buxton, Alfred E and Biering-S{\o}rensen, Tor and Solomon, Scott D and Post, Wendy S and Cappola, Thomas P and Siscovick, David S and Arking, Dan E} } @article {7794, title = {Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry.}, journal = {Pharmacogenomics J}, year = {2018}, month = {2018 Jun 01}, abstract = {

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 {\texttimes} 10) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 {\texttimes} 10; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

}, issn = {1473-1150}, doi = {10.1038/s41397-018-0021-9}, author = {Irvin, Marguerite R and Sitlani, Colleen M and Noordam, Raymond and Avery, Christie L and Bis, Joshua C and Floyd, James S and Li, Jin and Limdi, Nita A and Srinivasasainagendra, Vinodh and Stewart, James and de Mutsert, Ren{\'e}e and Mook-Kanamori, Dennis O and Lipovich, Leonard and Kleinbrink, Erica L and Smith, Albert and Bartz, Traci M and Whitsel, Eric A and Uitterlinden, Andr{\'e} G and Wiggins, Kerri L and Wilson, James G and Zhi, Degui and Stricker, Bruno H and Rotter, Jerome I and Arnett, Donna K and Psaty, Bruce M and Lange, Leslie A} } @article {7686, title = {A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 Mar 01}, pages = {375-400}, abstract = {

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined \~{}18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5~{\texttimes} 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5~{\texttimes} 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.01.015}, author = {Sung, Yun J and Winkler, Thomas W and de Las Fuentes, Lisa and Bentley, Amy R and Brown, Michael R and Kraja, Aldi T and Schwander, Karen and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Kilpel{\"a}inen, Tuomas O and Richard, Melissa A and Noordam, Raymond and Aslibekyan, Stella and Aschard, Hugues and Bartz, Traci M and Dorajoo, Rajkumar and Liu, Yongmei and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert Vernon and Tajuddin, Salman M and Tayo, Bamidele O and Warren, Helen R and Zhao, Wei and Zhou, Yanhua and Matoba, Nana and Sofer, Tamar and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Giulianini, Franco and Goel, Anuj and Harris, Sarah E and Hartwig, Fernando Pires and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and K{\"a}h{\"o}nen, Mika and Kasturiratne, Anuradhani and Kuhnel, Brigitte and Leander, Karin and Lee, Wen-Jane and Lin, Keng-Hung and {\textquoteright}an Luan, Jian and McKenzie, Colin A and Meian, He and Nelson, Christopher P and Rauramaa, Rainer and Schupf, Nicole and Scott, Robert A and Sheu, Wayne H H and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Wang, Heming and Wang, Yajuan and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Alfred, Tamuno and Amin, Najaf and Arking, Dan and Aung, Tin and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Braund, Peter S and Brody, Jennifer A and Broeckel, Ulrich and Cabrera, Claudia P and Cade, Brian and Caizheng, Yu and Campbell, Archie and Canouil, Micka{\"e}l and Chakravarti, Aravinda and Chauhan, Ganesh and Christensen, Kaare and Cocca, Massimiliano and Collins, Francis S and Connell, John M and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Debette, Stephanie and D{\"o}rr, Marcus and Duan, Qing and Eaton, Charles B and Ehret, Georg and Evangelou, Evangelos and Faul, Jessica D and Fisher, Virginia A and Forouhi, Nita G and Franco, Oscar H and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Graff, Misa and Gu, C Charles and Gu, Dongfeng and Gupta, Preeti and Hagenaars, Saskia P and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hofman, Albert and Howard, Barbara V and Hunt, Steven and Irvin, Marguerite R and Jia, Yucheng and Joehanes, Roby and Justice, Anne E and Katsuya, Tomohiro and Kaufman, Joel and Kerrison, Nicola D and Khor, Chiea Chuen and Koh, Woon-Puay and Koistinen, Heikki A and Komulainen, Pirjo and Kooperberg, Charles and Krieger, Jose E and Kubo, Michiaki and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Lim, Sing Hui and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Jingmin and Liu, Kiang and Liu, Yeheng and Loh, Marie and Lohman, Kurt K and Long, Jirong and Louie, Tin and M{\"a}gi, Reedik and Mahajan, Anubha and Meitinger, Thomas and Metspalu, Andres and Milani, Lili and Momozawa, Yukihide and Morris, Andrew P and Mosley, Thomas H and Munson, Peter and Murray, Alison D and Nalls, Mike A and Nasri, Ubaydah and Norris, Jill M and North, Kari and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmas, Walter R and Palmer, Nicholette D and Pankow, James S and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Raitakari, Olli T and Renstrom, Frida and Rice, Treva K and Ridker, Paul M and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Sabanayagam, Charumathi and Salako, Babatunde L and Sandow, Kevin and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Seshadri, Sudha and Sever, Peter and Sitlani, Colleen M and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Waldenberger, Melanie and Wang, Lihua and Wang, Ya X and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Yuan, Jian-Min and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Chen, Yii-Der Ida and de Faire, Ulf and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Forrester, Terrence and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo Lessa and Hung, Yi-Jen and Jonas, Jost B and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Lehtim{\"a}ki, Terho and Liang, Kae-Woei and Magnusson, Patrik K E and Newman, Anne B and Oldehinkel, Albertine J and Pereira, Alexandre C and Redline, Susan and Rettig, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zheng, Wei and Kamatani, Yoichiro and Laurie, Cathy C and Bouchard, Claude and Cooper, Richard S and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Kritchevsky, Stephen B and Levy, Daniel and O{\textquoteright}Connell, Jeff R and Psaty, Bruce M and van Dam, Rob M and Sims, Mario and Arnett, Donna K and Mook-Kanamori, Dennis O and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and Fornage, Myriam and Rotimi, Charles N and Province, Michael A and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Loos, Ruth J F and Reiner, Alex P and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Caulfield, Mark J and Elliott, Paul and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Cupples, L Adrienne and Rao, Dabeeru C and Chasman, Daniel I} } @article {7680, title = {Long-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study).}, journal = {Circ Heart Fail}, volume = {11}, year = {2018}, month = {2018 Mar}, pages = {e004476}, abstract = {

BACKGROUND: Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction.

METHODS AND RESULTS: Participants were 4864 men and women aged >=65 years without a history of HF and free of clinical stroke in the CHS (Cardiovascular Health Study)-a community-based prospective cohort study in the United States, with cognition assessed annually from 1989/1990 through 1998/1999. We identified 496 participants with incident HF by review of hospital discharge summaries and Medicare claims data, with adjudication according to standard criteria. Global cognitive ability was measured by the Modified Mini-Mental State Examination. In adjusted models, 5-year decline in model-predicted mean Modified Mini-Mental State Examination score was 10.2 points (95\% confidence interval, 8.6-11.8) after incident HF diagnosed at 80 years of age, compared with a mean 5-year decline of 5.8 points (95\% confidence interval, 5.3-6.2) from 80 to 85 years of age without HF. The association was stronger at older ages than at younger ages, did not vary significantly in the presence versus absence of atrial fibrillation (=0.084), and did not vary significantly by reduced versus preserved ejection fraction (=0.734).

CONCLUSIONS: Decline in global cognitive ability tends to be faster after HF diagnosis than without HF. Clinical and public health implications of this finding warrant further attention.

}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.117.004476}, author = {Hammond, Christa A and Blades, Natalie J and Chaudhry, Sarwat I and Dodson, John A and Longstreth, W T and Heckbert, Susan R and Psaty, Bruce M and Arnold, Alice M and Dublin, Sascha and Sitlani, Colleen M and Gardin, Julius M and Thielke, Stephen M and Nanna, Michael G and Gottesman, Rebecca F and Newman, Anne B and Thacker, Evan L} } @article {7795, title = {Meta-analysis of exome array data identifies six novel genetic loci for lung function.}, journal = {Wellcome Open Res}, volume = {3}, year = {2018}, month = {2018}, pages = {4}, abstract = {

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2{\textperiodcentered}8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

}, issn = {2398-502X}, doi = {10.12688/wellcomeopenres.12583.3}, author = {Jackson, Victoria E and Latourelle, Jeanne C and Wain, Louise V and Smith, Albert V and Grove, Megan L and Bartz, Traci M and Obeidat, Ma{\textquoteright}en and Province, Michael A and Gao, Wei and Qaiser, Beenish and Porteous, David J and Cassano, Patricia A and Ahluwalia, Tarunveer S and Grarup, Niels and Li, Jin and Altmaier, Elisabeth and Marten, Jonathan and Harris, Sarah E and Manichaikul, Ani and Pottinger, Tess D and Li-Gao, Ruifang and Lind-Thomsen, Allan and Mahajan, Anubha and Lahousse, Lies and Imboden, Medea and Teumer, Alexander and Prins, Bram and Lyytik{\"a}inen, Leo-Pekka and Eiriksdottir, Gudny and Franceschini, Nora and Sitlani, Colleen M and Brody, Jennifer A and Boss{\'e}, Yohan and Timens, Wim and Kraja, Aldi and Loukola, Anu and Tang, Wenbo and Liu, Yongmei and Bork-Jensen, Jette and Justesen, Johanne M and Linneberg, Allan and Lange, Leslie A and Rawal, Rajesh and Karrasch, Stefan and Huffman, Jennifer E and Smith, Blair H and Davies, Gail and Burkart, Kristin M and Mychaleckyj, Josyf C and Bonten, Tobias N and Enroth, Stefan and Lind, Lars and Brusselle, Guy G and Kumar, Ashish and Stubbe, Beate and K{\"a}h{\"o}nen, Mika and Wyss, Annah B and Psaty, Bruce M and Heckbert, Susan R and Hao, Ke and Rantanen, Taina and Kritchevsky, Stephen B and Lohman, Kurt and Skaaby, Tea and Pisinger, Charlotta and Hansen, Torben and Schulz, Holger and Polasek, Ozren and Campbell, Archie and Starr, John M and Rich, Stephen S and Mook-Kanamori, Dennis O and Johansson, Asa and Ingelsson, Erik and Uitterlinden, Andr{\'e} G and Weiss, Stefan and Raitakari, Olli T and Gudnason, Vilmundur and North, Kari E and Gharib, Sina A and Sin, Don D and Taylor, Kent D and O{\textquoteright}Connor, George T and Kaprio, Jaakko and Harris, Tamara B and Pederson, Oluf and Vestergaard, Henrik and Wilson, James G and Strauch, Konstantin and Hayward, Caroline and Kerr, Shona and Deary, Ian J and Barr, R Graham and de Mutsert, Ren{\'e}e and Gyllensten, Ulf and Morris, Andrew P and Ikram, M Arfan and Probst-Hensch, Nicole and Gl{\"a}ser, Sven and Zeggini, Eleftheria and Lehtim{\"a}ki, Terho and Strachan, David P and Dupuis, Jos{\'e}e and Morrison, Alanna C and Hall, Ian P and Tobin, Martin D and London, Stephanie J} } @article {7819, title = {Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jul 30}, pages = {2976}, abstract = {

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-05369-0}, author = {Wyss, Annah B and Sofer, Tamar and Lee, Mi Kyeong and Terzikhan, Natalie and Nguyen, Jennifer N and Lahousse, Lies and Latourelle, Jeanne C and Smith, Albert Vernon and Bartz, Traci M and Feitosa, Mary F and Gao, Wei and Ahluwalia, Tarunveer S and Tang, Wenbo and Oldmeadow, Christopher and Duan, Qing and de Jong, Kim and Wojczynski, Mary K and Wang, Xin-Qun and Noordam, Raymond and Hartwig, Fernando Pires and Jackson, Victoria E and Wang, Tianyuan and Obeidat, Ma{\textquoteright}en and Hobbs, Brian D and Huan, Tianxiao and Gui, Hongsheng and Parker, Margaret M and Hu, Donglei and Mogil, Lauren S and Kichaev, Gleb and Jin, Jianping and Graff, Mariaelisa and Harris, Tamara B and Kalhan, Ravi and Heckbert, Susan R and Paternoster, Lavinia and Burkart, Kristin M and Liu, Yongmei and Holliday, Elizabeth G and Wilson, James G and Vonk, Judith M and Sanders, Jason L and Barr, R Graham and de Mutsert, Ren{\'e}e and Menezes, Ana Maria Baptista and Adams, Hieab H H and van den Berge, Maarten and Joehanes, Roby and Levin, Albert M and Liberto, Jennifer and Launer, Lenore J and Morrison, Alanna C and Sitlani, Colleen M and Celed{\'o}n, Juan C and Kritchevsky, Stephen B and Scott, Rodney J and Christensen, Kaare and Rotter, Jerome I and Bonten, Tobias N and Wehrmeister, Fernando C{\'e}sar and Boss{\'e}, Yohan and Xiao, Shujie and Oh, Sam and Franceschini, Nora and Brody, Jennifer A and Kaplan, Robert C and Lohman, Kurt and McEvoy, Mark and Province, Michael A and Rosendaal, Frits R and Taylor, Kent D and Nickle, David C and Williams, L Keoki and Burchard, Esteban G and Wheeler, Heather E and Sin, Don D and Gudnason, Vilmundur and North, Kari E and Fornage, Myriam and Psaty, Bruce M and Myers, Richard H and O{\textquoteright}Connor, George and Hansen, Torben and Laurie, Cathy C and Cassano, Patricia A and Sung, Joohon and Kim, Woo Jin and Attia, John R and Lange, Leslie and Boezen, H Marike and Thyagarajan, Bharat and Rich, Stephen S and Mook-Kanamori, Dennis O and Horta, Bernardo Lessa and Uitterlinden, Andr{\'e} G and Im, Hae Kyung and Cho, Michael H and Brusselle, Guy G and Gharib, Sina A and Dupuis, Jos{\'e}e and Manichaikul, Ani and London, Stephanie J} } @article {7792, title = {Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0198166}, abstract = {

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0198166}, author = {Feitosa, Mary F and Kraja, Aldi T and Chasman, Daniel I and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K and Li, Changwei and Bentley, Amy R and Brown, Michael R and Schwander, Karen and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Wojczynski, Mary K and Alver, Maris and Boissel, Mathilde and Cai, Qiuyin and Campbell, Archie and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and K{\"a}h{\"o}nen, Mika and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Luan, Jian{\textquoteright}an and Matoba, Nana and Nolte, Ilja M and Padmanabhan, Sandosh and Riaz, Muhammad and Rueedi, Rico and Robino, Antonietta and Said, M Abdullah and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Vitart, Veronique and Wang, Yajuan and Ware, Erin B and Warren, Helen R and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Aung, Tin and Boerwinkle, Eric and Borecki, Ingrid and Broeckel, Ulrich and Brown, Morris and Brumat, Marco and Burke, Gregory L and Canouil, Micka{\"e}l and Chakravarti, Aravinda and Charumathi, Sabanayagam and Ida Chen, Yii-Der and Connell, John M and Correa, Adolfo and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Deng, Xuan and Ding, Jingzhong and Duan, Qing and Eaton, Charles B and Ehret, Georg and Eppinga, Ruben N and Evangelou, Evangelos and Faul, Jessica D and Felix, Stephan B and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gigante, Bruna and Gu, C Charles and Gu, Dongfeng and Hagenaars, Saskia P and Hallmans, G{\"o}ran and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Howard, Barbara V and Ikram, M Arfan and John, Ulrich and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Krieger, Jose E and Kritchevsky, Stephen B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Lin, Shiow and Liu, Jianjun and Liu, Jingmin and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Nalls, Mike A and Nelson, Christopher P and Sotoodehnia, Nona and Norris, Jill M and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Perls, Thomas and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Roll, Kathryn and Rose, Lynda M and Rosendaal, Frits R and Rotter, Jerome I and Schmidt, Carsten O and Schreiner, Pamela J and Schupf, Nicole and Scott, William R and Sever, Peter S and Shi, Yuan and Sidney, Stephen and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Stringham, Heather M and Tan, Nicholas Y Q and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Vollenweider, Peter and Waldenberger, Melanie and Wang, Lihua and Wang, Ya Xing and Wei, Wen Bin and Williams, Christine and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Kutalik, Zolt{\'a}n and Laakso, Markku and Laurie, Cathy C and Leander, Karin and Lehtim{\"a}ki, Terho and Study, Lifelines Cohort and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Polasek, Ozren and Porteous, David J and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zheng, Wei and Bouchard, Claude and Christensen, Kaare and Evans, Michele K and Gudnason, Vilmundur and Horta, Bernardo L and Kardia, Sharon L R and Liu, Yongmei and Pereira, Alexandre C and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Gauderman, W James and Zhu, Xiaofeng and Mook-Kanamori, Dennis O and Fornage, Myriam and Rotimi, Charles N and Cupples, L Adrienne and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Kooperberg, Charles and Palmas, Walter and Rice, Kenneth and Morrison, Alanna C and Elliott, Paul and Caulfield, Mark J and Munroe, Patricia B and Rao, Dabeeru C and Province, Michael A and Levy, Daniel} } @article {9372, title = {Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.}, journal = {Am J Hypertens}, volume = {32}, year = {2019}, month = {2019 Nov 15}, pages = {1146-1153}, abstract = {

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP >= 140 mm Hg and/or diastolic BP >= 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 {\texttimes} 10-8) and in the race-combined analysis (P = 1.5 {\texttimes} 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95\% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

}, keywords = {Aged, Antihypertensive Agents, Black or African American, Blood Pressure, Case-Control Studies, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, DNA-Binding Proteins, Drug Resistance, Dystrophin-Associated Proteins, Europe, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Myosin Heavy Chains, Myosin Type V, Neuropeptides, Pharmacogenetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Transcription Factors, United States, White People}, issn = {1941-7225}, doi = {10.1093/ajh/hpz150}, author = {Irvin, Marguerite R and Sitlani, Colleen M and Floyd, James S and Psaty, Bruce M and Bis, Joshua C and Wiggins, Kerri L and Whitsel, Eric A and St{\"u}rmer, Til and Stewart, James and Raffield, Laura and Sun, Fangui and Liu, Ching-Ti and Xu, Hanfei and Cupples, Adrienne L and Tanner, Rikki M and Rossing, Peter and Smith, Albert and Zilh{\~a}o, Nuno R and Launer, Lenore J and Noordam, Raymond and Rotter, Jerome I and Yao, Jie and Li, Xiaohui and Guo, Xiuqing and Limdi, Nita and Sundaresan, Aishwarya and Lange, Leslie and Correa, Adolfo and Stott, David J and Ford, Ian and Jukema, J Wouter and Gudnason, Vilmundur and Mook-Kanamori, Dennis O and Trompet, Stella and Palmas, Walter and Warren, Helen R and Hellwege, Jacklyn N and Giri, Ayush and O{\textquoteright}donnell, Christopher and Hung, Adriana M and Edwards, Todd L and Ahluwalia, Tarunveer S and Arnett, Donna K and Avery, Christy L} } @article {8511, title = {Genome-wide meta-analysis of SNP and antihypertensive medication interactions on left ventricular traits in African Americans.}, journal = {Mol Genet Genomic Med}, volume = {7}, year = {2019}, month = {2019 10}, pages = {e00788}, abstract = {

BACKGROUND: Left ventricular (LV) hypertrophy affects up to 43\% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography.

METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5~million SNP-by-drug interaction estimates.

RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p~=~0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p~=~4.7~{\texttimes}~10 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population.

CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.

}, keywords = {African Americans, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Calcium Channel Blockers, Humans, Observational Studies as Topic, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Sodium Chloride Symporter Inhibitors, Ventricular Dysfunction, Left}, issn = {2324-9269}, doi = {10.1002/mgg3.788}, author = {Do, Anh N and Zhao, Wei and Baldridge, Abigail S and Raffield, Laura M and Wiggins, Kerri L and Shah, Sanjiv J and Aslibekyan, Stella and Tiwari, Hemant K and Limdi, Nita and Zhi, Degui and Sitlani, Colleen M and Taylor, Kent D and Psaty, Bruce M and Sotoodehnia, Nona and Brody, Jennifer A and Rasmussen-Torvik, Laura J and Lloyd-Jones, Donald and Lange, Leslie A and Wilson, James G and Smith, Jennifer A and Kardia, Sharon L R and Mosley, Thomas H and Vasan, Ramachandran S and Arnett, Donna K and Irvin, Marguerite R} } @article {8202, title = {Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Nov 12}, pages = {5121}, abstract = {

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.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12958-0}, author = {Noordam, Raymond and Bos, Maxime M and Wang, Heming and Winkler, Thomas W and Bentley, Amy R and Kilpel{\"a}inen, Tuomas O and de Vries, Paul S and Sung, Yun Ju and Schwander, Karen and Cade, Brian E and Manning, Alisa and Aschard, Hugues and Brown, Michael R and Chen, Han and Franceschini, Nora and Musani, Solomon K and Richard, Melissa and Vojinovic, Dina and Aslibekyan, Stella and Bartz, Traci M and de Las Fuentes, Lisa and Feitosa, Mary and Horimoto, Andrea R and Ilkov, Marjan and Kho, Minjung and Kraja, Aldi and Li, Changwei and Lim, Elise and Liu, Yongmei and Mook-Kanamori, Dennis O and Rankinen, Tuomo and Tajuddin, Salman M and van der Spek, Ashley and Wang, Zhe and Marten, Jonathan and Laville, Vincent and Alver, Maris and Evangelou, Evangelos and Graff, Maria E and He, Meian and Kuhnel, Brigitte and Lyytik{\"a}inen, Leo-Pekka and Marques-Vidal, Pedro and Nolte, Ilja M and Palmer, Nicholette D and Rauramaa, Rainer and Shu, Xiao-Ou and Snieder, Harold and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Adolfo, Correa and Ballantyne, Christie and Bielak, Larry and Biermasz, Nienke R and Boerwinkle, Eric and Dimou, Niki and Eiriksdottir, Gudny and Gao, Chuan and Gharib, Sina A and Gottlieb, Daniel J and Haba-Rubio, Jos{\'e} and Harris, Tamara B and Heikkinen, Sami and Heinzer, Raphael and Hixson, James E and Homuth, Georg and Ikram, M Arfan and Komulainen, Pirjo and Krieger, Jose E and Lee, Jiwon and Liu, Jingmin and Lohman, Kurt K and Luik, Annemarie I and M{\"a}gi, Reedik and Martin, Lisa W and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Nalls, Mike A and O{\textquoteright}Connell, Jeff and Peters, Annette and Peyser, Patricia and Raitakari, Olli T and Reiner, Alex P and Rensen, Patrick C N and Rice, Treva K and Rich, Stephen S and Roenneberg, Till and Rotter, Jerome I and Schreiner, Pamela J and Shikany, James and Sidney, Stephen S and Sims, Mario and Sitlani, Colleen M and Sofer, Tamar and Strauch, Konstantin and Swertz, Morris A and Taylor, Kent D and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Waldenberger, Melanie and Wallance, Robert B and van Dijk, Ko Willems and Yu, Caizheng and Zonderman, Alan B and Becker, Diane M and Elliott, Paul and Esko, T{\~o}nu and Gieger, Christian and Grabe, Hans J and Lakka, Timo A and Lehtim{\"a}ki, Terho and North, Kari E and Penninx, Brenda W J H and Vollenweider, Peter and Wagenknecht, Lynne E and Wu, Tangchun and Xiang, Yong-Bing and Zheng, Wei and Arnett, Donna K and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon and Kelly, Tanika N and Kritchevsky, Stephen B and Loos, Ruth J F and Pereira, Alexandre C and Province, Mike and Psaty, Bruce M and Rotimi, Charles and Zhu, Xiaofeng and Amin, Najaf and Cupples, L Adrienne and Fornage, Myriam and Fox, Ervin F and Guo, Xiuqing and Gauderman, W James and Rice, Kenneth and Kooperberg, Charles and Munroe, Patricia B and Liu, Ching-Ti and Morrison, Alanna C and Rao, Dabeeru C and van Heemst, Diana and Redline, Susan} } @article {8102, title = {Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.}, journal = {PLoS One}, volume = {14}, year = {2019}, month = {2019}, pages = {e0218115}, abstract = {

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.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0218115}, author = {Floyd, James S and Bloch, Katarzyna M and Brody, Jennifer A and Maroteau, Cyrielle and Siddiqui, Moneeza K and Gregory, Richard and Carr, Daniel F and Molokhia, Mariam and Liu, Xiaoming and Bis, Joshua C and Ahmed, Ammar and Liu, Xuan and Hallberg, P{\"a}r and Yue, Qun-Ying and Magnusson, Patrik K E and Brisson, Diane and Wiggins, Kerri L and Morrison, Alanna C and Khoury, Etienne and McKeigue, Paul and Stricker, Bruno H and Lapeyre-Mestre, Maryse and Heckbert, Susan R and Gallagher, Arlene M and Chinoy, Hector and Gibbs, Richard A and Bondon-Guitton, Emmanuelle and Tracy, Russell and Boerwinkle, Eric and Gaudet, Daniel and Conforti, Anita and van Staa, Tjeerd and Sitlani, Colleen M and Rice, Kenneth M and Maitland-van der Zee, Anke-Hilse and Wadelius, Mia and Morris, Andrew P and Pirmohamed, Munir and Palmer, Colin A N and Psaty, Bruce M and Alfirevic, Ana} } @article {8632, title = {Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0242062}, abstract = {

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}, issn = {1932-6203}, doi = {10.1371/journal.pone.0242062}, author = {Rohmann, Jessica L and Longstreth, W T and Cushman, Mary and Fitzpatrick, Annette L and Heckbert, Susan R and Rice, Kenneth and Rosendaal, Frits R and Sitlani, Colleen M and Psaty, Bruce M and Siegerink, Bob} } @article {8381, title = {Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.}, journal = {Mol Psychiatry}, year = {2020}, month = {2020 May 05}, abstract = {

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 {\texttimes} 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.

}, issn = {1476-5578}, doi = {10.1038/s41380-020-0719-3}, author = {de Las Fuentes, Lisa and Sung, Yun Ju and Noordam, Raymond and Winkler, Thomas and Feitosa, Mary F and Schwander, Karen and Bentley, Amy R and Brown, Michael R and Guo, Xiuqing and Manning, Alisa and Chasman, Daniel I and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Cheng, Ching-Yu and Dorajoo, Rajkumar and Hartwig, Fernando P and Horimoto, A R V R and Li, Changwei and Li-Gao, Ruifang and Liu, Yongmei and Marten, Jonathan and Musani, Solomon K and Ntalla, Ioanna and Rankinen, Tuomo and Richard, Melissa and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Tayo, Bamidele O and Vojinovic, Dina and Warren, Helen R and Xuan, Deng and Alver, Maris and Boissel, Mathilde and Chai, Jin-Fang and Chen, Xu and Christensen, Kaare and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Girotto, Giorgia and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Rueedi, Rico and Shu, Xiao-Ou and Snieder, Harold and Sofer, Tamar and Takeuchi, Fumihiko and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Yanek, Lisa R and Amin, Najaf and Arking, Dan E and Arnett, Donna K and Bergmann, Sven and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Brumat, Marco and Burke, Gregory and Cabrera, Claudia P and Canouil, Micka{\"e}l and Chee, Miao Li and Chen, Yii-Der Ida and Cocca, Massimiliano and Connell, John and de Silva, H Janaka and de Vries, Paul S and Eiriksdottir, Gudny and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Fox, Ervin F and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven and Ikram, M Arfan and Irvin, Marguerite R and K{\"a}h{\"o}nen, Mika and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Kraja, Aldi T and Krieger, J E and Langefeld, Carl D and Li, Yize and Liang, Jingjing and Liewald, David C M and Liu, Ching-Ti and Liu, Jianjun and Lohman, Kurt K and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mook-Kanamori, Dennis O and Nalls, Mike A and Nelson, Christopher P and Norris, Jill M and O{\textquoteright}Connell, Jeff and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmer, Nicholette D and Pedersen, Nancy L and Perls, Thomas and Peters, Annette and Petersmann, Astrid and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Raffel, Leslie J and Rice, Treva K and Rotter, Jerome I and Rudan, Igor and Rueda-Ochoa, Oscar-Leonel and Sabanayagam, Charumathi and Salako, Babatunde L and Schreiner, Pamela J and Shikany, James M and Sidney, Stephen S and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Swertz, Morris A and Teumer, Alexander and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Ende, M Yldau and Waldenberger, Melanie and Wang, Lihua and Wang, Ya-Xing and Wei, Wen-Bin and Weir, David R and Wen, Wanqing and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Bowden, Donald W and Deary, Ian J and D{\"o}rr, Marcus and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kammerer, Candace M and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Marques-Vidal, Pedro and Penninx, Brenda W J H and Samani, Nilesh J and van der Harst, Pim and Wagenknecht, Lynne E and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Cooper, Richard S and Correa, Adolfo and Evans, Michele K and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Kritchevsky, Stephen B and Levy, Daniel and Palmas, Walter R and Pereira, A C and Province, Michael M and Psaty, Bruce M and Ridker, Paul M and Rotimi, Charles N and Tai, E Shyong and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Rice, Kenneth and Gauderman, W James and Morrison, Alanna C and North, Kari E and Kardia, Sharon L R and Caulfield, Mark J and Elliott, Paul and Munroe, Patricia B and Franks, Paul W and Rao, Dabeeru C and Fornage, Myriam} } @article {8491, title = {Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.}, journal = {Diabetes}, year = {2020}, month = {2020 Sep 11}, abstract = {

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.

}, issn = {1939-327X}, doi = {10.2337/db20-0070}, author = {Yaghootkar, Hanieh and Zhang, Yiying and Spracklen, Cassandra N and Karaderi, Tugce and Huang, Lam Opal and Bradfield, Jonathan and Schurmann, Claudia and Fine, Rebecca S and Preuss, Michael H and Kutalik, Zolt{\'a}n and Wittemans, Laura Bl and Lu, Yingchang and Metz, Sophia and Willems, Sara M and Li-Gao, Ruifang and Grarup, Niels and Wang, Shuai and Molnos, Sophie and Sandoval-Z{\'a}rate, Am{\'e}rica A and Nalls, Mike A and Lange, Leslie A and Haesser, Jeffrey and Guo, Xiuqing and Lyytik{\"a}inen, Leo-Pekka and Feitosa, Mary F and Sitlani, Colleen M and Venturini, Cristina and Mahajan, Anubha and Kacprowski, Tim and Wang, Carol A and Chasman, Daniel I and Amin, Najaf and Broer, Linda and Robertson, Neil and Young, Kristin L and Allison, Matthew and Auer, Paul L and Bl{\"u}her, Matthias and Borja, Judith B and Bork-Jensen, Jette and Carrasquilla, Germ{\'a}n D and Christofidou, Paraskevi and Demirkan, Ayse and Doege, Claudia A and Garcia, Melissa E and Graff, Mariaelisa and Guo, Kaiying and Hakonarson, Hakon and Hong, Jaeyoung and Ida Chen, Yii-Der and Jackson, Rebecca and Jakupovi{\'c}, Hermina and Jousilahti, Pekka and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Kizer, Jorge R and Kriebel, Jennifer and LeDuc, Charles A and Li, Jin and Lind, Lars and Luan, Jian{\textquoteright}an and Mackey, David and Mangino, Massimo and M{\"a}nnist{\"o}, Satu and Martin Carli, Jayne F and Medina-G{\'o}mez, Carolina and Mook-Kanamori, Dennis O and Morris, Andrew P and de Mutsert, Ren{\'e}e and Nauck, Matthias and Nedeljkovic, Ivana and Pennell, Craig E and Pradhan, Arund D and Psaty, Bruce M and Raitakari, Olli T and Scott, Robert A and Skaaby, Tea and Strauch, Konstantin and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Wu, Ying and Yao, Jie and Walker, Mark and North, Kari E and Kovacs, Peter and Ikram, M Arfan and van Duijn, Cornelia M and Ridker, Paul M and Lye, Stephen and Homuth, Georg and Ingelsson, Erik and Spector, Tim D and McKnight, Barbara and Province, Michael A and Lehtim{\"a}ki, Terho and Adair, Linda S and Rotter, Jerome I and Reiner, Alexander P and Wilson, James G and Harris, Tamara B and Ripatti, Samuli and Grallert, Harald and Meigs, James B and Salomaa, Veikko and Hansen, Torben and Willems van Dijk, Ko and Wareham, Nicholas J and Grant, Struan Fa and Langenberg, Claudia and Frayling, Timothy M and Lindgren, Cecilia M and Mohlke, Karen L and Leibel, Rudolph L and Loos, Ruth Jf and Kilpel{\"a}inen, Tuomas O} } @article {8405, title = {Incorporating sampling weights into robust estimation of Cox proportional hazards regression model, with illustration in the Multi-Ethnic Study of Atherosclerosis.}, journal = {BMC Med Res Methodol}, volume = {20}, year = {2020}, month = {2020 03 14}, pages = {62}, abstract = {

BACKGROUND: Cox proportional hazards regression models are used to evaluate associations between exposures of interest and time-to-event outcomes in observational data. When exposures are measured on only a sample of participants, as they are in a case-cohort design, the sampling weights must be incorporated into the regression model to obtain unbiased estimating equations.

METHODS: Robust Cox methods have been developed to better estimate associations when there are influential outliers in the exposure of interest, but these robust methods do not incorporate sampling weights. In this paper, we extend these robust methods, which already incorporate influence weights, so that they also accommodate sampling weights.

RESULTS: Simulations illustrate that in the presence of influential outliers, the association estimate from the weighted robust method is closer to the true value than the estimate from traditional weighted Cox regression. As expected, in the absence of outliers, the use of robust methods yields a small loss of efficiency. Using data from a case-cohort study that is nested within the Multi-Ethnic Study of Atherosclerosis (MESA) longitudinal cohort study, we illustrate differences between traditional and robust weighted Cox association estimates for the relationships between immune cell traits and risk of stroke.

CONCLUSIONS: Robust weighted Cox regression methods are a new tool to analyze time-to-event data with sampling, e.g. case-cohort data, when exposures of interest contain outliers.

}, issn = {1471-2288}, doi = {10.1186/s12874-020-00945-9}, author = {Sitlani, Colleen M and Lumley, Thomas and McKnight, Barbara and Rice, Kenneth M and Olson, Nels C and Doyle, Margaret F and Huber, Sally A and Tracy, Russell P and Psaty, Bruce M and C Delaney, Joseph A} } @article {8403, title = {Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts.}, journal = {Atherosclerosis}, volume = {300}, year = {2020}, month = {2020 05}, pages = {47-53}, abstract = {

BACKGROUND AND AIMS: Cell-mediated immunity is implicated in atherosclerosis. We evaluated whether innate and adaptive immune cell subsets in peripheral blood are risk factors for coronary heart disease.

METHODS: A nested case-cohort study (n~=~2155) was performed within the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Cases of incident myocardial infarction (MI) and incident angina (n~=~880 total cases) were compared with a cohort random sample (n~=~1275). Immune cell phenotypes (n~=~34, including CD14 monocytes, natural killer cells, γδ T cells, CD4, CD8 and CD19 lymphocyte subsets) were measured from cryopreserved cells by flow cytometry. Cox proportional hazards models with adjustment for cardiovascular disease risk factors were used to evaluate associations of cell phenotypes with incident MI and a composite phenotype of incident MI or incident angina (MI-angina) over a median 9.3 years of follow-up. Th1, Th2, Th17, T regulatory (CD4CD25CD127), naive (CD4CD45RA), memory (CD4CD45RO), and CD4CD28 cells were specified as primary hypotheses. In secondary analyses, 27 additional cell phenotypes were investigated.

RESULTS: After correction for multiple testing, there were no statistically significant associations of CD4 naive, memory, CD28, or T helper cell subsets with MI or MI-angina in MESA, CHS, or combined-cohort meta analyses. Null associations were also observed for monocyte subsets, natural killer cells, γδ T cells, CD19 B cell and differentiated CD4 and CD8 cell subsets.

CONCLUSIONS: The proportions of peripheral blood monocyte and lymphocyte subsets are not strongly related to the future occurrence of MI or angina in adults free of autoimmune disease.

}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2020.03.011}, author = {Olson, Nels C and Sitlani, Colleen M and Doyle, Margaret F and Huber, Sally A and Landay, Alan L and Tracy, Russell P and Psaty, Bruce M and Delaney, Joseph A} } @article {8284, title = {Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {9}, year = {2020}, month = {2020 Feb 18}, pages = {e012853}, abstract = {

Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76~years; 40\% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7~years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95\% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95\% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95\% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95\% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.012853}, author = {Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and Sitlani, Colleen M and McKnight, Barbara and King, Irena B and Siscovick, David S and Psaty, Bruce M and Heckbert, Susan R and Mozaffarian, Dariush and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {8407, title = {Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 Aug}, pages = {e002772}, abstract = {

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{\texttimes}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.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002772}, author = {Wang, Zhe and Chen, Han and Bartz, Traci M and Bielak, Lawrence F and Chasman, Daniel I and Feitosa, Mary F and Franceschini, Nora and Guo, Xiuqing and Lim, Elise and Noordam, Raymond and Richard, Melissa A and Wang, Heming and Cade, Brian and Cupples, L Adrienne and de Vries, Paul S and Giulanini, Franco and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Reiner, Alex P and Rich, Stephen S and Schreiner, Pamela J and Sidney, Stephen and Sitlani, Colleen M and Smith, Jennifer A and Willems van Dijk, Ko and Yao, Jie and Zhao, Wei and Fornage, Myriam and Kardia, Sharon L R and Kooperberg, Charles and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Psaty, Bruce M and Redline, Susan and Ridker, Paul M and Rotter, Jerome I and Boerwinkle, Eric and Morrison, Alanna C} } @article {8446, title = {Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 Aug}, pages = {e002766}, abstract = {

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{\texttimes}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{\texttimes}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{\texttimes}10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5{\texttimes}10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1{\texttimes}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.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002766}, author = {Ma, Jiantao and Rebholz, Casey M and Braun, Kim V E and Reynolds, Lindsay M and Aslibekyan, Stella and Xia, Rui and Biligowda, Niranjan G and Huan, Tianxiao and Liu, Chunyu and Mendelson, Michael M and Joehanes, Roby and Hu, Emily A and Vitolins, Mara Z and Wood, Alexis C and Lohman, Kurt and Ochoa-Rosales, Carolina and van Meurs, Joyce and Uitterlinden, Andre and Liu, Yongmei and Elhadad, Mohamed A and Heier, Margit and Waldenberger, Melanie and Peters, Annette and Colicino, Elena and Whitsel, Eric A and Baldassari, Antoine and Gharib, Sina A and Sotoodehnia, Nona and Brody, Jennifer A and Sitlani, Colleen M and Tanaka, Toshiko and Hill, W David and Corley, Janie and Deary, Ian J and Zhang, Yan and Sch{\"o}ttker, Ben and Brenner, Hermann and Walker, Maura E and Ye, Shumao and Nguyen, Steve and Pankow, Jim and Demerath, Ellen W and Zheng, Yinan and Hou, Lifang and Liang, Liming and Lichtenstein, Alice H and Hu, Frank B and Fornage, Myriam and Voortman, Trudy and Levy, Daniel} } @article {8910, title = {Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study.}, journal = {Clin Chem}, volume = {67}, year = {2021}, month = {2021 Nov 26}, pages = {1650-1659}, abstract = {

BACKGROUND: Recent studies suggest that associations of ceramides (Cer) and sphingomyelins (SM) with health outcomes differ according to the fatty acid acylated to the sphingoid backbone. The purpose of this study was to assess associations of Cer and SM species with mortality.

METHODS: The study population included participants from the Cardiovascular Health Study (CHS), a community-based cohort of adults aged >=65 years who were followed from 1992-2015 (n = 4612). Associations of plasma Cer and SM species carrying long-chain (i.e., 16:0) and very-long-chain (i.e., 20:0, 22:0, 24:0) saturated fatty acids with mortality were assessed using Cox proportional hazards models.

RESULTS: During a median follow-up of 10.2 years, 4099 deaths occurred. High concentrations of Cer and SM carrying fatty acid 16:0 were each associated with an increased risk of mortality. Conversely, high concentrations of several ceramide and sphingomyelin species carrying longer fatty acids were each associated with a decreased risk of mortality. The hazard ratios for total mortality per 2-fold difference in each Cer and SM species were: 1.89 (95\% CI), 1.65-2.17 for Cer-16, 0.79 (95\% CI, 0.70-0.88) for Cer-22, 0.74 (95\% CI, 0.65-0.84) for Cer-24, 2.51 (95\% CI, 2.01-3.14) for SM-16, 0.68 (95\% CI, 0.58-0.79) for SM-20, 0.57 (95\% CI, 0.49-0.67) for SM-22, and 0.66 (0.57-0.75) for SM-24. We found no association of Cer-20 with risk of death.

CONCLUSIONS: Associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid. Future studies are needed to explore mechanisms underlying these relationships.

}, issn = {1530-8561}, doi = {10.1093/clinchem/hvab182}, author = {Fretts, Amanda M and Jensen, Paul N and Hoofnagle, Andrew N and McKnight, Barbara and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Psaty, Bruce M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9001, title = {Epigenetic Age and the Risk of Incident Atrial Fibrillation.}, journal = {Circulation}, volume = {144}, year = {2021}, month = {2021 12 14}, pages = {1899-1911}, abstract = {

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.

METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.

RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1\%; Black, 50.7\%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19\% (adjusted hazard ratio [HR], 1.19 [95\% CI, 1.09-1.31]; <0.01) and 15\% (adjusted HR, 1.15 [95\% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.

CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

}, keywords = {Aged, Aging, Atrial Fibrillation, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Follow-Up Studies, Humans, Incidence, Male, Mendelian Randomization Analysis, Middle Aged, Models, Cardiovascular, Models, Genetic}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.121.056456}, author = {Roberts, Jason D and Vittinghoff, Eric and Lu, Ake T and Alonso, Alvaro and Wang, Biqi and Sitlani, Colleen M and Mohammadi-Shemirani, Pedrum and Fornage, Myriam and Kornej, Jelena and Brody, Jennifer A and Arking, Dan E and Lin, Honghuang and Heckbert, Susan R and Prokic, Ivana and Ghanbari, Mohsen and Skanes, Allan C and Bartz, Traci M and Perez, Marco V and Taylor, Kent D and Lubitz, Steven A and Ellinor, Patrick T and Lunetta, Kathryn L and Pankow, James S and Par{\'e}, Guillaume and Sotoodehnia, Nona and Benjamin, Emelia J and Horvath, Steve and Marcus, Gregory M} } @article {8658, title = {Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA).}, journal = {BMC Cardiovasc Disord}, volume = {21}, year = {2021}, month = {2021 Jan 22}, pages = {45}, abstract = {

BACKGROUND: Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP).

METHODS: We assayed immune cells from cryopreserved samples collected at the baseline examination (2000-2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10~years. The analysis provides estimates of the association with blood pressure level.

RESULTS: The mean age of the MESA participants at baseline was 64 {\textpm} 10~years and 53\% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40~mmHg [95\% confidence interval (CI) 1.34-3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88~mmHg (95\% CI 0.82-2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14CD16) was associated with 2.01 mmHG (95\% CI 0.79-3.24) lower average systolic blood pressure. There were no associations of CD4 T helper cell subsets with average systolic blood pressure.

CONCLUSION: These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.

}, issn = {1471-2261}, doi = {10.1186/s12872-021-01857-2}, author = {Delaney, Joseph A C and Olson, Nels C and Sitlani, Colleen M and Fohner, Alison E and Huber, Sally A and Landay, Alan L and Heckbert, Susan R and Tracy, Russell P and Psaty, Bruce M and Feinstein, Matt and Doyle, Margaret F} } @article {8909, title = {Plasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes.}, journal = {J Lipid Res}, year = {2021}, month = {2021 Sep 20}, pages = {100119}, abstract = {

Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here we investigated associations of 15 ceramide and sphingomyelin species (i.e., all sphingolipids, measured with coefficient of variation less than 20\%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease (CVD) among elderly adults who were followed from 1989-2015. Diabetes incidence was defined as fasting glucose >=126 mg/dL or non-fasting glucose >=200 mg/dL; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of ceramide with acylated palmitic acid (Cer-16), stearic acid containing ceramide (Cer-18), arachidic acid containing ceramide (Cer-20), and behenic acid containing ceramide (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each ceramide species were: 1.21 (95\% CI 1.09-1.34) for Cer-16, 1.23 (95\% CI 1.10-1.37) for Cer-18, 1.14 (95\% CI 1.02-1.26) for Cer-20, and 1.18 (95\% CI 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.

}, issn = {1539-7262}, doi = {10.1016/j.jlr.2021.100119}, author = {Fretts, Amanda M and Jensen, Paul N and Hoofnagle, Andrew N and McKnight, Barbara and Howard, Barbara V and Umans, Jason and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Djouss{\'e}, Luc and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9175, title = {Association of immune cell subsets with incident heart failure in two population-based cohorts.}, journal = {ESC Heart Fail}, year = {2022}, month = {2022 Sep 12}, abstract = {

AIMS: Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)].

METHODS AND RESULTS: Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0~{\textpm}~10.4~years with 51\% women, and in the CHS cohort, it was 79.6~{\textpm}~4.4~years with 62\% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95\% CI 0.83-0.99), P~=~0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95\% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF.

CONCLUSIONS: We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.

}, issn = {2055-5822}, doi = {10.1002/ehf2.14140}, author = {Sinha, Arjun and Sitlani, Colleen M and Doyle, Margaret F and Fohner, Alison E and B{\r u}zkov{\'a}, Petra and Floyd, James S and Huber, Sally A and Olson, Nels C and Njoroge, Joyce N and Kizer, Jorge R and Delaney, Joseph A and Shah, Sanjiv S and Tracy, Russell P and Psaty, Bruce and Feinstein, Matthew} } @article {9091, title = {Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 05 02}, pages = {e2213242}, abstract = {

Importance: Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population.

Objective: To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US.

Design, Setting, and Participants: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021.

Exposures: Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry.

Main Outcomes and Measures: Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models.

Results: Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3\%) were male, 3184 (59.7\%) were female, 848 (15.9\%) were African American, 4450 (83.4\%) were White, and 35 (0.01\%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95\% CI, 1.17-1.44) for TMAO, 1.19 (95\% CI, 1.08-1.32) for choline, 1.26 (95\% CI, 1.15-1.40) for carnitine, and 1.26 (95\% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality.

Conclusions and Relevance: In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.

}, keywords = {Aged, Betaine, Cardiovascular Diseases, Carnitine, Choline, Cohort Studies, Female, Humans, Male, Methylamines, Prospective Studies}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.13242}, author = {Fretts, Amanda M and Hazen, Stanley L and Jensen, Paul and Budoff, Matthew and Sitlani, Colleen M and Wang, Meng and de Oliveira Otto, Marcia C and DiDonato, Joseph A and Lee, Yujin and Psaty, Bruce M and Siscovick, David S and Sotoodehnia, Nona and Tang, W H Wilson and Lai, Heidi and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {9452, title = {Genome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus.}, journal = {Circ Res}, volume = {131}, year = {2022}, month = {2022 Jul 22}, pages = {277-279}, keywords = {Cholesterol, HDL, Cholesterol, LDL, Diuretics, Genome-Wide Association Study, Sodium Chloride Symporter Inhibitors, Thiazides, Triglycerides}, issn = {1524-4571}, doi = {10.1161/CIRCRESAHA.122.321120}, author = {Downie, Carolina G and Highland, Heather M and Lee, Moa P and Raffield, Laura M and Preuss, Michael and Whitsel, Eric A and Psaty, Bruce M and Sitlani, Colleen M and Graff, Mariaelisa and Avery, Christy L} } @article {9247, title = {Immune cell subpopulations as risk factors for atrial fibrillation: The Cardiovascular Health Study and Multi-Ethnic Study of Atherosclerosis.}, journal = {Heart Rhythm}, year = {2022}, month = {2022 Oct 18}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2022.10.012}, author = {Floyd, James S and Sitlani, Colleen M and Doyle, Margaret F and Feinstein, Matthew J and Olson, Nels C and Heckbert, Susan R and Huber, Sally A and Tracy, Russell P and Psaty, Bruce M and Delaney, Joseph A C} } @article {9094, title = {Integrative analysis of clinical and epigenetic biomarkers of mortality.}, journal = {Aging Cell}, volume = {21}, year = {2022}, month = {2022 Jun}, pages = {e13608}, abstract = {

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~{\texttimes}~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~{\texttimes}~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}, issn = {1474-9726}, doi = {10.1111/acel.13608}, author = {Huan, Tianxiao and Nguyen, Steve and Colicino, Elena and Ochoa-Rosales, Carolina and Hill, W David and Brody, Jennifer A and Soerensen, Mette and Zhang, Yan and Baldassari, Antoine and Elhadad, Mohamed Ahmed and Toshiko, Tanaka and Zheng, Yinan and Domingo-Relloso, Arce and Lee, Dong Heon and Ma, Jiantao and Yao, Chen and Liu, Chunyu and Hwang, Shih-Jen and Joehanes, Roby and Fornage, Myriam and Bressler, Jan and van Meurs, Joyce B J and Debrabant, Birgit and Mengel-From, Jonas and Hjelmborg, Jacob and Christensen, Kaare and Vokonas, Pantel and Schwartz, Joel and Gahrib, Sina A and Sotoodehnia, Nona and Sitlani, Colleen M and Kunze, Sonja and Gieger, Christian and Peters, Annette and Waldenberger, Melanie and Deary, Ian J and Ferrucci, Luigi and Qu, Yishu and Greenland, Philip and Lloyd-Jones, Donald M and Hou, Lifang and Bandinelli, Stefania and Voortman, Trudy and Hermann, Brenner and Baccarelli, Andrea and Whitsel, Eric and Pankow, James S and Levy, Daniel} } @article {9090, title = {Monocyte subsets, T cell activation profiles, and stroke in men and women: The Multi-Ethnic Study of Atherosclerosis and Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {351}, year = {2022}, month = {2022 06}, pages = {18-25}, abstract = {

BACKGROUND AND AIMS: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes - key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke.

METHODS: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models.

RESULTS: We observed associations of intermediate monocytes, early-activated CD4 T cells, and both CD4 and CD8 T cells producing interleukin-4 after cytokine stimulation (T and T, respectively) with higher risk for incident stroke; effect sizes ranged from 35\% to 62\% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women.

CONCLUSIONS: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention.

}, keywords = {Atherosclerosis, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, Female, Follow-Up Studies, Humans, Incidence, Inflammation, Interleukin-4, Ischemic Stroke, Lymphocyte Activation, Male, Monocytes, Stroke, T-Lymphocyte Subsets}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2022.05.007}, author = {Feinstein, Matthew J and B{\r u}zkov{\'a}, Petra and Olson, Nels C and Doyle, Margaret F and Sitlani, Colleen M and Fohner, Alison E and Huber, Sally A and Floyd, James and Sinha, Arjun and Thorp, Edward B and Landay, Alan and Freiberg, Matthew S and Longstreth, William T and Tracy, Russell P and Psaty, Bruce M and Delaney, Joseph Ac} } @article {9171, title = {Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study.}, journal = {EBioMedicine}, volume = {83}, year = {2022}, month = {2022 Sep}, pages = {104189}, abstract = {

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free~+~esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).

METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.

FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95\% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95\% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.

INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.

FUNDING: US National Institutes of Health.

}, keywords = {Animals, Arachidonic Acids, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Eicosanoids, Humans, Ischemic Stroke, Prospective Studies}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2022.104189}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Zeigler, Maxwell and Fretts, Amanda M and Umans, Jason G and Howard, Barbara V and Sitlani, Colleen M and McKnight, Barbara and Gharib, Sina A and King, Irena B and Siscovick, David S and Psaty, Bruce M and Sotoodehnia, Nona and Totah, Rheem A} } @article {9086, title = {Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing.}, journal = {Eur J Epidemiol}, year = {2022}, month = {2022 Jul 05}, abstract = {

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.

}, issn = {1573-7284}, doi = {10.1007/s10654-022-00888-z}, author = {Austin, Thomas R and McHugh, Caitlin P and Brody, Jennifer A and Bis, Joshua C and Sitlani, Colleen M and Bartz, Traci M and Biggs, Mary L and Bansal, Nisha and B{\r u}zkov{\'a}, Petra and Carr, Steven A and deFilippi, Christopher R and Elkind, Mitchell S V and Fink, Howard A and Floyd, James S and Fohner, Alison E and Gerszten, Robert E and Heckbert, Susan R and Katz, Daniel H and Kizer, Jorge R and Lemaitre, Rozenn N and Longstreth, W T and McKnight, Barbara and Mei, Hao and Mukamal, Kenneth J and Newman, Anne B and Ngo, Debby and Odden, Michelle C and Vasan, Ramachandran S and Shojaie, Ali and Simon, Noah and Smith, George Davey and Davies, Neil M and Siscovick, David S and Sotoodehnia, Nona and Tracy, Russell P and Wiggins, Kerri L and Zheng, Jie and Psaty, Bruce M} } @article {9258, title = {Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease.}, journal = {Hum Mol Genet}, year = {2022}, month = {2022 Nov 29}, abstract = {

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 {\texttimes} 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 {\texttimes} 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 {\texttimes} 10-8) and NPEPPS (P = 1.51 {\texttimes} 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.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddac290}, author = {Pan, Yang and Sun, Xiao and Mi, Xuenan and Huang, Zhijie and Hsu, Yenchih and Hixson, James E and Munzy, Donna and Metcalf, Ginger and Franceschini, Nora and Tin, Adrienne and K{\"o}ttgen, Anna and Francis, Michael and Brody, Jennifer A and Kestenbaum, Bryan and Sitlani, Colleen M and Mychaleckyj, Josyf C and Kramer, Holly and Lange, Leslie A and Guo, Xiuqing and Hwang, Shih-Jen and Irvin, Marguerite R and Smith, Jennifer A and Yanek, Lisa R and Vaidya, Dhananjay and Chen, Yii-Der Ida and Fornage, Myriam and Lloyd-Jones, Donald M and Hou, Lifang and Mathias, Rasika A and Mitchell, Braxton D and Peyser, Patricia A and Kardia, Sharon L R and Arnett, Donna K and Correa, Adolfo and Raffield, Laura M and Vasan, Ramachandran S and Cupple, L Adrienne and Levy, Daniel and Kaplan, Robert C and North, Kari E and Rotter, Jerome I and Kooperberg, Charles and Reiner, Alexander P and Psaty, Bruce M and Tracy, Russell P and Gibbs, Richard A and Morrison, Alanna C and Feldman, Harold and Boerwinkle, Eric and He, Jiang and Kelly, Tanika N} } @article {9240, title = {Circulating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.}, journal = {Endocrinol Diabetes Metab}, volume = {6}, year = {2023}, month = {2023 Jan}, pages = {e384}, abstract = {

INTRODUCTION: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain.

METHODS: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA ), memory (CD45RO ), senescent (CD28 ), and T effector memory RA (TEMRA) (CD28 CD57 CD45RA ) CD4 and CD8 T cells, and memory B cells (CD19 CD27 ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4 and CD8 subsets with incident DM risk.

RESULTS: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4 , CD8 or CD19 cell phenotypes with incident DM.

CONCLUSIONS: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults.

}, keywords = {CD28 Antigens, CD8-Positive T-Lymphocytes, Cellular Senescence, Diabetes Mellitus, Leukocytes, Mononuclear, Lymphocyte Subsets}, issn = {2398-9238}, doi = {10.1002/edm2.384}, author = {Olson, Nels C and Doyle, Margaret F and B{\r u}zkov{\'a}, Petra and Huber, Sally A and de Boer, Ian H and Sitlani, Colleen M and Tracy, Russell P and Psaty, Bruce M and Mukamal, Kenneth J and Delaney, Joseph A} } @article {9322, title = {Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 Mar 14}, pages = {1411}, abstract = {

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration.~Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism~and~genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle~and~their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

}, keywords = {Arrhythmias, Cardiac, Atrioventricular Block, Biomarkers, Cardiovascular Diseases, Electrocardiography, Genome-Wide Association Study, Humans, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-023-36997-w}, author = {Young, William J and Haessler, Jeffrey and Benjamins, Jan-Walter and Repetto, Linda and Yao, Jie and Isaacs, Aaron and Harper, Andrew R and Ramirez, Julia and Garnier, Sophie and Van Duijvenboden, Stefan and Baldassari, Antoine R and Concas, Maria Pina and Duong, ThuyVy and Foco, Luisa and Isaksen, Jonas L and Mei, Hao and Noordam, Raymond and Nursyifa, Casia and Richmond, Anne and Santolalla, Meddly L and Sitlani, Colleen M and Soroush, Negin and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Aeschbacher, Stefanie and Ahmadizar, Fariba and Alonso, Alvaro and Brody, Jennifer A and Campbell, Archie and Correa, Adolfo and Darbar, Dawood and De Luca, Antonio and Deleuze, Jean-Francois and Ellervik, Christina and Fuchsberger, Christian and Goel, Anuj and Grace, Christopher and Guo, Xiuqing and Hansen, Torben and Heckbert, Susan R and Jackson, Rebecca D and Kors, Jan A and Lima-Costa, Maria Fernanda and Linneberg, Allan and Macfarlane, Peter W and Morrison, Alanna C and Navarro, Pau and Porteous, David J and Pramstaller, Peter P and Reiner, Alexander P and Risch, Lorenz and Schotten, Ulrich and Shen, Xia and Sinagra, Gianfranco and Soliman, Elsayed Z and Stoll, Monika and Tarazona-Santos, Eduardo and Tinker, Andrew and Trajanoska, Katerina and Villard, Eric and Warren, Helen R and Whitsel, Eric A and Wiggins, Kerri L and Arking, Dan E and Avery, Christy L and Conen, David and Girotto, Giorgia and Grarup, Niels and Hayward, Caroline and Jukema, J Wouter and Mook-Kanamori, Dennis O and Olesen, Morten Salling and Padmanabhan, Sandosh and Psaty, Bruce M and Pattaro, Cristian and Ribeiro, Antonio Luiz P and Rotter, Jerome I and Stricker, Bruno H and van der Harst, Pim and van Duijn, Cornelia M and Verweij, Niek and Wilson, James G and Orini, Michele and Charron, Philippe and Watkins, Hugh and Kooperberg, Charles and Lin, Henry J and Wilson, James F and Kanters, J{\o}rgen K and Sotoodehnia, Nona and Mifsud, Borbala and Lambiase, Pier D and Tereshchenko, Larisa G and Munroe, Patricia B} } @article {9533, title = {Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Nov 01}, pages = {e2343854}, abstract = {

IMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.

OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.

EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.

MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.

RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1\%] women; 6 [0.1\%] American Indian; 4 [0.1\%] Asian; 718 [15.6\%] Black; 3869 [83.9\%] White, and 15 [0.3\%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95\% CI, 1.12-1.59]; HR for SM-16, 1.37 [95\% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95\% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95\% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95\% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95\% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95\% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95\% CI, 0.72-1.03]).

CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.

}, keywords = {Aged, Ceramides, Cohort Studies, Death, Sudden, Cardiac, Eicosanoic Acids, Fatty Acids, Female, Humans, Male, Sphingolipids, Sphingomyelins}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.43854}, author = {Bockus, Lee B and Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and McKnight, Barbara and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Psaty, Bruce M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9330, title = {Plasma sphingolipids, lung function and COPD: the Cardiovascular Health Study.}, journal = {ERJ Open Res}, volume = {9}, year = {2023}, month = {2023 Mar}, abstract = {

RATIONALE: COPD is the third leading cause of death in the United States. Sphingolipids, structural membrane constituents that play a role in cellular stress and apoptosis signalling, may be involved in lung function.

METHODS: In the Cardiovascular Health Study, a prospective cohort of older adults, we cross-sectionally examined the association of plasma levels of 17 sphingolipid species with lung function and COPD. Multivariable linear regression and logistic regression were used to evaluate associations of sphingolipid concentrations with forced expiratory volume in 1 s (FEV) and odds of COPD, respectively.

RESULTS: Of the 17 sphingolipids evaluated, ceramide-18 (Cer-18) and sphingomyelin-18 (SM-18) were associated with lower FEV values (-0.061 L per two-fold higher Cer-18, p=0.001; -0.092 L per two-fold higher SM-18, p=0.002) after correction for multiple testing. Several other associations were significant at a 0.05 level, but did not reach statistical significance after correction for multiple testing. Specifically, Cer-18 and SM-18 were associated with higher odds of COPD (odds ratio per two-fold higher Cer-18 1.29, p=0.03 and SM-18 1.73, p=0.008). Additionally, Cer-16 and SM-16 were associated with lower FEV values, and Cer-14, SM-14 and SM-16 with a higher odds of COPD.

CONCLUSION: In this large cross-sectional study, specific ceramides and sphingomyelins were associated with reduced lung function in a population-based study. Future studies are needed to examine whether these biomarkers are associated with longitudinal change in FEV within individuals or with incident COPD.

}, issn = {2312-0541}, doi = {10.1183/23120541.00346-2022}, author = {Gharib, Arya R and Jensen, Paul N and Psaty, Bruce M and Hoofnagle, Andrew N and Siscovick, David and Gharib, Sina A and Sitlani, Colleen M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9451, title = {Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Aug 15}, pages = {e8711}, abstract = {

Background The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60\% (CHS) and 53\% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Atherosclerosis, Female, Humans, Ischemic Stroke, Methylamines, Oxides, Prospective Studies, Risk Factors, Stroke, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029230}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Wang, Zeneng and Fretts, Amanda M and Sitlani, Colleen M and Nemet, Ina and Sotoodehnia, Nona and de Oliveira Otto, Marcia C and Zhu, Weifei and Budoff, Matt and Longstreth, W T and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9239, title = {Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Jan}, pages = {154-164}, abstract = {

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

}, keywords = {Exome Sequencing, Genome-Wide Association Study, Lipids, Phenotype, Whole Genome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-022-01225-6}, author = {Li, Xihao and Quick, Corbin and Zhou, Hufeng and Gaynor, Sheila M and Liu, Yaowu and Chen, Han and Selvaraj, Margaret Sunitha and Sun, Ryan and Dey, Rounak and Arnett, Donna K and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and de Vries, Paul S and Duggirala, Ravindranath and Freedman, Barry I and G{\"o}ring, Harald H H and Guo, Xiuqing and Haessler, Jeffrey and Kalyani, Rita R and Kooperberg, Charles and Kral, Brian G and Lange, Leslie A and Manichaikul, Ani and Martin, Lisa W and McGarvey, Stephen T and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Rice, Kenneth M and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Vasan, Ramachandran S and Willer, Cristen J and Wilson, James G and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Natarajan, Pradeep and Peloso, Gina M and Li, Zilin and Lin, Xihong} } @article {9543, title = {A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {bioRxiv}, year = {2023}, month = {2023 Nov 02}, abstract = {

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

}, doi = {10.1101/2023.10.30.564764}, author = {Li, Xihao and Chen, Han and Selvaraj, Margaret Sunitha and Van Buren, Eric and Zhou, Hufeng and Wang, Yuxuan and Sun, Ryan and McCaw, Zachary R and Yu, Zhi and Arnett, Donna K and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Carson, April P and Carlson, Jenna C and Chami, Nathalie and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Gu, Charles and Heard-Costa, Nancy L and He, Jiang and Hou, Lifang and Hung, Yi-Jen and Irvin, Marguerite R and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Tanika and Konigsberg, Iain and Kooperberg, Charles and Kral, Brian G and Li, Changwei and Loos, Ruth J F and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Minster, Ryan L and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Tiwari, Hemant and Vasan, Ramachandran S and Wang, Zhe and Yanek, Lisa R and Yu, Bing and Rice, Kenneth M and Rotter, Jerome I and Peloso, Gina M and Natarajan, Pradeep and Li, Zilin and Liu, Zhonghua and Lin, Xihong} } @article {9484, title = {WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 22}, abstract = {

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51\% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 {\texttimes} 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

}, doi = {10.1101/2023.08.21.23293271}, author = {Zhang, Xinruo and Brody, Jennifer A and Graff, Mariaelisa and Highland, Heather M and Chami, Nathalie and Xu, Hanfei and Wang, Zhe and Ferrier, Kendra and Chittoor, Geetha and Josyula, Navya S and Li, Xihao and Li, Zilin and Allison, Matthew A and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Boorgula, Meher Preethi and Bowden, Donald W and Broome, Jai G and Buth, Erin J and Carlson, Christopher S and Chang, Kyong-Mi and Chavan, Sameer and Chiu, Yen-Feng and Chuang, Lee-Ming and Conomos, Matthew P and DeMeo, Dawn L and Du, Margaret and Duggirala, Ravindranath and Eng, Celeste and Fohner, Alison E and Freedman, Barry I and Garrett, Melanie E and Guo, Xiuqing and Haiman, Chris and Heavner, Benjamin D and Hidalgo, Bertha and Hixson, James E and Ho, Yuk-Lam and Hobbs, Brian D and Hu, Donglei and Hui, Qin and Hwu, Chii-Min and Jackson, Rebecca D and Jain, Deepti and Kalyani, Rita R and Kardia, Sharon L R and Kelly, Tanika N and Lange, Ethan M and LeNoir, Michael and Li, Changwei and Marchand, Loic Le and McDonald, Merry-Lynn N and McHugh, Caitlin P and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donnell, Christopher J and Palmer, Nicholette D and Pankow, James S and Perry, James A and Peters, Ulrike and Preuss, Michael H and Rao, D C and Regan, Elizabeth A and Reupena, Sefuiva M and Roden, Dan M and Rodriguez-Santana, Jose and Sitlani, Colleen M and Smith, Jennifer A and Tiwari, Hemant K and Vasan, Ramachandran S and Wang, Zeyuan and Weeks, Daniel E and Wessel, Jennifer and Wiggins, Kerri L and Wilkens, Lynne R and Wilson, Peter W F and Yanek, Lisa R and Yoneda, Zachary T and Zhao, Wei and Z{\"o}llner, Sebastian and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Blangero, John and Boerwinkle, Eric and Burchard, Esteban G and Carson, April P and Chasman, Daniel I and Chen, Yii-Der Ida and Curran, Joanne E and Fornage, Myriam and Gordeuk, Victor R and He, Jiang and Heckbert, Susan R and Hou, Lifang and Irvin, Marguerite R and Kooperberg, Charles and Minster, Ryan L and Mitchell, Braxton D and Nouraie, Mehdi and Psaty, Bruce M and Raffield, Laura M and Reiner, Alexander P and Rich, Stephen S and Rotter, Jerome I and Shoemaker, M Benjamin and Smith, Nicholas L and Taylor, Kent D and Telen, Marilyn J and Weiss, Scott T and Zhang, Yingze and Costa, Nancy Heard- and Sun, Yan V and Lin, Xihong and Cupples, L Adrienne and Lange, Leslie A and Liu, Ching-Ti and Loos, Ruth J F and North, Kari E and Justice, Anne E} }