@article {1077, title = {Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations.}, journal = {Circulation}, volume = {119}, year = {2009}, month = {2009 Feb 24}, pages = {940-51}, abstract = {

BACKGROUND: The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOS1AP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOS1AP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study.

METHODS AND RESULTS: We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs10494366 and rs4657139 in NOS1AP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOS1AP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95\% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs12567209, which was not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95\% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs16847548 and SCD, and such adjustment had no effect on the association between rs12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOS1AP and either QT interval or SCD were observed in blacks.

CONCLUSIONS: In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white US adults.

}, keywords = {Adaptor Proteins, Signal Transducing, Aged, Death, Sudden, Cardiac, Electrocardiography, European Continental Ancestry Group, Genotype, Humans, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.108.791723}, author = {Kao, W H Linda and Arking, Dan E and Post, Wendy and Rea, Thomas D and Sotoodehnia, Nona and Prineas, Ronald J and Bishe, Bryan and Doan, Betty Q and Boerwinkle, Eric and Psaty, Bruce M and Tomaselli, Gordon F and Coresh, Josef and Siscovick, David S and Marb{\'a}n, Eduardo and Spooner, Peter M and Burke, Gregory L and Chakravarti, Aravinda} } @article {1098, title = {Genome-wide association study of blood pressure and hypertension.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {677-87}, abstract = {

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 {\texttimes} 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 {\texttimes} 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

}, keywords = {Blood Pressure, Cell Line, Chromosome Mapping, Chromosomes, Human, Diastole, Gene Expression Regulation, Genetic Association Studies, Genome-Wide Association Study, Humans, Hypertension, Liver, Lymphocytes, Meta-Analysis as Topic, Odds Ratio, Phenotype, Prevalence, Risk Assessment, Systole}, issn = {1546-1718}, doi = {10.1038/ng.384}, author = {Levy, Daniel and Ehret, Georg B and Rice, Kenneth and Verwoert, Germaine C and Launer, Lenore J and Dehghan, Abbas and Glazer, Nicole L and Morrison, Alanna C and Johnson, Andrew D and Aspelund, Thor and Aulchenko, Yurii and Lumley, Thomas and K{\"o}ttgen, Anna and Vasan, Ramachandran S and Rivadeneira, Fernando and Eiriksdottir, Gudny and Guo, Xiuqing and Arking, Dan E and Mitchell, Gary F and Mattace-Raso, Francesco U S and Smith, Albert V and Taylor, Kent and Scharpf, Robert B and Hwang, Shih-Jen and Sijbrands, Eric J G and Bis, Joshua and Harris, Tamara B and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Hofman, Albert and Rotter, Jerome I and Coresh, Josef and Benjamin, Emelia J and Uitterlinden, Andr{\'e} G and Heiss, Gerardo and Fox, Caroline S and Witteman, Jacqueline C M and Boerwinkle, Eric and Wang, Thomas J and Gudnason, Vilmundur and Larson, Martin G and Chakravarti, Aravinda and Psaty, Bruce M and van Duijn, Cornelia M} } @article {1074, title = {Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.}, journal = {PLoS One}, volume = {4}, year = {2009}, month = {2009}, pages = {e4333}, abstract = {

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, African Americans, Aged, Death, Sudden, Cardiac, Electrocardiography, Ethnic Groups, European Continental Ancestry Group, Female, Genome-Wide Association Study, Heart Diseases, Heart Rate, Hispanic Americans, Humans, Linear Models, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Sex Factors, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0004333}, author = {Arking, Dan E and Khera, Amit and Xing, Chao and Kao, W H Linda and Post, Wendy and Boerwinkle, Eric and Chakravarti, Aravinda} } @article {1099, title = {Multiple loci associated with indices of renal function and chronic kidney disease.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {712-7}, abstract = {

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 {\texttimes} 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

}, keywords = {Chromosome Mapping, Cohort Studies, Genetic Variation, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Meta-Analysis as Topic, Mucoproteins, Netherlands, Polymorphism, Single Nucleotide, Prevalence, Uromodulin}, issn = {1546-1718}, doi = {10.1038/ng.377}, author = {K{\"o}ttgen, Anna and Glazer, Nicole L and Dehghan, Abbas and Hwang, Shih-Jen and Katz, Ronit and Li, Man and Yang, Qiong and Gudnason, Vilmundur and Launer, Lenore J and Harris, Tamara B and Smith, Albert V and Arking, Dan E and Astor, Brad C and Boerwinkle, Eric and Ehret, Georg B and Ruczinski, Ingo and Scharpf, Robert B and Chen, Yii-Der Ida and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Sarnak, Mark and Siscovick, David and Benjamin, Emelia J and Levy, Daniel and Upadhyay, Ashish and Aulchenko, Yurii S and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Chasman, Daniel I and Par{\'e}, Guillaume and Ridker, Paul M and Kao, W H Linda and Witteman, Jacqueline C and Coresh, Josef and Shlipak, Michael G and Fox, Caroline S} } @article {1114, title = {Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Aug}, pages = {879-81}, abstract = {

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

}, keywords = {Atrial Fibrillation, Chromosomes, Human, Pair 16, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins, Humans, Meta-Analysis as Topic, Mutation, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.416}, author = {Benjamin, Emelia J and Rice, Kenneth M and Arking, Dan E and Pfeufer, Arne and van Noord, Charlotte and Smith, Albert V and Schnabel, Renate B and Bis, Joshua C and Boerwinkle, Eric and Sinner, Moritz F and Dehghan, Abbas and Lubitz, Steven A and D{\textquoteright}Agostino, Ralph B and Lumley, Thomas and Ehret, Georg B and Heeringa, Jan and Aspelund, Thor and Newton-Cheh, Christopher and Larson, Martin G and Marciante, Kristin D and Soliman, Elsayed Z and Rivadeneira, Fernando and Wang, Thomas J and Eiriksdottir, Gudny and Levy, Daniel and Psaty, Bruce M and Li, Man and Chamberlain, Alanna M and Hofman, Albert and Vasan, Ramachandran S and Harris, Tamara B and Rotter, Jerome I and Kao, W H Linda and Agarwal, Sunil K and Stricker, Bruno H Ch and Wang, Ke and Launer, Lenore J and Smith, Nicholas L and Chakravarti, Aravinda and Uitterlinden, Andr{\'e} G and Wolf, Philip A and Sotoodehnia, Nona and K{\"o}ttgen, Anna and van Duijn, Cornelia M and Meitinger, Thomas and Mueller, Martina and Perz, Siegfried and Steinbeck, Gerhard and Wichmann, H-Erich and Lunetta, Kathryn L and Heckbert, Susan R and Gudnason, Vilmundur and Alonso, Alvaro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T and Witteman, Jacqueline C M} } @article {1206, title = {Common genetic variants associate with serum phosphorus concentration.}, journal = {J Am Soc Nephrol}, volume = {21}, year = {2010}, month = {2010 Jul}, pages = {1223-32}, abstract = {

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

}, keywords = {Adult, Aged, European Continental Ancestry Group, Female, Fibroblast Growth Factors, Gene Frequency, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans, Kidney, Male, Middle Aged, Phosphorus, Polymorphism, Single Nucleotide, Receptors, Calcium-Sensing, Sex Factors, Sodium-Phosphate Cotransporter Proteins, Type IIa}, issn = {1533-3450}, doi = {10.1681/ASN.2009111104}, author = {Kestenbaum, Bryan and Glazer, Nicole L and K{\"o}ttgen, Anna and Felix, Janine F and Hwang, Shih-Jen and Liu, Yongmei and Lohman, Kurt and Kritchevsky, Stephen B and Hausman, Dorothy B and Petersen, Ann-Kristin and Gieger, Christian and Ried, Janina S and Meitinger, Thomas and Strom, Tim M and Wichmann, H Erich and Campbell, Harry and Hayward, Caroline and Rudan, Igor and de Boer, Ian H and Psaty, Bruce M and Rice, Kenneth M and Chen, Yii-Der Ida and Li, Man and Arking, Dan E and Boerwinkle, Eric and Coresh, Josef and Yang, Qiong and Levy, Daniel and van Rooij, Frank J A and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and van Duijn, Cornelia M and Shlipak, Michael G and Kao, W H Linda and Witteman, Jacqueline C M and Siscovick, David S and Fox, Caroline S} } @article {1244, title = {Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Dec}, pages = {1068-76}, abstract = {

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 {\texttimes} 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

}, keywords = {Animals, Animals, Newborn, Chromosomes, Human, Computational Biology, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Mice, Mice, Transgenic, Models, Animal, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sodium Channels}, issn = {1546-1718}, doi = {10.1038/ng.716}, author = {Sotoodehnia, Nona and Isaacs, Aaron and de Bakker, Paul I W and D{\"o}rr, Marcus and Newton-Cheh, Christopher and Nolte, Ilja M and van der Harst, Pim and M{\"u}ller, Martina and Eijgelsheim, Mark and Alonso, Alvaro and Hicks, Andrew A and Padmanabhan, Sandosh and Hayward, Caroline and Smith, Albert Vernon and Polasek, Ozren and Giovannone, Steven and Fu, Jingyuan and Magnani, Jared W and Marciante, Kristin D and Pfeufer, Arne and Gharib, Sina A and Teumer, Alexander and Li, Man and Bis, Joshua C and Rivadeneira, Fernando and Aspelund, Thor and K{\"o}ttgen, Anna and Johnson, Toby and Rice, Kenneth and Sie, Mark P S and Wang, Ying A and Klopp, Norman and Fuchsberger, Christian and Wild, Sarah H and Mateo Leach, Irene and Estrada, Karol and V{\"o}lker, Uwe and Wright, Alan F and Asselbergs, Folkert W and Qu, Jiaxiang and Chakravarti, Aravinda and Sinner, Moritz F and Kors, Jan A and Petersmann, Astrid and Harris, Tamara B and Soliman, Elsayed Z and Munroe, Patricia B and Psaty, Bruce M and Oostra, Ben A and Cupples, L Adrienne and Perz, Siegfried and de Boer, Rudolf A and Uitterlinden, Andr{\'e} G and V{\"o}lzke, Henry and Spector, Timothy D and Liu, Fang-Yu and Boerwinkle, Eric and Dominiczak, Anna F and Rotter, Jerome I and van Herpen, G{\'e} and Levy, Daniel and Wichmann, H-Erich and van Gilst, Wiek H and Witteman, Jacqueline C M and Kroemer, Heyo K and Kao, W H Linda and Heckbert, Susan R and Meitinger, Thomas and Hofman, Albert and Campbell, Harry and Folsom, Aaron R and van Veldhuisen, Dirk J and Schwienbacher, Christine and O{\textquoteright}Donnell, Christopher J and Volpato, Claudia Beu and Caulfield, Mark J and Connell, John M and Launer, Lenore and Lu, Xiaowen and Franke, Lude and Fehrmann, Rudolf S N and te Meerman, Gerard and Groen, Harry J M and Weersma, Rinse K and van den Berg, Leonard H and Wijmenga, Cisca and Ophoff, Roel A and Navis, Gerjan and Rudan, Igor and Snieder, Harold and Wilson, James F and Pramstaller, Peter P and Siscovick, David S and Wang, Thomas J and Gudnason, Vilmundur and van Duijn, Cornelia M and Felix, Stephan B and Fishman, Glenn I and Jamshidi, Yalda and Stricker, Bruno H Ch and Samani, Nilesh J and K{\"a}{\"a}b, Stefan and Arking, Dan E} } @article {1170, title = {Common variants in KCNN3 are associated with lone atrial fibrillation.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Mar}, pages = {240-4}, abstract = {

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95\% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

}, keywords = {Adolescent, Adult, Aged, Atrial Fibrillation, Case-Control Studies, Cohort Studies, Female, Genome-Wide Association Study, Humans, Introns, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Small-Conductance Calcium-Activated Potassium Channels, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.537}, author = {Ellinor, Patrick T and Lunetta, Kathryn L and Glazer, Nicole L and Pfeufer, Arne and Alonso, Alvaro and Chung, Mina K and Sinner, Moritz F and de Bakker, Paul I W and Mueller, Martina and Lubitz, Steven A and Fox, Ervin and Darbar, Dawood and Smith, Nicholas L and Smith, Jonathan D and Schnabel, Renate B and Soliman, Elsayed Z and Rice, Kenneth M and Van Wagoner, David R and Beckmann, Britt-M and van Noord, Charlotte and Wang, Ke and Ehret, Georg B and Rotter, Jerome I and Hazen, Stanley L and Steinbeck, Gerhard and Smith, Albert V and Launer, Lenore J and Harris, Tamara B and Makino, Seiko and Nelis, Mari and Milan, David J and Perz, Siegfried and Esko, T{\~o}nu and K{\"o}ttgen, Anna and Moebus, Susanne and Newton-Cheh, Christopher and Li, Man and M{\"o}hlenkamp, Stefan and Wang, Thomas J and Kao, W H Linda and Vasan, Ramachandran S and N{\"o}then, Markus M and MacRae, Calum A and Stricker, Bruno H Ch and Hofman, Albert and Uitterlinden, Andr{\'e} G and Levy, Daniel and Boerwinkle, Eric and Metspalu, Andres and Topol, Eric J and Chakravarti, Aravinda and Gudnason, Vilmundur and Psaty, Bruce M and Roden, Dan M and Meitinger, Thomas and Wichmann, H-Erich and Witteman, Jacqueline C M and Barnard, John and Arking, Dan E and Benjamin, Emelia J and Heckbert, Susan R and K{\"a}{\"a}b, Stefan} } @article {1217, title = {Genome-wide association analysis identifies multiple loci related to resting heart rate.}, journal = {Hum Mol Genet}, volume = {19}, year = {2010}, month = {2010 Oct 01}, pages = {3885-94}, abstract = {

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 {\texttimes} 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7\% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6\%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

}, keywords = {Adult, Aged, Base Pairing, Cohort Studies, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Heart Rate, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Rest}, issn = {1460-2083}, doi = {10.1093/hmg/ddq303}, author = {Eijgelsheim, Mark and Newton-Cheh, Christopher and Sotoodehnia, Nona and de Bakker, Paul I W and M{\"u}ller, Martina and Morrison, Alanna C and Smith, Albert V and Isaacs, Aaron and Sanna, Serena and D{\"o}rr, Marcus and Navarro, Pau and Fuchsberger, Christian and Nolte, Ilja M and de Geus, Eco J C and Estrada, Karol and Hwang, Shih-Jen and Bis, Joshua C and R{\"u}ckert, Ina-Maria and Alonso, Alvaro and Launer, Lenore J and Hottenga, Jouke Jan and Rivadeneira, Fernando and Noseworthy, Peter A and Rice, Kenneth M and Perz, Siegfried and Arking, Dan E and Spector, Tim D and Kors, Jan A and Aulchenko, Yurii S and Tarasov, Kirill V and Homuth, Georg and Wild, Sarah H and Marroni, Fabio and Gieger, Christian and Licht, Carmilla M and Prineas, Ronald J and Hofman, Albert and Rotter, Jerome I and Hicks, Andrew A and Ernst, Florian and Najjar, Samer S and Wright, Alan F and Peters, Annette and Fox, Ervin R and Oostra, Ben A and Kroemer, Heyo K and Couper, David and V{\"o}lzke, Henry and Campbell, Harry and Meitinger, Thomas and Uda, Manuela and Witteman, Jacqueline C M and Psaty, Bruce M and Wichmann, H-Erich and Harris, Tamara B and K{\"a}{\"a}b, Stefan and Siscovick, David S and Jamshidi, Yalda and Uitterlinden, Andr{\'e} G and Folsom, Aaron R and Larson, Martin G and Wilson, James F and Penninx, Brenda W and Snieder, Harold and Pramstaller, Peter P and van Duijn, Cornelia M and Lakatta, Edward G and Felix, Stephan B and Gudnason, Vilmundur and Pfeufer, Arne and Heckbert, Susan R and Stricker, Bruno H Ch and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {1182, title = {Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Mar 25}, pages = {e9879}, abstract = {

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.

METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95\% CI 0.74 to 0.98; p<0.01).

CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

}, keywords = {Aged, Alleles, Case-Control Studies, Cohort Studies, Death, Sudden, Cardiac, Ethnic Groups, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glypicans, Heart Diseases, Humans, Male, Middle Aged, Models, Genetic, Oligonucleotide Array Sequence Analysis, Oregon, Polymorphism, Single Nucleotide}, issn = {1932-6203}, doi = {10.1371/journal.pone.0009879}, author = {Arking, Dan E and Reinier, Kyndaron and Post, Wendy and Jui, Jonathan and Hilton, Gina and O{\textquoteright}Connor, Ashley and Prineas, Ronald J and Boerwinkle, Eric and Psaty, Bruce M and Tomaselli, Gordon F and Rea, Thomas and Sotoodehnia, Nona and Siscovick, David S and Burke, Gregory L and Marb{\'a}n, Eduardo and Spooner, Peter M and Chakravarti, Aravinda and Chugh, Sumeet S} } @article {1159, title = {Genome-wide association study of PR interval.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Feb}, pages = {153-9}, abstract = {

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

}, keywords = {Aged, Atrial Fibrillation, Cohort Studies, Electrocardiography, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Meta-Analysis as Topic}, issn = {1546-1718}, doi = {10.1038/ng.517}, author = {Pfeufer, Arne and van Noord, Charlotte and Marciante, Kristin D and Arking, Dan E and Larson, Martin G and Smith, Albert Vernon and Tarasov, Kirill V and M{\"u}ller, Martina and Sotoodehnia, Nona and Sinner, Moritz F and Verwoert, Germaine C and Li, Man and Kao, W H Linda and K{\"o}ttgen, Anna and Coresh, Josef and Bis, Joshua C and Psaty, Bruce M and Rice, Kenneth and Rotter, Jerome I and Rivadeneira, Fernando and Hofman, Albert and Kors, Jan A and Stricker, Bruno H C and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Beckmann, Britt M and Sauter, Wiebke and Gieger, Christian and Lubitz, Steven A and Newton-Cheh, Christopher and Wang, Thomas J and Magnani, Jared W and Schnabel, Renate B and Chung, Mina K and Barnard, John and Smith, Jonathan D and Van Wagoner, David R and Vasan, Ramachandran S and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Launer, Lenore J and Najjar, Samer S and Lakatta, Edward and Schlessinger, David and Uda, Manuela and Abecasis, Goncalo R and M{\"u}ller-Myhsok, Bertram and Ehret, Georg B and Boerwinkle, Eric and Chakravarti, Aravinda and Soliman, Elsayed Z and Lunetta, Kathryn L and Perz, Siegfried and Wichmann, H-Erich and Meitinger, Thomas and Levy, Daniel and Gudnason, Vilmundur and Ellinor, Patrick T and Sanna, Serena and K{\"a}{\"a}b, Stefan and Witteman, Jacqueline C M and Alonso, Alvaro and Benjamin, Emelia J and Heckbert, Susan R} } @article {1226, title = {Independent susceptibility markers for atrial fibrillation on chromosome 4q25.}, journal = {Circulation}, volume = {122}, year = {2010}, month = {2010 Sep 07}, pages = {976-84}, abstract = {

BACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.

METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95\% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.

CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.

}, keywords = {Aged, Aged, 80 and over, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.109.886440}, author = {Lubitz, Steven A and Sinner, Moritz F and Lunetta, Kathryn L and Makino, Seiko and Pfeufer, Arne and Rahman, Rosanna and Veltman, Caroline E and Barnard, John and Bis, Joshua C and Danik, Stephan P and Sonni, Akshata and Shea, Marisa A and Del Monte, Federica and Perz, Siegfried and M{\"u}ller, Martina and Peters, Annette and Greenberg, Steven M and Furie, Karen L and van Noord, Charlotte and Boerwinkle, Eric and Stricker, Bruno H C and Witteman, Jacqueline and Smith, Jonathan D and Chung, Mina K and Heckbert, Susan R and Benjamin, Emelia J and Rosand, Jonathan and Arking, Dan E and Alonso, Alvaro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T} } @article {1235, title = {Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Dec}, pages = {523-30}, abstract = {

BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).

METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women{\textquoteright}s Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4{\texttimes}10(-8) to 2{\texttimes}10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3{\texttimes}10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women{\textquoteright}s Genome Health Study.

CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

}, keywords = {Cardiovascular Diseases, Coronary Disease, Female, Genetic Loci, Genome-Wide Association Study, Gout, Humans, Male, Risk Factors, Uric Acid}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.934455}, author = {Yang, Qiong and K{\"o}ttgen, Anna and Dehghan, Abbas and Smith, Albert V and Glazer, Nicole L and Chen, Ming-Huei and Chasman, Daniel I and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Launer, Lenore and Nalls, Michael and Hernandez, Dena and Arking, Dan E and Boerwinkle, Eric and Grove, Megan L and Li, Man and Linda Kao, W H and Chonchol, Michel and Haritunians, Talin and Li, Guo and Lumley, Thomas and Psaty, Bruce M and Shlipak, Michael and Hwang, Shih-Jen and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Upadhyay, Ashish and van Duijn, Cornelia M and Hofman, Albert and Rivadeneira, Fernando and Stricker, Bruno and Uitterlinden, Andr{\'e} G and Par{\'e}, Guillaume and Parker, Alex N and Ridker, Paul M and Siscovick, David S and Gudnason, Vilmundur and Witteman, Jacqueline C and Fox, Caroline S and Coresh, Josef} } @article {1183, title = {New loci associated with kidney function and chronic kidney disease.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 May}, pages = {376-84}, abstract = {

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

}, keywords = {Cohort Studies, Creatinine, Cystatin C, Diet, Europe, Genetic Markers, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Models, Genetic, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.568}, author = {K{\"o}ttgen, Anna and Pattaro, Cristian and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Glazer, Nicole L and Parsa, Afshin and Gao, Xiaoyi and Yang, Qiong and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Li, Man and Schmidt, Helena and Tanaka, Toshiko and Isaacs, Aaron and Ketkar, Shamika and Hwang, Shih-Jen and Johnson, Andrew D and Dehghan, Abbas and Teumer, Alexander and Par{\'e}, Guillaume and Atkinson, Elizabeth J and Zeller, Tanja and Lohman, Kurt and Cornelis, Marilyn C and Probst-Hensch, Nicole M and Kronenberg, Florian and T{\"o}njes, Anke and Hayward, Caroline and Aspelund, Thor and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Rampersaud, Evadnie and Mitchell, Braxton D and Arking, Dan E and Boerwinkle, Eric and Struchalin, Maksim and Cavalieri, Margherita and Singleton, Andrew and Giallauria, Francesco and Metter, Jeffrey and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Siscovick, David and Psaty, Bruce M and Zillikens, M Carola and Oostra, Ben A and Feitosa, Mary and Province, Michael and de Andrade, Mariza and Turner, Stephen T and Schillert, Arne and Ziegler, Andreas and Wild, Philipp S and Schnabel, Renate B and Wilde, Sandra and Munzel, Thomas F and Leak, Tennille S and Illig, Thomas and Klopp, Norman and Meisinger, Christa and Wichmann, H-Erich and Koenig, Wolfgang and Zgaga, Lina and Zemunik, Tatijana and Kolcic, Ivana and Minelli, Cosetta and Hu, Frank B and Johansson, Asa and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and Schreiber, Stefan and Aulchenko, Yurii S and Felix, Janine F and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Imboden, Medea and Nitsch, Dorothea and Brandst{\"a}tter, Anita and Kollerits, Barbara and Kedenko, Lyudmyla and M{\"a}gi, Reedik and Stumvoll, Michael and Kovacs, Peter and Boban, Mladen and Campbell, Susan and Endlich, Karlhans and V{\"o}lzke, Henry and Kroemer, Heyo K and Nauck, Matthias and V{\"o}lker, Uwe and Polasek, Ozren and Vitart, Veronique and Badola, Sunita and Parker, Alexander N and Ridker, Paul M and Kardia, Sharon L R and Blankenberg, Stefan and Liu, Yongmei and Curhan, Gary C and Franke, Andre and Rochat, Thierry and Paulweber, Bernhard and Prokopenko, Inga and Wang, Wei and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Shlipak, Michael G and van Duijn, Cornelia M and Borecki, Ingrid and Kr{\"a}mer, Bernhard K and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Witteman, Jacqueline C and Pramstaller, Peter P and Rettig, Rainer and Hastie, Nick and Chasman, Daniel I and Kao, W H and Heid, Iris M and Fox, Caroline S} } @article {1205, title = {Polymorphisms in the mitochondrial DNA control region and frailty in older adults.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Jun 10}, pages = {e11069}, abstract = {

BACKGROUND: Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults.

METHODOLOGY/PRINCIPAL FINDINGS: To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989-1990, 1992-1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95\% CI = 1.07-3.60, p = 0.020) and lower grip strength (adjusted coefficient = -2.04, 95\% CI = -3.33- -0.74, p = 0.002).

CONCLUSIONS: This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.

}, keywords = {Aged, Aged, 80 and over, DNA, Mitochondrial, Female, Frail Elderly, Genotype, Humans, Male, Polymorphism, Genetic}, issn = {1932-6203}, doi = {10.1371/journal.pone.0011069}, author = {Moore, Ann Z and Biggs, Mary L and Matteini, Amy and O{\textquoteright}Connor, Ashley and McGuire, Sarah and Beamer, Brock A and Fallin, M Danielle and Fried, Linda P and Walston, Jeremy and Chakravarti, Aravinda and Arking, Dan E} } @article {1271, title = {CUBN is a gene locus for albuminuria.}, journal = {J Am Soc Nephrol}, volume = {22}, year = {2011}, month = {2011 Mar}, pages = {555-70}, abstract = {

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 {\texttimes} 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41\% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

}, keywords = {African Continental Ancestry Group, Albuminuria, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Humans, Mutation, Missense, Receptors, Cell Surface}, issn = {1533-3450}, doi = {10.1681/ASN.2010060598}, author = {B{\"o}ger, Carsten A and Chen, Ming-Huei and Tin, Adrienne and Olden, Matthias and K{\"o}ttgen, Anna and de Boer, Ian H and Fuchsberger, Christian and O{\textquoteright}Seaghdha, Conall M and Pattaro, Cristian and Teumer, Alexander and Liu, Ching-Ti and Glazer, Nicole L and Li, Man and O{\textquoteright}Connell, Jeffrey R and Tanaka, Toshiko and Peralta, Carmen A and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Zhao, Jing Hua and Hwang, Shih-Jen and Akylbekova, Ermeg and Kramer, Holly and van der Harst, Pim and Smith, Albert V and Lohman, Kurt and de Andrade, Mariza and Hayward, Caroline and Kollerits, Barbara and T{\"o}njes, Anke and Aspelund, Thor and Ingelsson, Erik and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Shuldiner, Alan R and Mitchell, Braxton D and Arking, Dan E and Franceschini, Nora and Boerwinkle, Eric and Egan, Josephine and Hernandez, Dena and Reilly, Muredach and Townsend, Raymond R and Lumley, Thomas and Siscovick, David S and Psaty, Bruce M and Kestenbaum, Bryan and Haritunians, Talin and Bergmann, Sven and Vollenweider, Peter and Waeber, G{\'e}rard and Mooser, Vincent and Waterworth, Dawn and Johnson, Andrew D and Florez, Jose C and Meigs, James B and Lu, Xiaoning and Turner, Stephen T and Atkinson, Elizabeth J and Leak, Tennille S and Aasar{\o}d, Knut and Skorpen, Frank and Syv{\"a}nen, Ann-Christine and Illig, Thomas and Baumert, Jens and Koenig, Wolfgang and Kr{\"a}mer, Bernhard K and Devuyst, Olivier and Mychaleckyj, Josyf C and Minelli, Cosetta and Bakker, Stephan J L and Kedenko, Lyudmyla and Paulweber, Bernhard and Coassin, Stefan and Endlich, Karlhans and Kroemer, Heyo K and Biffar, Reiner and Stracke, Sylvia and V{\"o}lzke, Henry and Stumvoll, Michael and M{\"a}gi, Reedik and Campbell, Harry and Vitart, Veronique and Hastie, Nicholas D and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Polasek, Ozren and Curhan, Gary and Kronenberg, Florian and Prokopenko, Inga and Rudan, Igor and Arnl{\"o}v, Johan and Hallan, Stein and Navis, Gerjan and Parsa, Afshin and Ferrucci, Luigi and Coresh, Josef and Shlipak, Michael G and Bull, Shelley B and Paterson, Nicholas J and Wichmann, H-Erich and Wareham, Nicholas J and Loos, Ruth J F and Rotter, Jerome I and Pramstaller, Peter P and Cupples, L Adrienne and Beckmann, Jacques S and Yang, Qiong and Heid, Iris M and Rettig, Rainer and Dreisbach, Albert W and Bochud, Murielle and Fox, Caroline S and Kao, W H L} } @article {1325, title = {Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.}, journal = {Nature}, volume = {478}, year = {2011}, month = {2011 Sep 11}, pages = {103-9}, abstract = {

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>=140 mm Hg systolic blood pressure or >=90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

}, keywords = {Africa, Asia, Blood Pressure, Cardiovascular Diseases, Coronary Artery Disease, Europe, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Kidney Diseases, Polymorphism, Single Nucleotide, Stroke}, issn = {1476-4687}, doi = {10.1038/nature10405}, author = {Ehret, Georg B and Munroe, Patricia B and Rice, Kenneth M and Bochud, Murielle and Johnson, Andrew D and Chasman, Daniel I and Smith, Albert V and Tobin, Martin D and Verwoert, Germaine C and Hwang, Shih-Jen and Pihur, Vasyl and Vollenweider, Peter and O{\textquoteright}Reilly, Paul F and Amin, Najaf and Bragg-Gresham, Jennifer L and Teumer, Alexander and Glazer, Nicole L and Launer, Lenore and Zhao, Jing Hua and Aulchenko, Yurii and Heath, Simon and S{\~o}ber, Siim and Parsa, Afshin and Luan, Jian{\textquoteright}an and Arora, Pankaj and Dehghan, Abbas and Zhang, Feng and Lucas, Gavin and Hicks, Andrew A and Jackson, Anne U and Peden, John F and Tanaka, Toshiko and Wild, Sarah H and Rudan, Igor and Igl, Wilmar and Milaneschi, Yuri and Parker, Alex N and Fava, Cristiano and Chambers, John C and Fox, Ervin R and Kumari, Meena and Go, Min Jin and van der Harst, Pim and Kao, Wen Hong Linda and Sj{\"o}gren, Marketa and Vinay, D G and Alexander, Myriam and Tabara, Yasuharu and Shaw-Hawkins, Sue and Whincup, Peter H and Liu, Yongmei and Shi, Gang and Kuusisto, Johanna and Tayo, Bamidele and Seielstad, Mark and Sim, Xueling and Nguyen, Khanh-Dung Hoang and Lehtim{\"a}ki, Terho and Matullo, Giuseppe and Wu, Ying and Gaunt, Tom R and Onland-Moret, N Charlotte and Cooper, Matthew N and Platou, Carl G P and Org, Elin and Hardy, Rebecca and Dahgam, Santosh and Palmen, Jutta and Vitart, Veronique and Braund, Peter S and Kuznetsova, Tatiana and Uiterwaal, Cuno S P M and Adeyemo, Adebowale and Palmas, Walter and Campbell, Harry and Ludwig, Barbara and Tomaszewski, Maciej and Tzoulaki, Ioanna and Palmer, Nicholette D and Aspelund, Thor and Garcia, Melissa and Chang, Yen-Pei C and O{\textquoteright}Connell, Jeffrey R and Steinle, Nanette I and Grobbee, Diederick E and Arking, Dan E and Kardia, Sharon L and Morrison, Alanna C and Hernandez, Dena and Najjar, Samer and McArdle, Wendy L and Hadley, David and Brown, Morris J and Connell, John M and Hingorani, Aroon D and Day, Ian N M and Lawlor, Debbie A and Beilby, John P and Lawrence, Robert W and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Dreisbach, Albert W and Li, Yali and Young, J Hunter and Bis, Joshua C and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Adair, Linda S and Lee, Nanette R and Chen, Ming-Huei and Olden, Matthias and Pattaro, Cristian and Bolton, Judith A Hoffman and K{\"o}ttgen, Anna and Bergmann, Sven and Mooser, Vincent and Chaturvedi, Nish and Frayling, Timothy M and Islam, Muhammad and Jafar, Tazeen H and Erdmann, Jeanette and Kulkarni, Smita R and Bornstein, Stefan R and Gr{\"a}ssler, J{\"u}rgen and Groop, Leif and Voight, Benjamin F and Kettunen, Johannes and Howard, Philip and Taylor, Andrew and Guarrera, Simonetta and Ricceri, Fulvio and Emilsson, Valur and Plump, Andrew and Barroso, In{\^e}s and Khaw, Kay-Tee and Weder, Alan B and Hunt, Steven C and Sun, Yan V and Bergman, Richard N and Collins, Francis S and Bonnycastle, Lori L and Scott, Laura J and Stringham, Heather M and Peltonen, Leena and Perola, Markus and Vartiainen, Erkki and Brand, Stefan-Martin and Staessen, Jan A and Wang, Thomas J and Burton, Paul R and Soler Artigas, Maria and Dong, Yanbin and Snieder, Harold and Wang, Xiaoling and Zhu, Haidong and Lohman, Kurt K and Rudock, Megan E and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Doumatey, Ayo and Shriner, Daniel and Veldre, Gudrun and Viigimaa, Margus and Kinra, Sanjay and Prabhakaran, Dorairaj and Tripathy, Vikal and Langefeld, Carl D and Rosengren, Annika and Thelle, Dag S and Corsi, Anna Maria and Singleton, Andrew and Forrester, Terrence and Hilton, Gina and McKenzie, Colin A and Salako, Tunde and Iwai, Naoharu and Kita, Yoshikuni and Ogihara, Toshio and Ohkubo, Takayoshi and Okamura, Tomonori and Ueshima, Hirotsugu and Umemura, Satoshi and Eyheramendy, Susana and Meitinger, Thomas and Wichmann, H-Erich and Cho, Yoon Shin and Kim, Hyung-Lae and Lee, Jong-Young and Scott, James and Sehmi, Joban S and Zhang, Weihua and Hedblad, Bo and Nilsson, Peter and Smith, George Davey and Wong, Andrew and Narisu, Narisu and Stan{\v c}{\'a}kov{\'a}, Alena and Raffel, Leslie J and Yao, Jie and Kathiresan, Sekar and O{\textquoteright}Donnell, Christopher J and Schwartz, Stephen M and Ikram, M Arfan and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Shrine, Nick R G and Wain, Louise V and Morken, Mario A and Swift, Amy J and Laitinen, Jaana and Prokopenko, Inga and Zitting, Paavo and Cooper, Jackie A and Humphries, Steve E and Danesh, John and Rasheed, Asif and Goel, Anuj and Hamsten, Anders and Watkins, Hugh and Bakker, Stephan J L and van Gilst, Wiek H and Janipalli, Charles S and Mani, K Radha and Yajnik, Chittaranjan S and Hofman, Albert and Mattace-Raso, Francesco U S and Oostra, Ben A and Demirkan, Ayse and Isaacs, Aaron and Rivadeneira, Fernando and Lakatta, Edward G and Orr{\`u}, Marco and Scuteri, Angelo and Ala-Korpela, Mika and Kangas, Antti J and Lyytik{\"a}inen, Leo-Pekka and Soininen, Pasi and Tukiainen, Taru and W{\"u}rtz, Peter and Ong, Rick Twee-Hee and D{\"o}rr, Marcus and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Zelenika, Diana and Deloukas, Panos and Mangino, Massimo and Spector, Tim D and Zhai, Guangju and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Terzic, Janos and Kumar, M V Kranthi and Denniff, Matthew and Zukowska-Szczechowska, Ewa and Wagenknecht, Lynne E and Fowkes, F Gerald R and Charchar, Fadi J and Schwarz, Peter E H and Hayward, Caroline and Guo, Xiuqing and Rotimi, Charles and Bots, Michiel L and Brand, Eva and Samani, Nilesh J and Polasek, Ozren and Talmud, Philippa J and Nyberg, Fredrik and Kuh, Diana and Laan, Maris and Hveem, Kristian and Palmer, Lyle J and van der Schouw, Yvonne T and Casas, Juan P and Mohlke, Karen L and Vineis, Paolo and Raitakari, Olli and Ganesh, Santhi K and Wong, Tien Y and Tai, E Shyong and Cooper, Richard S and Laakso, Markku and Rao, Dabeeru C and Harris, Tamara B and Morris, Richard W and Dominiczak, Anna F and Kivimaki, Mika and Marmot, Michael G and Miki, Tetsuro and Saleheen, Danish and Chandak, Giriraj R and Coresh, Josef and Navis, Gerjan and Salomaa, Veikko and Han, Bok-Ghee and Zhu, Xiaofeng and Kooner, Jaspal S and Melander, Olle and Ridker, Paul M and Bandinelli, Stefania and Gyllensten, Ulf B and Wright, Alan F and Wilson, James F and Ferrucci, Luigi and Farrall, Martin and Tuomilehto, Jaakko and Pramstaller, Peter P and Elosua, Roberto and Soranzo, Nicole and Sijbrands, Eric J G and Altshuler, David and Loos, Ruth J F and Shuldiner, Alan R and Gieger, Christian and Meneton, Pierre and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Gudnason, Vilmundur and Rotter, Jerome I and Rettig, Rainer and Uda, Manuela and Strachan, David P and Witteman, Jacqueline C M and Hartikainen, Anna-Liisa and Beckmann, Jacques S and Boerwinkle, Eric and Vasan, Ramachandran S and Boehnke, Michael and Larson, Martin G and Jarvelin, Marjo-Riitta and Psaty, Bruce M and Abecasis, Goncalo R and Chakravarti, Aravinda and Elliott, Paul and van Duijn, Cornelia M and Newton-Cheh, Christopher and Levy, Daniel and Caulfield, Mark J and Johnson, Toby} } @article {1304, title = {Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002158}, abstract = {

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8{\texttimes}10(-10)). The risk allele, while ancestral, has a frequency of ~1.4\%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95\% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

}, keywords = {Adult, Aged, Alleles, Chromosomes, Human, Pair 2, Death, Sudden, Cardiac, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Contraction, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002158}, author = {Arking, Dan E and Junttila, M Juhani and Goyette, Philippe and Huertas-Vazquez, Adriana and Eijgelsheim, Mark and Blom, Marieke T and Newton-Cheh, Christopher and Reinier, Kyndaron and Teodorescu, Carmen and Uy-Evanado, Audrey and Carter-Monroe, Naima and Kaikkonen, Kari S and Kortelainen, Marja-Leena and Boucher, Gabrielle and Lagac{\'e}, Caroline and Moes, Anna and Zhao, XiaoQing and Kolodgie, Frank and Rivadeneira, Fernando and Hofman, Albert and Witteman, Jacqueline C M and Uitterlinden, Andr{\'e} G and Marsman, Roos F and Pazoki, Raha and Bardai, Abdennasser and Koster, Rudolph W and Dehghan, Abbas and Hwang, Shih-Jen and Bhatnagar, Pallav and Post, Wendy and Hilton, Gina and Prineas, Ronald J and Li, Man and K{\"o}ttgen, Anna and Ehret, Georg and Boerwinkle, Eric and Coresh, Josef and Kao, W H Linda and Psaty, Bruce M and Tomaselli, Gordon F and Sotoodehnia, Nona and Siscovick, David S and Burke, Greg L and Marb{\'a}n, Eduardo and Spooner, Peter M and Cupples, L Adrienne and Jui, Jonathan and Gunson, Karen and Kesaniemi, Y Antero and Wilde, Arthur A M and Tardif, Jean-Claude and O{\textquoteright}Donnell, Christopher J and Bezzina, Connie R and Virmani, Renu and Stricker, Bruno H C H and Tan, Hanno L and Albert, Christine M and Chakravarti, Aravinda and Rioux, John D and Huikuri, Heikki V and Chugh, Sumeet S} } @article {1316, title = {Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute{\textquoteright}s Candidate Gene Association Resource (CARe) project.}, journal = {Circ Cardiovasc Genet}, volume = {4}, year = {2011}, month = {2011 Oct}, pages = {557-64}, abstract = {

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute{\textquoteright}s Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95\% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95\% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95\% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95\% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

}, keywords = {African Americans, Aged, Alleles, Atrial Fibrillation, Chromosomes, Human, Pair 4, Cohort Studies, European Continental Ancestry Group, Female, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Risk Factors, Stroke, United States}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.110.959197}, author = {Schnabel, Renate B and Kerr, Kathleen F and Lubitz, Steven A and Alkylbekova, Ermeg L and Marcus, Gregory M and Sinner, Moritz F and Magnani, Jared W and Wolf, Philip A and Deo, Rajat and Lloyd-Jones, Donald M and Lunetta, Kathryn L and Mehra, Reena and Levy, Daniel and Fox, Ervin R and Arking, Dan E and Mosley, Thomas H and M{\"u}ller-Nurasyid, Martina and Young, Taylor R and Wichmann, H-Erich and Seshadri, Sudha and Farlow, Deborah N and Rotter, Jerome I and Soliman, Elsayed Z and Glazer, Nicole L and Wilson, James G and Breteler, Monique M B and Sotoodehnia, Nona and Newton-Cheh, Christopher and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T and Alonso, Alvaro and Benjamin, Emelia J and Heckbert, Susan R} } @article {6083, title = {Fine-mapping and initial characterization of QT interval loci in African Americans.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002870}, abstract = {

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women{\textquoteright}s Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P<=1.20{\texttimes}10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P<=1.37{\texttimes}10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

}, keywords = {African Americans, Aged, Computational Biology, Electrocardiography, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Metagenomics, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Risk Factors, Tachycardia, United States}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002870}, author = {Avery, Christy L and Sethupathy, Praveen and Buyske, Steven and He, Qianchuan and Lin, Dan-Yu and Arking, Dan E and Carty, Cara L and Duggan, David and Fesinmeyer, Megan D and Hindorff, Lucia A and Jeff, Janina M and Klein, Liviu and Patton, Kristen K and Peters, Ulrike and Shohet, Ralph V and Sotoodehnia, Nona and Young, Alicia M and Kooperberg, Charles and Haiman, Christopher A and Mohlke, Karen L and Whitsel, Eric A and North, Kari E} } @article {6179, title = {Impact of ancestry and common genetic variants on QT interval in African Americans.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Dec}, pages = {647-55}, abstract = {

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 {\texttimes} 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 {\texttimes} 10(-15)) and ATP1B1 (rs1320976, P=2 {\texttimes} 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

}, keywords = {Adult, African Americans, Aged, Electrocardiography, European Continental Ancestry Group, Female, Genealogy and Heraldry, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.962787}, author = {Smith, J Gustav and Avery, Christy L and Evans, Daniel S and Nalls, Michael A and Meng, Yan A and Smith, Erin N and Palmer, Cameron and Tanaka, Toshiko and Mehra, Reena and Butler, Anne M and Young, Taylor and Buxbaum, Sarah G and Kerr, Kathleen F and Berenson, Gerald S and Schnabel, Renate B and Li, Guo and Ellinor, Patrick T and Magnani, Jared W and Chen, Wei and Bis, Joshua C and Curb, J David and Hsueh, Wen-Chi and Rotter, Jerome I and Liu, Yongmei and Newman, Anne B and Limacher, Marian C and North, Kari E and Reiner, Alexander P and Quibrera, P Miguel and Schork, Nicholas J and Singleton, Andrew B and Psaty, Bruce M and Soliman, Elsayed Z and Solomon, Allen J and Srinivasan, Sathanur R and Alonso, Alvaro and Wallace, Robert and Redline, Susan and Zhang, Zhu-Ming and Post, Wendy S and Zonderman, Alan B and Taylor, Herman A and Murray, Sarah S and Ferrucci, Luigi and Arking, Dan E and Evans, Michele K and Fox, Ervin R and Sotoodehnia, Nona and Heckbert, Susan R and Whitsel, Eric A and Newton-Cheh, Christopher} } @article {1383, title = {Meta-analysis identifies six new susceptibility loci for atrial fibrillation.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 29}, pages = {670-5}, abstract = {

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 {\texttimes} 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Atrial Fibrillation, Child, Child, Preschool, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.2261}, author = {Ellinor, Patrick T and Lunetta, Kathryn L and Albert, Christine M and Glazer, Nicole L and Ritchie, Marylyn D and Smith, Albert V and Arking, Dan E and M{\"u}ller-Nurasyid, Martina and Krijthe, Bouwe P and Lubitz, Steven A and Bis, Joshua C and Chung, Mina K and D{\"o}rr, Marcus and Ozaki, Kouichi and Roberts, Jason D and Smith, J Gustav and Pfeufer, Arne and Sinner, Moritz F and Lohman, Kurt and Ding, Jingzhong and Smith, Nicholas L and Smith, Jonathan D and Rienstra, Michiel and Rice, Kenneth M and Van Wagoner, David R and Magnani, Jared W and Wakili, Reza and Clauss, Sebastian and Rotter, Jerome I and Steinbeck, Gerhard and Launer, Lenore J and Davies, Robert W and Borkovich, Matthew and Harris, Tamara B and Lin, Honghuang and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Milan, David J and Hofman, Albert and Boerwinkle, Eric and Chen, Lin Y and Soliman, Elsayed Z and Voight, Benjamin F and Li, Guo and Chakravarti, Aravinda and Kubo, Michiaki and Tedrow, Usha B and Rose, Lynda M and Ridker, Paul M and Conen, David and Tsunoda, Tatsuhiko and Furukawa, Tetsushi and Sotoodehnia, Nona and Xu, Siyan and Kamatani, Naoyuki and Levy, Daniel and Nakamura, Yusuke and Parvez, Babar and Mahida, Saagar and Furie, Karen L and Rosand, Jonathan and Muhammad, Raafia and Psaty, Bruce M and Meitinger, Thomas and Perz, Siegfried and Wichmann, H-Erich and Witteman, Jacqueline C M and Kao, W H Linda and Kathiresan, Sekar and Roden, Dan M and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and McKnight, Barbara and Sj{\"o}gren, Marketa and Newman, Anne B and Liu, Yongmei and Gollob, Michael H and Melander, Olle and Tanaka, Toshihiro and Stricker, Bruno H Ch and Felix, Stephan B and Alonso, Alvaro and Darbar, Dawood and Barnard, John and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Gudnason, Vilmundur and K{\"a}{\"a}b, Stefan} } @article {6084, title = {Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Dec}, pages = {639-46}, abstract = {

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 {\texttimes} 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 {\texttimes} 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

}, keywords = {Adult, African Americans, Cohort Studies, Electrocardiography, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.963991}, author = {Butler, Anne M and Yin, Xiaoyan and Evans, Daniel S and Nalls, Michael A and Smith, Erin N and Tanaka, Toshiko and Li, Guo and Buxbaum, Sarah G and Whitsel, Eric A and Alonso, Alvaro and Arking, Dan E and Benjamin, Emelia J and Berenson, Gerald S and Bis, Josh C and Chen, Wei and Deo, Rajat and Ellinor, Patrick T and Heckbert, Susan R and Heiss, Gerardo and Hsueh, Wen-Chi and Keating, Brendan J and Kerr, Kathleen F and Li, Yun and Limacher, Marian C and Liu, Yongmei and Lubitz, Steven A and Marciante, Kristin D and Mehra, Reena and Meng, Yan A and Newman, Anne B and Newton-Cheh, Christopher and North, Kari E and Palmer, Cameron D and Psaty, Bruce M and Quibrera, P Miguel and Redline, Susan and Reiner, Alex P and Rotter, Jerome I and Schnabel, Renate B and Schork, Nicholas J and Singleton, Andrew B and Smith, J Gustav and Soliman, Elsayed Z and Srinivasan, Sathanur R and Zhang, Zhu-Ming and Zonderman, Alan B and Ferrucci, Luigi and Murray, Sarah S and Evans, Michele K and Sotoodehnia, Nona and Magnani, Jared W and Avery, Christy L} } @article {8015, title = {Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Jun}, pages = {621-31}, abstract = {

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

}, keywords = {Animals, Arrhythmias, Cardiac, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Heart Rate, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1546-1718}, doi = {10.1038/ng.2610}, author = {den Hoed, Marcel and Eijgelsheim, Mark and Esko, T{\~o}nu and Brundel, Bianca J J M and Peal, David S and Evans, David M and Nolte, Ilja M and Segr{\`e}, Ayellet V and Holm, Hilma and Handsaker, Robert E and Westra, Harm-Jan and Johnson, Toby and Isaacs, Aaron and Yang, Jian and Lundby, Alicia and Zhao, Jing Hua and Kim, Young Jin and Go, Min Jin and Almgren, Peter and Bochud, Murielle and Boucher, Gabrielle and Cornelis, Marilyn C and Gudbjartsson, Daniel and Hadley, David and van der Harst, Pim and Hayward, Caroline and den Heijer, Martin and Igl, Wilmar and Jackson, Anne U and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Kemp, John P and Kristiansson, Kati and Ladenvall, Claes and Lorentzon, Mattias and Montasser, May E and Njajou, Omer T and O{\textquoteright}Reilly, Paul F and Padmanabhan, Sandosh and St Pourcain, Beate and Rankinen, Tuomo and Salo, Perttu and Tanaka, Toshiko and Timpson, Nicholas J and Vitart, Veronique and Waite, Lindsay and Wheeler, William and Zhang, Weihua and Draisma, Harmen H M and Feitosa, Mary F and Kerr, Kathleen F and Lind, Penelope A and Mihailov, Evelin and Onland-Moret, N Charlotte and Song, Ci and Weedon, Michael N and Xie, Weijia and Yengo, Loic and Absher, Devin and Albert, Christine M and Alonso, Alvaro and Arking, Dan E and de Bakker, Paul I W and Balkau, Beverley and Barlassina, Cristina and Benaglio, Paola and Bis, Joshua C and Bouatia-Naji, Nabila and Brage, S{\o}ren and Chanock, Stephen J and Chines, Peter S and Chung, Mina and Darbar, Dawood and Dina, Christian and D{\"o}rr, Marcus and Elliott, Paul and Felix, Stephan B and Fischer, Krista and Fuchsberger, Christian and de Geus, Eco J C and Goyette, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Hartikainen, Anna-Liisa and Havulinna, Aki S and Heckbert, Susan R and Hicks, Andrew A and Hofman, Albert and Holewijn, Suzanne and Hoogstra-Berends, Femke and Hottenga, Jouke-Jan and Jensen, Majken K and Johansson, Asa and Junttila, Juhani and K{\"a}{\"a}b, Stefan and Kanon, Bart and Ketkar, Shamika and Khaw, Kay-Tee and Knowles, Joshua W and Kooner, Angrad S and Kors, Jan A and Kumari, Meena and Milani, Lili and Laiho, P{\"a}ivi and Lakatta, Edward G and Langenberg, Claudia and Leusink, Maarten and Liu, Yongmei and Luben, Robert N and Lunetta, Kathryn L and Lynch, Stacey N and Markus, Marcello R P and Marques-Vidal, Pedro and Mateo Leach, Irene and McArdle, Wendy L and McCarroll, Steven A and Medland, Sarah E and Miller, Kathryn A and Montgomery, Grant W and Morrison, Alanna C and M{\"u}ller-Nurasyid, Martina and Navarro, Pau and Nelis, Mari and O{\textquoteright}Connell, Jeffrey R and O{\textquoteright}Donnell, Christopher J and Ong, Ken K and Newman, Anne B and Peters, Annette and Polasek, Ozren and Pouta, Anneli and Pramstaller, Peter P and Psaty, Bruce M and Rao, Dabeeru C and Ring, Susan M and Rossin, Elizabeth J and Rudan, Diana and Sanna, Serena and Scott, Robert A and Sehmi, Jaban S and Sharp, Stephen and Shin, Jordan T and Singleton, Andrew B and Smith, Albert V and Soranzo, Nicole and Spector, Tim D and Stewart, Chip and Stringham, Heather M and Tarasov, Kirill V and Uitterlinden, Andr{\'e} G and Vandenput, Liesbeth and Hwang, Shih-Jen and Whitfield, John B and Wijmenga, Cisca and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Witteman, Jacqueline C M and Wong, Andrew and Wong, Quenna and Jamshidi, Yalda and Zitting, Paavo and Boer, Jolanda M A and Boomsma, Dorret I and Borecki, Ingrid B and van Duijn, Cornelia M and Ekelund, Ulf and Forouhi, Nita G and Froguel, Philippe and Hingorani, Aroon and Ingelsson, Erik and Kivimaki, Mika and Kronmal, Richard A and Kuh, Diana and Lind, Lars and Martin, Nicholas G and Oostra, Ben A and Pedersen, Nancy L and Quertermous, Thomas and Rotter, Jerome I and van der Schouw, Yvonne T and Verschuren, W M Monique and Walker, Mark and Albanes, Demetrius and Arnar, David O and Assimes, Themistocles L and Bandinelli, Stefania and Boehnke, Michael and de Boer, Rudolf A and Bouchard, Claude and Caulfield, W L Mark and Chambers, John C and Curhan, Gary and Cusi, Daniele and Eriksson, Johan and Ferrucci, Luigi and van Gilst, Wiek H and Glorioso, Nicola and de Graaf, Jacqueline and Groop, Leif and Gyllensten, Ulf and Hsueh, Wen-Chi and Hu, Frank B and Huikuri, Heikki V and Hunter, David J and Iribarren, Carlos and Isomaa, Bo and Jarvelin, Marjo-Riitta and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kiemeney, Lambertus A and van der Klauw, Melanie M and Kooner, Jaspal S and Kraft, Peter and Iacoviello, Licia and Lehtim{\"a}ki, Terho and Lokki, Marja-Liisa L and Mitchell, Braxton D and Navis, Gerjan and Nieminen, Markku S and Ohlsson, Claes and Poulter, Neil R and Qi, Lu and Raitakari, Olli T and Rimm, Eric B and Rioux, John D and Rizzi, Federica and Rudan, Igor and Salomaa, Veikko and Sever, Peter S and Shields, Denis C and Shuldiner, Alan R and Sinisalo, Juha and Stanton, Alice V and Stolk, Ronald P and Strachan, David P and Tardif, Jean-Claude and Thorsteinsdottir, Unnur and Tuomilehto, Jaako and van Veldhuisen, Dirk J and Virtamo, Jarmo and Viikari, Jorma and Vollenweider, Peter and Waeber, G{\'e}rard and Widen, Elisabeth and Cho, Yoon Shin and Olsen, Jesper V and Visscher, Peter M and Willer, Cristen and Franke, Lude and Erdmann, Jeanette and Thompson, John R and Pfeufer, Arne and Sotoodehnia, Nona and Newton-Cheh, Christopher and Ellinor, Patrick T and Stricker, Bruno H Ch and Metspalu, Andres and Perola, Markus and Beckmann, Jacques S and Smith, George Davey and Stefansson, Kari and Wareham, Nicholas J and Munroe, Patricia B and Sibon, Ody C M and Milan, David J and Snieder, Harold and Samani, Nilesh J and Loos, Ruth J F} } @article {6291, title = {Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003796}, abstract = {

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

}, keywords = {Animals, Bone and Bones, Bone Density, Calcium, European Continental Ancestry Group, Gene Expression Regulation, Genome-Wide Association Study, Homeostasis, Humans, Kidney, Mice, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003796}, author = {O{\textquoteright}Seaghdha, Conall M and Wu, Hongsheng and Yang, Qiong and Kapur, Karen and Guessous, Idris and Zuber, Annie Mercier and K{\"o}ttgen, Anna and Stoudmann, Candice and Teumer, Alexander and Kutalik, Zolt{\'a}n and Mangino, Massimo and Dehghan, Abbas and Zhang, Weihua and Eiriksdottir, Gudny and Li, Guo and Tanaka, Toshiko and Portas, Laura and Lopez, Lorna M and Hayward, Caroline and Lohman, Kurt and Matsuda, Koichi and Padmanabhan, Sandosh and Firsov, Dmitri and Sorice, Rossella and Ulivi, Sheila and Brockhaus, A Catharina and Kleber, Marcus E and Mahajan, Anubha and Ernst, Florian D and Gudnason, Vilmundur and Launer, Lenore J and Mace, Aurelien and Boerwinckle, Eric and Arking, Dan E and Tanikawa, Chizu and Nakamura, Yusuke and Brown, Morris J and Gaspoz, Jean-Michel and Theler, Jean-Marc and Siscovick, David S and Psaty, Bruce M and Bergmann, Sven and Vollenweider, Peter and Vitart, Veronique and Wright, Alan F and Zemunik, Tatijana and Boban, Mladen and Kolcic, Ivana and Navarro, Pau and Brown, Edward M and Estrada, Karol and Ding, Jingzhong and Harris, Tamara B and Bandinelli, Stefania and Hernandez, Dena and Singleton, Andrew B and Girotto, Giorgia and Ruggiero, Daniela and d{\textquoteright}Adamo, Adamo Pio and Robino, Antonietta and Meitinger, Thomas and Meisinger, Christa and Davies, Gail and Starr, John M and Chambers, John C and Boehm, Bernhard O and Winkelmann, Bernhard R and Huang, Jie and Murgia, Federico and Wild, Sarah H and Campbell, Harry and Morris, Andrew P and Franco, Oscar H and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and V{\"o}lker, Uwe and Hannemann, Anke and Biffar, Reiner and Hoffmann, Wolfgang and Shin, So-Youn and Lescuyer, Pierre and Henry, Hughes and Schurmann, Claudia and Munroe, Patricia B and Gasparini, Paolo and Pirastu, Nicola and Ciullo, Marina and Gieger, Christian and M{\"a}rz, Winfried and Lind, Lars and Spector, Tim D and Smith, Albert V and Rudan, Igor and Wilson, James F and Polasek, Ozren and Deary, Ian J and Pirastu, Mario and Ferrucci, Luigi and Liu, Yongmei and Kestenbaum, Bryan and Kooner, Jaspal S and Witteman, Jacqueline C M and Nauck, Matthias and Kao, W H Linda and Wallaschofski, Henri and Bonny, Olivier and Fox, Caroline S and Bochud, Murielle} } @article {5998, title = {The QT interval and risk of incident atrial fibrillation.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Oct}, pages = {1562-8}, abstract = {

BACKGROUND: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.

OBJECTIVE: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.

METHODS: We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.

RESULTS: Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95\% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95\% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95\% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.

CONCLUSIONS: A prolonged QT interval is associated with an increased risk of incident AF.

}, keywords = {Aged, Atrial Fibrillation, Cohort Studies, Electrocardiography, Female, Humans, Incidence, Long QT Syndrome, Male, Middle Aged, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2013.07.023}, author = {Mandyam, Mala C and Soliman, Elsayed Z and Alonso, Alvaro and Dewland, Thomas A and Heckbert, Susan R and Vittinghoff, Eric and Cummings, Steven R and Ellinor, Patrick T and Chaitman, Bernard R and Stocke, Karen and Applegate, William B and Arking, Dan E and Butler, Javed and Loehr, Laura R and Magnani, Jared W and Murphy, Rachel A and Satterfield, Suzanne and Newman, Anne B and Marcus, Gregory M} } @article {6570, title = {A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans.}, journal = {J Cardiovasc Electrophysiol}, volume = {25}, year = {2014}, month = {2014 Nov}, pages = {1150-7}, abstract = {

OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.

BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.

METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).

RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2{\texttimes}10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 {\texttimes} 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).

CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Atrial Fibrillation, Case-Control Studies, Cohort Studies, Death, Sudden, Cardiac, Female, Genetic Variation, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Prospective Studies, Risk Factors, Single-Blind Method}, issn = {1540-8167}, doi = {10.1111/jce.12483}, author = {Ilkhanoff, Leonard and Arking, Dan E and Lemaitre, Rozenn N and Alonso, Alvaro and Chen, Lin Y and Durda, Peter and Hesselson, Stephanie E and Kerr, Kathleen F and Magnani, Jared W and Marcus, Gregory M and Schnabel, Renate B and Smith, J Gustav and Soliman, Elsayed Z and Reiner, Alexander P and Sotoodehnia, Nona} } @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 {6544, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain \~{}8-10\% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and D{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orr{\`u}, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} } @article {6690, title = {Genetic diversity is a predictor of mortality in humans.}, journal = {BMC Genet}, volume = {15}, year = {2014}, month = {2014}, pages = {159}, abstract = {

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person{\textquoteright}s risk of death by 1.57\%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

}, keywords = {Genome-Wide Association Study, Heterozygote, Humans, Mortality, Polymorphism, Single Nucleotide, Proportional Hazards Models}, issn = {1471-2156}, doi = {10.1186/s12863-014-0159-7}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Smith, Albert Vernon and Lunetta, Kathryn L and Nalls, Mike and Smith, Jennifer A and Tanaka, Toshiko and Davies, Gail and Yu, Lei and Mirza, Saira Saeed and Teumer, Alexander and Coresh, Josef and Pankow, James S and Franceschini, Nora and Scaria, Anish and Oshima, Junko and Psaty, Bruce M and Gudnason, Vilmundur and Eiriksdottir, Gudny and Harris, Tamara B and Li, Hanyue and Karasik, David and Kiel, Douglas P and Garcia, Melissa and Liu, Yongmei and Faul, Jessica D and Kardia, Sharon Lr and Zhao, Wei and Ferrucci, Luigi and Allerhand, Michael and Liewald, David C and Redmond, Paul and Starr, John M and De Jager, Philip L and Evans, Denis A and Direk, Nese and Ikram, Mohammed Arfan and Uitterlinden, Andre and Homuth, Georg and Lorbeer, Roberto and Grabe, Hans J and Launer, Lenore and Murabito, Joanne M and Singleton, Andrew B and Weir, David R and Bandinelli, Stefania and Deary, Ian J and Bennett, David A and Tiemeier, Henning and Kocher, Thomas and Lumley, Thomas and Arking, Dan E} } @article {6820, title = {Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.}, journal = {J Am Coll Cardiol}, volume = {63}, year = {2014}, month = {2014 Apr 1}, pages = {1200-10}, abstract = {

OBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

}, keywords = {Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Europe, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Polymorphism, Single Nucleotide, Transcription Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2013.12.015}, author = {Lubitz, Steven A and Lunetta, Kathryn L and Lin, Honghuang and Arking, Dan E and Trompet, Stella and Li, Guo and Krijthe, Bouwe P and Chasman, Daniel I and Barnard, John and Kleber, Marcus E and D{\"o}rr, Marcus and Ozaki, Kouichi and Smith, Albert V and M{\"u}ller-Nurasyid, Martina and Walter, Stefan and Agarwal, Sunil K and Bis, Joshua C and Brody, Jennifer A and Chen, Lin Y and Everett, Brendan M and Ford, Ian and Franco, Oscar H and Harris, Tamara B and Hofman, Albert and K{\"a}{\"a}b, Stefan and Mahida, Saagar and Kathiresan, Sekar and Kubo, Michiaki and Launer, Lenore J and Macfarlane, Peter W and Magnani, Jared W and McKnight, Barbara and McManus, David D and Peters, Annette and Psaty, Bruce M and Rose, Lynda M and Rotter, Jerome I and Silbernagel, Guenther and Smith, Jonathan D and Sotoodehnia, Nona and Stott, David J and Taylor, Kent D and Tomaschitz, Andreas and Tsunoda, Tatsuhiko and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Murabito, Joanne M and Sinner, Moritz F and Gudnason, Vilmundur and Felix, Stephan B and M{\"a}rz, Winfried and Chung, Mina and Albert, Christine M and Stricker, Bruno H and Tanaka, Toshihiro and Heckbert, Susan R and Jukema, J Wouter and Alonso, Alvaro and Benjamin, Emelia J and Ellinor, Patrick T} } @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 {6149, title = {Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.}, journal = {Heart Rhythm}, volume = {11}, year = {2014}, month = {2014 Mar}, pages = {452-7}, abstract = {

BACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.

OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.

RESULTS: One common variant (rs11265611; P = 1.70 {\texttimes} 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95\% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).

CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

}, keywords = {Aged, Atrial Fibrillation, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interleukin-6}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2013.11.012}, author = {Lin, Honghuang and Sinner, Moritz F and Brody, Jennifer A and Arking, Dan E and Lunetta, Kathryn L and Rienstra, Michiel and Lubitz, Steven A and Magnani, Jared W and Sotoodehnia, Nona and McKnight, Barbara and McManus, David D and Boerwinkle, Eric and Psaty, Bruce M and Rotter, Jerome I and Bis, Joshua C and Gibbs, Richard A and Muzny, Donna and Kovar, Christie L and Morrison, Alanna C and Gupta, Mayetri and Folsom, Aaron R and K{\"a}{\"a}b, Stefan and Heckbert, Susan R and Alonso, Alvaro and Ellinor, Patrick T and Benjamin, Emelia J} } @article {6545, title = {Association of mitochondrial DNA levels with frailty and all-cause mortality.}, journal = {J Mol Med (Berl)}, volume = {93}, year = {2015}, month = {2015 Feb}, pages = {177-186}, abstract = {

Mitochondrial function is altered with age and variants in mitochondrial DNA (mtDNA) modulate risk for several age-related disease states. However, the association of mtDNA copy number, a readily available marker which reflects mitochondrial depletion, energy reserves, and oxidative stress, on aging and mortality in the general population has not been addressed. To assess the association between mtDNA copy number and two primary outcomes--prevalent frailty and all-cause mortality--we utilize data from participants who were from two multicenter, multiethnic, community-based, prospective studies--the Cardiovascular Health Study (CHS) (1989-2006) and the Atherosclerosis Risk in Communities (ARIC) study (1987-2013). A total of 4892 participants (43.3\% men) from CHS and 11,509 participants (44.9\% men) from ARIC self-identifying as white or black were included in the analysis. mtDNA copy number, the trait of interest, was measured using a qPCR-based method in CHS and an array-based method in ARIC from DNA isolated from whole blood in participants from both cohorts. In race-stratified meta-analyses, we observe a significant inverse association of mtDNA copy number with age and higher mtDNA copy number in women relative to men. Lower mtDNA copy number was also significantly associated with prevalent frailty in white participants from CHS (OR 0.91, 95\% CI 0.85-0.97). Additionally, mtDNA copy number was a strong independent predictor of all-cause mortality in an age- and sex-adjusted, race-stratified analysis of 16,401 participants from both cohorts with a pooled hazard ratio of 1.47 (95\% CI 1.33-1.62) for the lowest quintile of mtDNA copy number relative to the highest quintile. Key messages: Mitochondrial DNA (mtDNA) copy number is associated with age and sex. Lower mtDNA copy number is also associated with prevalent frailty. mtDNA copy number is a significant predictor of all-cause mortality in a multiethnic population.

}, keywords = {African Americans, Aged, Aged, 80 and over, Aging, DNA, Mitochondrial, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Dosage, Geriatric Assessment, Humans, Kaplan-Meier Estimate, Male, Mortality, Odds Ratio, Population Surveillance, Prospective Studies, Surveys and Questionnaires, United States}, issn = {1432-1440}, doi = {10.1007/s00109-014-1233-3}, author = {Ashar, Foram N and Moes, Anna and Moore, Ann Z and Grove, Megan L and Chaves, Paulo H M and Coresh, Josef and Newman, Anne B and Matteini, Amy M and Bandeen-Roche, Karen and Boerwinkle, Eric and Walston, Jeremy D and Arking, Dan E} } @article {7262, title = {52 Genetic Loci Influencing Myocardial~Mass.}, journal = {J Am Coll Cardiol}, volume = {68}, year = {2016}, month = {2016 Sep 27}, pages = {1435-48}, abstract = {

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.

OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.

METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.

RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p~< 1~{\texttimes} 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67~candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in~vitro and in~vivo.

CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2016.07.729}, author = {van der Harst, Pim and van Setten, Jessica and Verweij, Niek and Vogler, Georg and Franke, Lude and Maurano, Matthew T and Wang, Xinchen and Mateo Leach, Irene and Eijgelsheim, Mark and Sotoodehnia, Nona and Hayward, Caroline and Sorice, Rossella and Meirelles, Osorio and Lyytik{\"a}inen, Leo-Pekka and Polasek, Ozren and Tanaka, Toshiko and Arking, Dan E and Ulivi, Sheila and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Smith, Albert V and D{\"o}rr, Marcus and Kerr, Kathleen F and Magnani, Jared W and del Greco M, Fabiola and Zhang, Weihua and Nolte, Ilja M and Silva, Claudia T and Padmanabhan, Sandosh and Tragante, Vinicius and Esko, T{\~o}nu and Abecasis, Goncalo R and Adriaens, Michiel E and Andersen, Karl and Barnett, Phil and Bis, Joshua C and Bodmer, Rolf and Buckley, Brendan M and Campbell, Harry and Cannon, Megan V and Chakravarti, Aravinda and Chen, Lin Y and Delitala, Alessandro and Devereux, Richard B and Doevendans, Pieter A and Dominiczak, Anna F and Ferrucci, Luigi and Ford, Ian and Gieger, Christian and Harris, Tamara B and Haugen, Eric and Heinig, Matthias and Hernandez, Dena G and Hillege, Hans L and Hirschhorn, Joel N and Hofman, Albert and Hubner, Norbert and Hwang, Shih-Jen and Iorio, Annamaria and K{\"a}h{\"o}nen, Mika and Kellis, Manolis and Kolcic, Ivana and Kooner, Ishminder K and Kooner, Jaspal S and Kors, Jan A and Lakatta, Edward G and Lage, Kasper and Launer, Lenore J and Levy, Daniel and Lundby, Alicia and Macfarlane, Peter W and May, Dalit and Meitinger, Thomas and Metspalu, Andres and Nappo, Stefania and Naitza, Silvia and Neph, Shane and Nord, Alex S and Nutile, Teresa and Okin, Peter M and Olsen, Jesper V and Oostra, Ben A and Penninger, Josef M and Pennacchio, Len A and Pers, Tune H and Perz, Siegfried and Peters, Annette and Pinto, Yigal M and Pfeufer, Arne and Pilia, Maria Grazia and Pramstaller, Peter P and Prins, Bram P and Raitakari, Olli T and Raychaudhuri, Soumya and Rice, Ken M and Rossin, Elizabeth J and Rotter, Jerome I and Schafer, Sebastian and Schlessinger, David and Schmidt, Carsten O and Sehmi, Jobanpreet and Sillj{\'e}, Herman H W and Sinagra, Gianfranco and Sinner, Moritz F and Slowikowski, Kamil and Soliman, Elsayed Z and Spector, Timothy D and Spiering, Wilko and Stamatoyannopoulos, John A and Stolk, Ronald P and Strauch, Konstantin and Tan, Sian-Tsung and Tarasov, Kirill V and Trinh, Bosco and Uitterlinden, Andr{\'e} G and van den Boogaard, Malou and van Duijn, Cornelia M and van Gilst, Wiek H and Viikari, Jorma S and Visscher, Peter M and Vitart, Veronique and V{\"o}lker, Uwe and Waldenberger, Melanie and Weichenberger, Christian X and Westra, Harm-Jan and Wijmenga, Cisca and Wolffenbuttel, Bruce H and Yang, Jian and Bezzina, Connie R and Munroe, Patricia B and Snieder, Harold and Wright, Alan F and Rudan, Igor and Boyer, Laurie A and Asselbergs, Folkert W and van Veldhuisen, Dirk J and Stricker, Bruno H and Psaty, Bruce M and Ciullo, Marina and Sanna, Serena and Lehtim{\"a}ki, Terho and Wilson, James F and Bandinelli, Stefania and Alonso, Alvaro and Gasparini, Paolo and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and Gudnason, Vilmundur and Felix, Stephan B and Heckbert, Susan R and de Boer, Rudolf A and Newton-Cheh, Christopher and Hicks, Andrew A and Chambers, John C and Jamshidi, Yalda and Visel, Axel and Christoffels, Vincent M and Isaacs, Aaron and Samani, Nilesh J and de Bakker, Paul I W} } @article {7259, title = {Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.}, journal = {Hum Mol Genet}, year = {2016}, month = {2016 Aug 29}, abstract = {

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 {\texttimes} 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 {\texttimes} 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 {\texttimes} 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 {\texttimes} 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 {\texttimes} 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddw284}, author = {Evans, Daniel S and Avery, Christy L and Nalls, Mike A and Li, Guo and Barnard, John and Smith, Erin N and Tanaka, Toshiko and Butler, Anne M and Buxbaum, Sarah G and Alonso, Alvaro and Arking, Dan E and Berenson, Gerald S and Bis, Joshua C and Buyske, Steven and Carty, Cara L and Chen, Wei and Chung, Mina K and Cummings, Steven R and Deo, Rajat and Eaton, Charles B and Fox, Ervin R and Heckbert, Susan R and Heiss, Gerardo and Hindorff, Lucia A and Hsueh, Wen-Chi and Isaacs, Aaron and Jamshidi, Yalda and Kerr, Kathleen F and Liu, Felix and Liu, Yongmei and Lohman, Kurt K and Magnani, Jared W and Maher, Joseph F and Mehra, Reena and Meng, Yan A and Musani, Solomon K and Newton-Cheh, Christopher and North, Kari E and Psaty, Bruce M and Redline, Susan and Rotter, Jerome I and Schnabel, Renate B and Schork, Nicholas J and Shohet, Ralph V and Singleton, Andrew B and Smith, Jonathan D and Soliman, Elsayed Z and Srinivasan, Sathanur R and Taylor, Herman A and Van Wagoner, David R and Wilson, James G and Young, Taylor and Zhang, Zhu-Ming and Zonderman, Alan B and Evans, Michele K and Ferrucci, Luigi and Murray, Sarah S and Tranah, Gregory J and Whitsel, Eric A and Reiner, Alex P and Sotoodehnia, Nona} } @article {7165, title = {Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.}, journal = {JAMA Cardiol}, volume = {1}, year = {2016}, month = {2016 Jul 1}, pages = {442-50}, abstract = {

IMPORTANCE: White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors.

OBJECTIVES: To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon.

DESIGN, SETTING, AND PARTICIPANTS: Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015.

MAIN OUTCOMES AND MEASURES: Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data.

RESULTS: A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4\%; 95\% CI, 2.9\%-29.9\%) and ARIC (31.7\%; 95\% CI, 16.0\%-53.0\%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified.

CONCLUSIONS AND RELEVANCE: The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2016.1185}, author = {Roberts, Jason D and Hu, Donglei and Heckbert, Susan R and Alonso, Alvaro and Dewland, Thomas A and Vittinghoff, Eric and Liu, Yongmei and Psaty, Bruce M and Olgin, Jeffrey E and Magnani, Jared W and Huntsman, Scott and Burchard, Esteban G and Arking, Dan E and Bibbins-Domingo, Kirsten and Harris, Tamara B and Perez, Marco V and Ziv, Elad and Marcus, Gregory M} } @article {7142, title = {GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.}, journal = {Aging Cell}, volume = {15}, year = {2016}, month = {2016 Oct}, pages = {792-800}, abstract = {

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27~581 individuals of European descent over 65~years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5~{\texttimes}~10(-8) ) and 39 suggestive (P-value< 5~{\texttimes}~10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β~=~0.47, SE~=~0.08, P-value~=~5.20~{\texttimes}~10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

}, issn = {1474-9726}, doi = {10.1111/acel.12468}, author = {Matteini, Amy M and Tanaka, Toshiko and Karasik, David and Atzmon, Gil and Chou, Wen-Chi and Eicher, John D and Johnson, Andrew D and Arnold, Alice M and Callisaya, Michele L and Davies, Gail and Evans, Daniel S and Holtfreter, Birte and Lohman, Kurt and Lunetta, Kathryn L and Mangino, Massimo and Smith, Albert V and Smith, Jennifer A and Teumer, Alexander and Yu, Lei and Arking, Dan E and Buchman, Aron S and Chibinik, Lori B and De Jager, Philip L and Evans, Denis A and Faul, Jessica D and Garcia, Melissa E and Gillham-Nasenya, Irina and Gudnason, Vilmundur and Hofman, Albert and Hsu, Yi-Hsiang and Ittermann, Till and Lahousse, Lies and Liewald, David C and Liu, Yongmei and Lopez, Lorna and Rivadeneira, Fernando and Rotter, Jerome I and Siggeirsdottir, Kristin and Starr, John M and Thomson, Russell and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Weir, David R and Yaffe, Kristine and Zhao, Wei and Zhuang, Wei Vivian and Zmuda, Joseph M and Bennett, David A and Cummings, Steven R and Deary, Ian J and Ferrucci, Luigi and Harris, Tamara B and Kardia, Sharon L R and Kocher, Thomas and Kritchevsky, Stephen B and Psaty, Bruce M and Seshadri, Sudha and Spector, Timothy D and Srikanth, Velandai K and Windham, B Gwen and Zillikens, M Carola and Newman, Anne B and Walston, Jeremy D and Kiel, Douglas P and Murabito, Joanne M} } @article {7166, title = {Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.}, journal = {Am Heart J}, volume = {175}, year = {2016}, month = {2016 May}, pages = {9-17}, abstract = {

BACKGROUND: Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.

METHODS: We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.

RESULTS: Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.

CONCLUSIONS: Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.

}, issn = {1097-6744}, doi = {10.1016/j.ahj.2016.02.002}, author = {Roberts, Jason D and Dewland, Thomas A and Glidden, David V and Hoffmann, Thomas J and Arking, Dan E and Chen, Lin Y and Psaty, Bruce M and Olgin, Jeffrey E and Alonso, Alvaro and Heckbert, Susan R and Marcus, Gregory M} } @article {7011, title = {Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 Jul}, pages = {441-9}, abstract = {

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from \~{}60 000 individuals in the discovery stage and \~{}90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103439}, author = {van Leeuwen, Elisabeth M and Sabo, Aniko and Bis, Joshua C and Huffman, Jennifer E and Manichaikul, Ani and Smith, Albert V and Feitosa, Mary F and Demissie, Serkalem and Joshi, Peter K and Duan, Qing and Marten, Jonathan and van Klinken, Jan B and Surakka, Ida and Nolte, Ilja M and Zhang, Weihua and Mbarek, Hamdi and Li-Gao, Ruifang and Trompet, Stella and Verweij, Niek and Evangelou, Evangelos and Lyytik{\"a}inen, Leo-Pekka and Tayo, Bamidele O and Deelen, Joris and van der Most, Peter J and van der Laan, Sander W and Arking, Dan E and Morrison, Alanna and Dehghan, Abbas and Franco, Oscar H and Hofman, Albert and Rivadeneira, Fernando and Sijbrands, Eric J and Uitterlinden, Andr{\'e} G and Mychaleckyj, Josyf C and Campbell, Archie and Hocking, Lynne J and Padmanabhan, Sandosh and Brody, Jennifer A and Rice, Kenneth M and White, Charles C and Harris, Tamara and Isaacs, Aaron and Campbell, Harry and Lange, Leslie A and Rudan, Igor and Kolcic, Ivana and Navarro, Pau and Zemunik, Tatijana and Salomaa, Veikko and Kooner, Angad S and Kooner, Jaspal S and Lehne, Benjamin and Scott, William R and Tan, Sian-Tsung and de Geus, Eco J and Milaneschi, Yuri and Penninx, Brenda W J H and Willemsen, Gonneke and de Mutsert, Ren{\'e}e and Ford, Ian and Gansevoort, Ron T and Segura-Lepe, Marcelo P and Raitakari, Olli T and Viikari, Jorma S and Nikus, Kjell and Forrester, Terrence and McKenzie, Colin A and de Craen, Anton J M and de Ruijter, Hester M and Pasterkamp, Gerard and Snieder, Harold and Oldehinkel, Albertine J and Slagboom, P Eline and Cooper, Richard S and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Elliott, Paul and van der Harst, Pim and Jukema, J Wouter and Mook-Kanamori, Dennis O and Boomsma, Dorret I and Chambers, John C and Swertz, Morris and Ripatti, Samuli and Willems van Dijk, Ko and Vitart, Veronique and Polasek, Ozren and Hayward, Caroline and Wilson, James G and Wilson, James F and Gudnason, Vilmundur and Rich, Stephen S and Psaty, Bruce M and Borecki, Ingrid B and Boerwinkle, Eric and Rotter, Jerome I and Cupples, L Adrienne and van Duijn, Cornelia M} } @article {7255, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, year = {2016}, month = {2016 Dec 05}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7{\texttimes}10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4{\texttimes}10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {7604, title = {Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 05 15}, pages = {2093-2103}, abstract = {

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.

}, keywords = {Adaptor Proteins, Signal Transducing, Arrhythmias, Cardiac, Basic Helix-Loop-Helix Transcription Factors, Brugada Syndrome, Cardiac Conduction System Disease, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Conduction System, Humans, Male, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Repressor Proteins, Shab Potassium Channels, Shal Potassium Channels}, issn = {1460-2083}, doi = {10.1093/hmg/ddw058}, author = {Verweij, Niek and Mateo Leach, Irene and Isaacs, Aaron and Arking, Dan E and Bis, Joshua C and Pers, Tune H and van den Berg, Marten E and Lyytik{\"a}inen, Leo-Pekka and Barnett, Phil and Wang, Xinchen and Soliman, Elsayed Z and van Duijn, Cornelia M and K{\"a}h{\"o}nen, Mika and van Veldhuisen, Dirk J and Kors, Jan A and Raitakari, Olli T and Silva, Claudia T and Lehtim{\"a}ki, Terho and Hillege, Hans L and Hirschhorn, Joel N and Boyer, Laurie A and van Gilst, Wiek H and Alonso, Alvaro and Sotoodehnia, Nona and Eijgelsheim, Mark and de Boer, Rudolf A and de Bakker, Paul I W and Franke, Lude and van der Harst, Pim} } @article {7250, title = {Whole Exome Sequencing in Atrial Fibrillation.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Sep}, pages = {e1006284}, abstract = {

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78\%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86\%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95\% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006284}, author = {Lubitz, Steven A and Brody, Jennifer A and Bihlmeyer, Nathan A and Roselli, Carolina and Weng, Lu-Chen and Christophersen, Ingrid E and Alonso, Alvaro and Boerwinkle, Eric and Gibbs, Richard A and Bis, Joshua C and Cupples, L Adrienne and Mohler, Peter J and Nickerson, Deborah A and Muzny, Donna and Perez, Marco V and Psaty, Bruce M and Soliman, Elsayed Z and Sotoodehnia, Nona and Lunetta, Kathryn L and Benjamin, Emelia J and Heckbert, Susan R and Arking, Dan E and Ellinor, Patrick T and Lin, Honghuang} } @article {7594, title = {Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.}, journal = {JAMA Oncol}, volume = {3}, year = {2017}, month = {2017 May 01}, pages = {636-651}, abstract = {

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95\% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95\% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95\% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95\% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95\% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95\% CI, 0.05-0.15]).

Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis}, issn = {2374-2445}, doi = {10.1001/jamaoncol.2016.5945}, author = {Haycock, Philip C and Burgess, Stephen and Nounu, Aayah and Zheng, Jie and Okoli, George N and Bowden, Jack and Wade, Kaitlin Hazel and Timpson, Nicholas J and Evans, David M and Willeit, Peter and Aviv, Abraham and Gaunt, Tom R and Hemani, Gibran and Mangino, Massimo and Ellis, Hayley Patricia and Kurian, Kathreena M and Pooley, Karen A and Eeles, Rosalind A and Lee, Jeffrey E and Fang, Shenying and Chen, Wei V and Law, Matthew H and Bowdler, Lisa M and Iles, Mark M and Yang, Qiong and Worrall, Bradford B and Markus, Hugh Stephen and Hung, Rayjean J and Amos, Chris I and Spurdle, Amanda B and Thompson, Deborah J and O{\textquoteright}Mara, Tracy A and Wolpin, Brian and Amundadottir, Laufey and Stolzenberg-Solomon, Rachael and Trichopoulou, Antonia and Onland-Moret, N Charlotte and Lund, Eiliv and Duell, Eric J and Canzian, Federico and Severi, Gianluca and Overvad, Kim and Gunter, Marc J and Tumino, Rosario and Svenson, Ulrika and van Rij, Andre and Baas, Annette F and Bown, Matthew J and Samani, Nilesh J and van t{\textquoteright}Hof, Femke N G and Tromp, Gerard and Jones, Gregory T and Kuivaniemi, Helena and Elmore, James R and Johansson, Mattias and Mckay, James and Scelo, Ghislaine and Carreras-Torres, Robert and Gaborieau, Valerie and Brennan, Paul and Bracci, Paige M and Neale, Rachel E and Olson, Sara H and Gallinger, Steven and Li, Donghui and Petersen, Gloria M and Risch, Harvey A and Klein, Alison P and Han, Jiali and Abnet, Christian C and Freedman, Neal D and Taylor, Philip R and Maris, John M and Aben, Katja K and Kiemeney, Lambertus A and Vermeulen, Sita H and Wiencke, John K and Walsh, Kyle M and Wrensch, Margaret and Rice, Terri and Turnbull, Clare and Litchfield, Kevin and Paternoster, Lavinia and Standl, Marie and Abecasis, Goncalo R and SanGiovanni, John Paul and Li, Yong and Mijatovic, Vladan and Sapkota, Yadav and Low, Siew-Kee and Zondervan, Krina T and Montgomery, Grant W and Nyholt, Dale R and van Heel, David A and Hunt, Karen and Arking, Dan E and Ashar, Foram N and Sotoodehnia, Nona and Woo, Daniel and Rosand, Jonathan and Comeau, Mary E and Brown, W Mark and Silverman, Edwin K and Hokanson, John E and Cho, Michael H and Hui, Jennie and Ferreira, Manuel A and Thompson, Philip J and Morrison, Alanna C and Felix, Janine F and Smith, Nicholas L and Christiano, Angela M and Petukhova, Lynn and Betz, Regina C and Fan, Xing and Zhang, Xuejun and Zhu, Caihong and Langefeld, Carl D and Thompson, Susan D and Wang, Feijie and Lin, Xu and Schwartz, David A and Fingerlin, Tasha and Rotter, Jerome I and Cotch, Mary Frances and Jensen, Richard A and Munz, Matthias and Dommisch, Henrik and Schaefer, Arne S and Han, Fang and Ollila, Hanna M and Hillary, Ryan P and Albagha, Omar and Ralston, Stuart H and Zeng, Chenjie and Zheng, Wei and Shu, Xiao-Ou and Reis, Andre and Uebe, Steffen and H{\"u}ffmeier, Ulrike and Kawamura, Yoshiya and Otowa, Takeshi and Sasaki, Tsukasa and Hibberd, Martin Lloyd and Davila, Sonia and Xie, Gang and Siminovitch, Katherine and Bei, Jin-Xin and Zeng, Yi-Xin and F{\"o}rsti, Asta and Chen, Bowang and Landi, Stefano and Franke, Andre and Fischer, Annegret and Ellinghaus, David and Flores, Carlos and Noth, Imre and Ma, Shwu-Fan and Foo, Jia Nee and Liu, Jianjun and Kim, Jong-Won and Cox, David G and Delattre, Olivier and Mirabeau, Olivier and Skibola, Christine F and Tang, Clara S and Garcia-Barcelo, Merce and Chang, Kai-Ping and Su, Wen-Hui and Chang, Yu-Sun and Martin, Nicholas G and Gordon, Scott and Wade, Tracey D and Lee, Chaeyoung and Kubo, Michiaki and Cha, Pei-Chieng and Nakamura, Yusuke and Levy, Daniel and Kimura, Masayuki and Hwang, Shih-Jen and Hunt, Steven and Spector, Tim and Soranzo, Nicole and Manichaikul, Ani W and Barr, R Graham and Kahali, Bratati and Speliotes, Elizabeth and Yerges-Armstrong, Laura M and Cheng, Ching-Yu and Jonas, Jost B and Wong, Tien Yin and Fogh, Isabella and Lin, Kuang and Powell, John F and Rice, Kenneth and Relton, Caroline L and Martin, Richard M and Davey Smith, George} } @article {7548, title = {Association of Mitochondrial DNA Copy Number With Cardiovascular Disease.}, journal = {JAMA Cardiol}, volume = {2}, year = {2017}, month = {2017 Nov 01}, pages = {1247-1255}, abstract = {

Importance: Mitochondrial dysfunction is a core component of the aging process and may play a key role in atherosclerotic cardiovascular disease. Mitochondrial DNA copy number (mtDNA-CN), which represents the number of mitochondria per cell and number of mitochondrial genomes per mitochondrion, is an indirect biomarker of mitochondrial function.

Objective: To determine whether mtDNA-CN, measured in an easily accessible tissue (buffy coat/circulating leukocytes), can improve risk classification for cardiovascular disease (CVD) and help guide initiation of statin therapy for primary prevention of CVD.

Design, Setting, and Participants: Prospective, population-based cohort analysis including 21 870 participants (20 163 free from CVD at baseline) from 3 studies: Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities Study (ARIC), and Multiethnic Study of Atherosclerosis (MESA). The mean follow-up was 13.5 years. The study included 11 153 participants from ARIC, 4830 from CHS, and 5887 from MESA. Analysis of the data was conducted from March 10, 2014, to January 29, 2017.

Exposures: Mitochondrial DNA-CN measured from buffy coat/circulating leukocytes.

Main Outcomes and Measures: Incident CVD, which combines coronary heart disease, defined as the first incident myocardial infarction or death owing to coronary heart disease, and stroke, defined as the first nonfatal stroke or death owing to stroke.

Results: Of the 21 870 participants, the mean age was 62.4 years (ARIC, 57.9 years; MESA, 62.4 years; and CHS, 72.5 years), and 54.7\% of participants were women. The hazard ratios for incident coronary heart disease, stroke, and CVD associated with a 1-SD decrease in mtDNA-CN were 1.29 (95\% CI, 1.24-1.33), 1.11 (95\% CI, 1.06-1.16), and 1.23 (95\% CI, 1.19-1.26). The associations persisted after adjustment for traditional CVD risk factors. Addition of mtDNA-CN to the 2013 American College of Cardiology/American Heart Association Pooled Cohorts Equations for estimating 10-year hard atherosclerosis CVD risk was associated with improved risk classification (continuous net reclassification index, 0.194; 95\% CI, 0.130-0.258; P < .001). Mitochondrial DNA-CN further improved sensitivity and specificity for the 2013 American College of Cardiology/American Heart Association recommendations on initiating statin therapy for primary prevention of ASCVD (net 221 individuals appropriately downclassified and net 15 individuals appropriately upclassified).

Conclusions and Relevance: Mitochondrial DNA-CN was independently associated with incident CVD in 3 large prospective studies and may have potential clinical utility in improving CVD risk classification.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2017.3683}, author = {Ashar, Foram N and Zhang, Yiyi and Longchamps, Ryan J and Lane, John and Moes, Anna and Grove, Megan L and Mychaleckyj, Josyf C and Taylor, Kent D and Coresh, Josef and Rotter, Jerome I and Boerwinkle, Eric and Pankratz, Nathan and Guallar, Eliseo and Arking, Dan E} } @article {7363, title = {Discovery of novel heart rate-associated loci using the Exome Chip.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

Background Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9\% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx113}, author = {van den Berg, Marten E and Warren, Helen R and Cabrera, Claudia P and Verweij, Niek and Mifsud, Borbala and Haessler, Jeffrey and Bihlmeyer, Nathan A and Fu, Yi-Ping and Weiss, Stefan and Lin, Henry J and Grarup, Niels and Li-Gao, Ruifang and Pistis, Giorgio and Shah, Nabi and Brody, Jennifer A and M{\"u}ller-Nurasyid, Martina and Lin, Honghuang and Mei, Hao and Smith, Albert V and Lyytik{\"a}inen, Leo-Pekka and Hall, Leanne M and van Setten, Jessica and Trompet, Stella and Prins, Bram P and Isaacs, Aaron and Radmanesh, Farid and Marten, Jonathan and Entwistle, Aiman and Kors, Jan A and Silva, Claudia T and Alonso, Alvaro and Bis, Joshua C and de Boer, Rudolf and de Haan, Hugoline G and de Mutsert, Ren{\'e}e and Dedoussis, George and Dominiczak, Anna F and Doney, Alex S F and Ellinor, Patrick T and Eppinga, Ruben N and Felix, Stephan B and Guo, Xiuqing and Hagemeijer, Yanick and Hansen, Torben and Harris, Tamara B and Heckbert, Susan R and Huang, Paul L and Hwang, Shih-Jen and K{\"a}h{\"o}nen, Mika and Kanters, J{\o}rgen K and Kolcic, Ivana and Launer, Lenore J and Li, Man and Yao, Jie and Linneberg, Allan and Liu, Simin and Macfarlane, Peter W and Mangino, Massimo and Morris, Andrew D and Mulas, Antonella and Murray, Alison D and Nelson, Christopher P and Orr{\`u}, Marco and Padmanabhan, Sandosh and Peters, Annette and Porteous, David J and Poulter, Neil and Psaty, Bruce M and Qi, Lihong and Raitakari, Olli T and Rivadeneira, Fernando and Roselli, Carolina and Rudan, Igor and Sattar, Naveed and Sever, Peter and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Timothy D and Stanton, Alice V and Stirrups, Kathleen E and Taylor, Kent D and Tobin, Martin D and Uitterlinden, Andre and Vaartjes, Ilonca and Hoes, Arno W and van der Meer, Peter and V{\"o}lker, Uwe and Waldenberger, Melanie and Xie, Zhijun and Zoledziewska, Magdalena and Tinker, Andrew and Polasek, Ozren and Rosand, Jonathan and Jamshidi, Yalda and van Duijn, Cornelia M and Zeggini, Eleftheria and Wouter Jukema, J and Asselbergs, Folkert W and Samani, Nilesh J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Wilson, James and Lubitz, Steven A and K{\"a}{\"a}b, Stefan and Sotoodehnia, Nona and Caulfield, Mark J and Palmer, Colin N A and Sanna, Serena and Mook-Kanamori, Dennis O and Deloukas, Panos and Pedersen, Oluf and Rotter, Jerome I and D{\"o}rr, Marcus and O{\textquoteright}Donnell, Chris J and Hayward, Caroline and Arking, Dan E and Kooperberg, Charles and van der Harst, Pim and Eijgelsheim, Mark and Stricker, Bruno H and Munroe, Patricia B} } @article {7557, title = {Fifteen Genetic Loci Associated With the Electrocardiographic P Wave.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, abstract = {

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.

METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16\%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5{\texttimes}10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.

CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

}, keywords = {Arrhythmias, Cardiac, Caveolin 1, Caveolin 2, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Genotype, Heart Atria, Humans, NAV1.5 Voltage-Gated Sodium Channel, NAV1.8 Voltage-Gated Sodium Channel, T-Box Domain Proteins}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001667}, author = {Christophersen, Ingrid E and Magnani, Jared W and Yin, Xiaoyan and Barnard, John and Weng, Lu-Chen and Arking, Dan E and Niemeijer, Maartje N and Lubitz, Steven A and Avery, Christy L and Duan, Qing and Felix, Stephan B and Bis, Joshua C and Kerr, Kathleen F and Isaacs, Aaron and M{\"u}ller-Nurasyid, Martina and M{\"u}ller, Christian and North, Kari E and Reiner, Alex P and Tinker, Lesley F and Kors, Jan A and Teumer, Alexander and Petersmann, Astrid and Sinner, Moritz F and B{\r u}zkov{\'a}, Petra and Smith, Jonathan D and Van Wagoner, David R and V{\"o}lker, Uwe and Waldenberger, Melanie and Peters, Annette and Meitinger, Thomas and Limacher, Marian C and Wilhelmsen, Kirk C and Psaty, Bruce M and Hofman, Albert and Uitterlinden, Andre and Krijthe, Bouwe P and Zhang, Zhu-Ming and Schnabel, Renate B and K{\"a}{\"a}b, Stefan and van Duijn, Cornelia and Rotter, Jerome I and Sotoodehnia, Nona and D{\"o}rr, Marcus and Li, Yun and Chung, Mina K and Soliman, Elsayed Z and Alonso, Alvaro and Whitsel, Eric A and Stricker, Bruno H and Benjamin, Emelia J and Heckbert, Susan R and Ellinor, Patrick T} } @article {7595, title = {Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 Sep 12}, pages = {11303}, abstract = {

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects <= 65 years of age than among those > 65 years (interaction p-value = 4.0 {\texttimes} 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 {\texttimes} 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

}, issn = {2045-2322}, doi = {10.1038/s41598-017-09396-7}, author = {Weng, Lu-Chen and Lunetta, Kathryn L and M{\"u}ller-Nurasyid, Martina and Smith, Albert Vernon and Th{\'e}riault, S{\'e}bastien and Weeke, Peter E and Barnard, John and Bis, Joshua C and Lyytik{\"a}inen, Leo-Pekka and Kleber, Marcus E and Martinsson, Andreas and Lin, Henry J and Rienstra, Michiel and Trompet, Stella and Krijthe, Bouwe P and D{\"o}rr, Marcus and Klarin, Derek and Chasman, Daniel I and Sinner, Moritz F and Waldenberger, Melanie and Launer, Lenore J and Harris, Tamara B and Soliman, Elsayed Z and Alonso, Alvaro and Par{\'e}, Guillaume and Teixeira, Pedro L and Denny, Joshua C and Shoemaker, M Benjamin and Van Wagoner, David R and Smith, Jonathan D and Psaty, Bruce M and Sotoodehnia, Nona and Taylor, Kent D and K{\"a}h{\"o}nen, Mika and Nikus, Kjell and Delgado, Graciela E and Melander, Olle and Engstr{\"o}m, Gunnar and Yao, Jie and Guo, Xiuqing and Christophersen, Ingrid E and Ellinor, Patrick T and Geelhoed, Bastiaan and Verweij, Niek and Macfarlane, Peter and Ford, Ian and Heeringa, Jan and Franco, Oscar H and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Teumer, Alexander and Rose, Lynda M and K{\"a}{\"a}b, Stefan and Gudnason, Vilmundur and Arking, Dan E and Conen, David and Roden, Dan M and Chung, Mina K and Heckbert, Susan R and Benjamin, Emelia J and Lehtim{\"a}ki, Terho and M{\"a}rz, Winfried and Smith, J Gustav and Rotter, Jerome I and van der Harst, Pim and Jukema, J Wouter and Stricker, Bruno H and Felix, Stephan B and Albert, Christine M and Lubitz, Steven A} } @article {7396, title = {Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {946-952}, abstract = {

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

}, issn = {1546-1718}, doi = {10.1038/ng.3843}, author = {Christophersen, Ingrid E and Rienstra, Michiel and Roselli, Carolina and Yin, Xiaoyan and Geelhoed, Bastiaan and Barnard, John and Lin, Honghuang and Arking, Dan E and Smith, Albert V and Albert, Christine M and Chaffin, Mark and Tucker, Nathan R and Li, Molong and Klarin, Derek and Bihlmeyer, Nathan A and Low, Siew-Kee and Weeke, Peter E and M{\"u}ller-Nurasyid, Martina and Smith, J Gustav and Brody, Jennifer A and Niemeijer, Maartje N and D{\"o}rr, Marcus and Trompet, Stella and Huffman, Jennifer and Gustafsson, Stefan and Schurmann, Claudia and Kleber, Marcus E and Lyytik{\"a}inen, Leo-Pekka and Sepp{\"a}l{\"a}, Ilkka and Malik, Rainer and Horimoto, Andrea R V R and Perez, Marco and Sinisalo, Juha and Aeschbacher, Stefanie and Th{\'e}riault, S{\'e}bastien and Yao, Jie and Radmanesh, Farid and Weiss, Stefan and Teumer, Alexander and Choi, Seung Hoan and Weng, Lu-Chen and Clauss, Sebastian and Deo, Rajat and Rader, Daniel J and Shah, Svati H and Sun, Albert and Hopewell, Jemma C and Debette, Stephanie and Chauhan, Ganesh and Yang, Qiong and Worrall, Bradford B and Par{\'e}, Guillaume and Kamatani, Yoichiro and Hagemeijer, Yanick P and Verweij, Niek and Siland, Joylene E and Kubo, Michiaki and Smith, Jonathan D and Van Wagoner, David R and Bis, Joshua C and Perz, Siegfried and Psaty, Bruce M and Ridker, Paul M and Magnani, Jared W and Harris, Tamara B and Launer, Lenore J and Shoemaker, M Benjamin and Padmanabhan, Sandosh and Haessler, Jeffrey and Bartz, Traci M and Waldenberger, Melanie and Lichtner, Peter and Arendt, Marina and Krieger, Jose E and K{\"a}h{\"o}nen, Mika and Risch, Lorenz and Mansur, Alfredo J and Peters, Annette and Smith, Blair H and Lind, Lars and Scott, Stuart A and Lu, Yingchang and Bottinger, Erwin B and Hernesniemi, Jussi and Lindgren, Cecilia M and Wong, Jorge A and Huang, Jie and Eskola, Markku and Morris, Andrew P and Ford, Ian and Reiner, Alex P and Delgado, Graciela and Chen, Lin Y and Chen, Yii-Der Ida and Sandhu, Roopinder K and Li, Man and Boerwinkle, Eric and Eisele, Lewin and Lannfelt, Lars and Rost, Natalia and Anderson, Christopher D and Taylor, Kent D and Campbell, Archie and Magnusson, Patrik K and Porteous, David and Hocking, Lynne J and Vlachopoulou, Efthymia and Pedersen, Nancy L and Nikus, Kjell and Orho-Melander, Marju and Hamsten, Anders and Heeringa, Jan and Denny, Joshua C and Kriebel, Jennifer and Darbar, Dawood and Newton-Cheh, Christopher and Shaffer, Christian and Macfarlane, Peter W and Heilmann-Heimbach, Stefanie and Almgren, Peter and Huang, Paul L and Sotoodehnia, Nona and Soliman, Elsayed Z and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and V{\"o}lker, Uwe and J{\"o}ckel, Karl-Heinz and Sinner, Moritz F and Lin, Henry J and Guo, Xiuqing and Dichgans, Martin and Ingelsson, Erik and Kooperberg, Charles and Melander, Olle and Loos, Ruth J F and Laurikka, Jari and Conen, David and Rosand, Jonathan and van der Harst, Pim and Lokki, Marja-Liisa and Kathiresan, Sekar and Pereira, Alexandre and Jukema, J Wouter and Hayward, Caroline and Rotter, Jerome I and M{\"a}rz, Winfried and Lehtim{\"a}ki, Terho and Stricker, Bruno H and Chung, Mina K and Felix, Stephan B and Gudnason, Vilmundur and Alonso, Alvaro and Roden, Dan M and K{\"a}{\"a}b, Stefan and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Tanaka, Toshihiro and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} } @article {7687, title = {Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.}, journal = {Cell Rep}, volume = {21}, year = {2017}, month = {2017 Nov 28}, pages = {2597-2613}, abstract = {

Here, we present a large (n~= 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2017.11.028}, author = {Lam, Max and Trampush, Joey W and Yu, Jin and Knowles, Emma and Davies, Gail and Liewald, David C and Starr, John M and Djurovic, Srdjan and Melle, Ingrid and Sundet, Kjetil and Christoforou, Andrea and Reinvang, Ivar and DeRosse, Pamela and Lundervold, Astri J and Steen, Vidar M and Espeseth, Thomas and R{\"a}ikk{\"o}nen, Katri and Widen, Elisabeth and Palotie, Aarno and Eriksson, Johan G and Giegling, Ina and Konte, Bettina and Roussos, Panos and Giakoumaki, Stella and Burdick, Katherine E and Payton, Antony and Ollier, William and Chiba-Falek, Ornit and Attix, Deborah K and Need, Anna C and Cirulli, Elizabeth T and Voineskos, Aristotle N and Stefanis, Nikos C and Avramopoulos, Dimitrios and Hatzimanolis, Alex and Arking, Dan E and Smyrnis, Nikolaos and Bilder, Robert M and Freimer, Nelson A and Cannon, Tyrone D and London, Edythe and Poldrack, Russell A and Sabb, Fred W and Congdon, Eliza and Conley, Emily Drabant and Scult, Matthew A and Dickinson, Dwight and Straub, Richard E and Donohoe, Gary and Morris, Derek and Corvin, Aiden and Gill, Michael and Hariri, Ahmad R and Weinberger, Daniel R and Pendleton, Neil and Bitsios, Panos and Rujescu, Dan and Lahti, Jari and Le Hellard, Stephanie and Keller, Matthew C and Andreassen, Ole A and Deary, Ian J and Glahn, David C and Malhotra, Anil K and Lencz, Todd} } @article {7492, title = {Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.}, journal = {Hypertension}, year = {2017}, month = {2017 Jul 24}, abstract = {

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.09438}, author = {Wain, Louise V and Vaez, Ahmad and Jansen, Rick and Joehanes, Roby and van der Most, Peter J and Erzurumluoglu, A Mesut and O{\textquoteright}Reilly, Paul F and Cabrera, Claudia P and Warren, Helen R and Rose, Lynda M and Verwoert, Germaine C and Hottenga, Jouke-Jan and Strawbridge, Rona J and Esko, T{\~o}nu and Arking, Dan E and Hwang, Shih-Jen and Guo, Xiuqing and Kutalik, Zolt{\'a}n and Trompet, Stella and Shrine, Nick and Teumer, Alexander and Ried, Janina S and Bis, Joshua C and Smith, Albert V and Amin, Najaf and Nolte, Ilja M and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Wareham, Nicholas J and Hofer, Edith and Joshi, Peter K and Kristiansson, Kati and Traglia, Michela and Havulinna, Aki S and Goel, Anuj and Nalls, Mike A and S{\~o}ber, Siim and Vuckovic, Dragana and Luan, Jian{\textquoteright}an and del Greco M, Fabiola and Ayers, Kristin L and Marrugat, Jaume and Ruggiero, Daniela and Lopez, Lorna M and Niiranen, Teemu and Enroth, Stefan and Jackson, Anne U and Nelson, Christopher P and Huffman, Jennifer E and Zhang, Weihua and Marten, Jonathan and Gandin, Ilaria and Harris, Sarah E and Zemunik, Tatijana and Lu, Yingchang and Evangelou, Evangelos and Shah, Nabi and de Borst, Martin H and Mangino, Massimo and Prins, Bram P and Campbell, Archie and Li-Gao, Ruifang and Chauhan, Ganesh and Oldmeadow, Christopher and Abecasis, Goncalo and Abedi, Maryam and Barbieri, Caterina M and Barnes, Michael R and Batini, Chiara and Beilby, John and Blake, Tineka and Boehnke, Michael and Bottinger, Erwin P and Braund, Peter S and Brown, Morris and Brumat, Marco and Campbell, Harry and Chambers, John C and Cocca, Massimiliano and Collins, Francis and Connell, John and Cordell, Heather J and Damman, Jeffrey J and Davies, Gail and de Geus, Eco J and de Mutsert, Ren{\'e}e and Deelen, Joris and Demirkale, Yusuf and Doney, Alex S F and D{\"o}rr, Marcus and Farrall, Martin and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Gao, He and Giedraitis, Vilmantas and Gieger, Christian and Giulianini, Franco and Gow, Alan J and Hamsten, Anders and Harris, Tamara B and Hofman, Albert and Holliday, Elizabeth G and Hui, Jennie and Jarvelin, Marjo-Riitta and Johansson, Asa and Johnson, Andrew D and Jousilahti, Pekka and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Khaw, Kay-Tee and Kolcic, Ivana and Koskinen, Seppo and Langenberg, Claudia and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Liewald, David C M and Lin, Li and Lind, Lars and Mach, Fran{\c c}ois and Mamasoula, Chrysovalanto and Menni, Cristina and Mifsud, Borbala and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew D and Morrison, Alanna C and Munson, Peter J and Nandakumar, Priyanka and Nguyen, Quang Tri and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and Org, Elin and Padmanabhan, Sandosh and Palotie, Aarno and Par{\'e}, Guillaume and Pattie, Alison and Penninx, Brenda W J H and Poulter, Neil and Pramstaller, Peter P and Raitakari, Olli T and Ren, Meixia and Rice, Kenneth and Ridker, Paul M and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rotter, Jerome I and Rudan, Igor and Saba, Yasaman and Saint Pierre, Aude and Sala, Cinzia F and Sarin, Antti-Pekka and Schmidt, Reinhold and Scott, Rodney and Seelen, Marc A and Shields, Denis C and Siscovick, David and Sorice, Rossella and Stanton, Alice and Stott, David J and Sundstr{\"o}m, Johan and Swertz, Morris and Taylor, Kent D and Thom, Simon and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Vollenweider, Peter and Wild, Sarah and Willemsen, Gonneke and Wright, Alan F and Yao, Jie and Th{\'e}riault, S{\'e}bastien and Conen, David and Attia, John and Sever, Peter and Debette, Stephanie and Mook-Kanamori, Dennis O and Zeggini, Eleftheria and Spector, Tim D and van der Harst, Pim and Palmer, Colin N A and Vergnaud, Anne-Claire and Loos, Ruth J F and Polasek, Ozren and Starr, John M and Girotto, Giorgia and Hayward, Caroline and Kooner, Jaspal S and Lindgren, Cecila M and Vitart, Veronique and Samani, Nilesh J and Tuomilehto, Jaakko and Gyllensten, Ulf and Knekt, Paul and Deary, Ian J and Ciullo, Marina and Elosua, Roberto and Keavney, Bernard D and Hicks, Andrew A and Scott, Robert A and Gasparini, Paolo and Laan, Maris and Liu, Yongmei and Watkins, Hugh and Hartman, Catharina A and Salomaa, Veikko and Toniolo, Daniela and Perola, Markus and Wilson, James F and Schmidt, Helena and Zhao, Jing Hua and Lehtim{\"a}ki, Terho and van Duijn, Cornelia M and Gudnason, Vilmundur and Psaty, Bruce M and Peters, Annette and Rettig, Rainer and James, Alan and Jukema, J Wouter and Strachan, David P and Palmas, Walter and Metspalu, Andres and Ingelsson, Erik and Boomsma, Dorret I and Franco, Oscar H and Bochud, Murielle and Newton-Cheh, Christopher and Munroe, Patricia B and Elliott, Paul and Chasman, Daniel I and Chakravarti, Aravinda and Knight, Joanne and Morris, Andrew P and Levy, Daniel and Tobin, Martin D and Snieder, Harold and Caulfield, Mark J and Ehret, Georg B} } @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 {7778, title = {A comprehensive evaluation of the genetic architecture of sudden cardiac arrest.}, journal = {Eur Heart J}, year = {2018}, month = {2018 Aug 28}, abstract = {

Aims: Sudden cardiac arrest (SCA) accounts for 10\% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.

Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25~989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.

Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehy474}, author = {Ashar, Foram N and Mitchell, Rebecca N and Albert, Christine M and Newton-Cheh, Christopher and Brody, Jennifer A and M{\"u}ller-Nurasyid, Martina and Moes, Anna and Meitinger, Thomas and Mak, Angel and Huikuri, Heikki and Junttila, M Juhani and Goyette, Philippe and Pulit, Sara L and Pazoki, Raha and Tanck, Michael W and Blom, Marieke T and Zhao, XiaoQing and Havulinna, Aki S and Jabbari, Reza and Glinge, Charlotte and Tragante, Vinicius and Escher, Stefan A and Chakravarti, Aravinda and Ehret, Georg and Coresh, Josef and Li, Man and Prineas, Ronald J and Franco, Oscar H and Kwok, Pui-Yan and Lumley, Thomas and Dumas, Florence and McKnight, Barbara and Rotter, Jerome I and Lemaitre, Rozenn N and Heckbert, Susan R and O{\textquoteright}Donnell, Christopher J and Hwang, Shih-Jen and Tardif, Jean-Claude and VanDenburgh, Martin and Uitterlinden, Andr{\'e} G and Hofman, Albert and Stricker, Bruno H C and de Bakker, Paul I W and Franks, Paul W and Jansson, Jan-H{\r a}kan and Asselbergs, Folkert W and Halushka, Marc K and Maleszewski, Joseph J and Tfelt-Hansen, Jacob and Engstr{\o}m, Thomas and Salomaa, Veikko and Virmani, Renu and Kolodgie, Frank and Wilde, Arthur A M and Tan, Hanno L and Bezzina, Connie R and Eijgelsheim, Mark and Rioux, John D and Jouven, Xavier and K{\"a}{\"a}b, Stefan and Psaty, Bruce M and Siscovick, David S and Arking, Dan E and Sotoodehnia, Nona} } @article {7809, title = {Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.}, journal = {Genome Biol}, volume = {19}, year = {2018}, month = {2018 07 17}, pages = {87}, abstract = {

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874~individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

}, issn = {1474-760X}, doi = {10.1186/s13059-018-1457-6}, author = {Prins, Bram P and Mead, Timothy J and Brody, Jennifer A and Sveinbjornsson, Gardar and Ntalla, Ioanna and Bihlmeyer, Nathan A and van den Berg, Marten and Bork-Jensen, Jette and Cappellani, Stefania and Van Duijvenboden, Stefan and Klena, Nikolai T and Gabriel, George C and Liu, Xiaoqin and Gulec, Cagri and Grarup, Niels and Haessler, Jeffrey and Hall, Leanne M and Iorio, Annamaria and Isaacs, Aaron and Li-Gao, Ruifang and Lin, Honghuang and Liu, Ching-Ti and Lyytik{\"a}inen, Leo-Pekka and Marten, Jonathan and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Orini, Michele and Padmanabhan, Sandosh and Radmanesh, Farid and Ramirez, Julia and Robino, Antonietta and Schwartz, Molly and van Setten, Jessica and Smith, Albert V and Verweij, Niek and Warren, Helen R and Weiss, Stefan and Alonso, Alvaro and Arnar, David O and Bots, Michiel L and de Boer, Rudolf A and Dominiczak, Anna F and Eijgelsheim, Mark and Ellinor, Patrick T and Guo, Xiuqing and Felix, Stephan B and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Huang, Paul L and Jukema, J W and K{\"a}h{\"o}nen, Mika and Kors, Jan A and Lambiase, Pier D and Launer, Lenore J and Li, Man and Linneberg, Allan and Nelson, Christopher P and Pedersen, Oluf and Perez, Marco and Peters, Annette and Polasek, Ozren and Psaty, Bruce M and Raitakari, Olli T and Rice, Kenneth M and Rotter, Jerome I and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Tim D and Strauch, Konstantin and Thorsteinsdottir, Unnur and Tinker, Andrew and Trompet, Stella and Uitterlinden, Andre and Vaartjes, Ilonca and van der Meer, Peter and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wilson, James G and Xie, Zhijun and Asselbergs, Folkert W and D{\"o}rr, Marcus and van Duijn, Cornelia M and Gasparini, Paolo and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Hansen, Torben and K{\"a}{\"a}b, Stefan and Kanters, J{\o}rgen K and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Lin, Henry J and Lubitz, Steven A and Mook-Kanamori, Dennis O and Conti, Francesco J and Newton-Cheh, Christopher H and Rosand, Jonathan and Rudan, Igor and Samani, Nilesh J and Sinagra, Gianfranco and Smith, Blair H and Holm, Hilma and Stricker, Bruno H and Ulivi, Sheila and Sotoodehnia, Nona and Apte, Suneel S and van der Harst, Pim and Stefansson, Kari and Munroe, Patricia B and Arking, Dan E and Lo, Cecilia W and Jamshidi, Yalda} } @article {7784, title = {ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 Jan}, pages = {e001758}, abstract = {

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.

METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.

CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.001758}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Smith, Albert Vernon and Warren, Helen R and Lin, Honghuang and Isaacs, Aaron and Liu, Ching-Ti and Marten, Jonathan and Radmanesh, Farid and Hall, Leanne M and Grarup, Niels and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Huffman, Jennifer E and Verweij, Niek and Guo, Xiuqing and Yao, Jie and Li-Gao, Ruifang and van den Berg, Marten and Weiss, Stefan and Prins, Bram P and van Setten, Jessica and Haessler, Jeffrey and Lyytik{\"a}inen, Leo-Pekka and Li, Man and Alonso, Alvaro and Soliman, Elsayed Z and Bis, Joshua C and Austin, Tom and Chen, Yii-Der Ida and Psaty, Bruce M and Harrris, Tamara B and Launer, Lenore J and Padmanabhan, Sandosh and Dominiczak, Anna and Huang, Paul L and Xie, Zhijun and Ellinor, Patrick T and Kors, Jan A and Campbell, Archie and Murray, Alison D and Nelson, Christopher P and Tobin, Martin D and Bork-Jensen, Jette and Hansen, Torben and Pedersen, Oluf and Linneberg, Allan and Sinner, Moritz F and Peters, Annette and Waldenberger, Melanie and Meitinger, Thomas and Perz, Siegfried and Kolcic, Ivana and Rudan, Igor and de Boer, Rudolf A and van der Meer, Peter and Lin, Henry J and Taylor, Kent D and de Mutsert, Ren{\'e}e and Trompet, Stella and Jukema, J Wouter and Maan, Arie C and Stricker, Bruno H C and Rivadeneira, Fernando and Uitterlinden, Andre and V{\"o}lker, Uwe and Homuth, Georg and V{\"o}lzke, Henry and Felix, Stephan B and Mangino, Massimo and Spector, Timothy D and Bots, Michiel L and Perez, Marco and Raitakari, Olli T and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Gudnason, Vilmundur and Munroe, Patricia B and Lubitz, Steven A and van Duijn, Cornelia M and Newton-Cheh, Christopher H and Hayward, Caroline and Rosand, Jonathan and Samani, Nilesh J and Kanters, J{\o}rgen K and Wilson, James G and K{\"a}{\"a}b, Stefan and Polasek, Ozren and van der Harst, Pim and Heckbert, Susan R and Rotter, Jerome I and Mook-Kanamori, Dennis O and Eijgelsheim, Mark and D{\"o}rr, Marcus and Jamshidi, Yalda and Asselbergs, Folkert W and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Arking, Dan E and Sotoodehnia, Nona} } @article {7845, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, Stephanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and Borst, Martin H de and Geus, Eco J de and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and Jarvelin, Marjo-Riitta and Joehanes, Roby and Johansson, Asa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @article {7927, title = {Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 10 26}, pages = {4455}, abstract = {

Thyroid dysfunction is an important public health problem, which affects 10\% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves{\textquoteright} disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-06356-1}, author = {Teumer, Alexander and Chaker, Layal and Groeneweg, Stefan and Li, Yong and Di Munno, Celia and Barbieri, Caterina and Schultheiss, Ulla T and Traglia, Michela and Ahluwalia, Tarunveer S and Akiyama, Masato and Appel, Emil Vincent R and Arking, Dan E and Arnold, Alice and Astrup, Arne and Beekman, Marian and Beilby, John P and Bekaert, Sofie and Boerwinkle, Eric and Brown, Suzanne J and De Buyzere, Marc and Campbell, Purdey J and Ceresini, Graziano and Cerqueira, Charlotte and Cucca, Francesco and Deary, Ian J and Deelen, Joris and Eckardt, Kai-Uwe and Ekici, Arif B and Eriksson, Johan G and Ferrrucci, Luigi and Fiers, Tom and Fiorillo, Edoardo and Ford, Ian and Fox, Caroline S and Fuchsberger, Christian and Galesloot, Tessel E and Gieger, Christian and G{\"o}gele, Martin and De Grandi, Alessandro and Grarup, Niels and Greiser, Karin Halina and Haljas, Kadri and Hansen, Torben and Harris, Sarah E and van Heemst, Diana and den Heijer, Martin and Hicks, Andrew A and den Hollander, Wouter and Homuth, Georg and Hui, Jennie and Ikram, M Arfan and Ittermann, Till and Jensen, Richard A and Jing, Jiaojiao and Jukema, J Wouter and Kajantie, Eero and Kamatani, Yoichiro and Kasbohm, Elisa and Kaufman, Jean-Marc and Kiemeney, Lambertus A and Kloppenburg, Margreet and Kronenberg, Florian and Kubo, Michiaki and Lahti, Jari and Lapauw, Bruno and Li, Shuo and Liewald, David C M and Lim, Ee Mun and Linneberg, Allan and Marina, Michela and Mascalzoni, Deborah and Matsuda, Koichi and Medenwald, Daniel and Meisinger, Christa and Meulenbelt, Ingrid and De Meyer, Tim and Meyer zu Schwabedissen, Henriette E and Mikolajczyk, Rafael and Moed, Matthijs and Netea-Maier, Romana T and Nolte, Ilja M and Okada, Yukinori and Pala, Mauro and Pattaro, Cristian and Pedersen, Oluf and Petersmann, Astrid and Porcu, Eleonora and Postmus, Iris and Pramstaller, Peter P and Psaty, Bruce M and Ramos, Yolande F M and Rawal, Rajesh and Redmond, Paul and Richards, J Brent and Rietzschel, Ernst R and Rivadeneira, Fernando and Roef, Greet and Rotter, Jerome I and Sala, Cinzia F and Schlessinger, David and Selvin, Elizabeth and Slagboom, P Eline and Soranzo, Nicole and S{\o}rensen, Thorkild I A and Spector, Timothy D and Starr, John M and Stott, David J and Taes, Youri and Taliun, Daniel and Tanaka, Toshiko and Thuesen, Betina and Tiller, Daniel and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Visser, W Edward and Walsh, John P and Wilson, Scott G and Wolffenbuttel, Bruce H R and Yang, Qiong and Zheng, Hou-Feng and Cappola, Anne and Peeters, Robin P and Naitza, Silvia and V{\"o}lzke, Henry and Sanna, Serena and K{\"o}ttgen, Anna and Visser, Theo J and Medici, Marco} } @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 {7811, title = {Multi-ethnic genome-wide association study for atrial fibrillation.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1225-1233}, abstract = {

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0133-9}, author = {Roselli, Carolina and Chaffin, Mark D and Weng, Lu-Chen and Aeschbacher, Stefanie and Ahlberg, Gustav and Albert, Christine M and Almgren, Peter and Alonso, Alvaro and Anderson, Christopher D and Aragam, Krishna G and Arking, Dan E and Barnard, John and Bartz, Traci M and Benjamin, Emelia J and Bihlmeyer, Nathan A and Bis, Joshua C and Bloom, Heather L and Boerwinkle, Eric and Bottinger, Erwin B and Brody, Jennifer A and Calkins, Hugh and Campbell, Archie and Cappola, Thomas P and Carlquist, John and Chasman, Daniel I and Chen, Lin Y and Chen, Yii-Der Ida and Choi, Eue-Keun and Choi, Seung Hoan and Christophersen, Ingrid E and Chung, Mina K and Cole, John W and Conen, David and Cook, James and Crijns, Harry J and Cutler, Michael J and Damrauer, Scott M and Daniels, Brian R and Darbar, Dawood and Delgado, Graciela and Denny, Joshua C and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton A and Dudley, Samuel C and Esa, Nada and Esko, T{\~o}nu and Eskola, Markku and Fatkin, Diane and Felix, Stephan B and Ford, Ian and Franco, Oscar H and Geelhoed, Bastiaan and Grewal, Raji P and Gudnason, Vilmundur and Guo, Xiuqing and Gupta, Namrata and Gustafsson, Stefan and Gutmann, Rebecca and Hamsten, Anders and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Hernesniemi, Jussi and Hocking, Lynne J and Hofman, Albert and Horimoto, Andrea R V R and Huang, Jie and Huang, Paul L and Huffman, Jennifer and Ingelsson, Erik and Ipek, Esra Gucuk and Ito, Kaoru and Jimenez-Conde, Jordi and Johnson, Renee and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kane, John P and Kastrati, Adnan and Kathiresan, Sekar and Katschnig-Winter, Petra and Kavousi, Maryam and Kessler, Thorsten and Kietselaer, Bas L and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Krieger, Jose E and Kubo, Michiaki and Launer, Lenore J and Laurikka, Jari and Lehtim{\"a}ki, Terho and Leineweber, Kirsten and Lemaitre, Rozenn N and Li, Man and Lim, Hong Euy and Lin, Henry J and Lin, Honghuang and Lind, Lars and Lindgren, Cecilia M and Lokki, Marja-Liisa and London, Barry and Loos, Ruth J F and Low, Siew-Kee and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Macfarlane, Peter W and Magnusson, Patrik K and Mahajan, Anubha and Malik, Rainer and Mansur, Alfredo J and Marcus, Gregory M and Margolin, Lauren and Margulies, Kenneth B and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Mohanty, Sanghamitra and Montgomery, Jay A and Morley, Michael P and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Natale, Andrea and Nazarian, Saman and Neumann, Benjamin and Newton-Cheh, Christopher and Niemeijer, Maartje N and Nikus, Kjell and Nilsson, Peter and Noordam, Raymond and Oellers, Heidi and Olesen, Morten S and Orho-Melander, Marju and Padmanabhan, Sandosh and Pak, Hui-Nam and Par{\'e}, Guillaume and Pedersen, Nancy L and Pera, Joanna and Pereira, Alexandre and Porteous, David and Psaty, Bruce M and Pulit, Sara L and Pullinger, Clive R and Rader, Daniel J and Refsgaard, Lena and Ribas{\'e}s, Marta and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rosand, Jonathan and Rosenberg, Michael A and Rost, Natalia and Rotter, Jerome I and Saba, Samir and Sandhu, Roopinder K and Schnabel, Renate B and Schramm, Katharina and Schunkert, Heribert and Schurman, Claudia and Scott, Stuart A and Sepp{\"a}l{\"a}, Ilkka and Shaffer, Christian and Shah, Svati and Shalaby, Alaa A and Shim, Jaemin and Shoemaker, M Benjamin and Siland, Joylene E and Sinisalo, Juha and Sinner, Moritz F and Slowik, Agnieszka and Smith, Albert V and Smith, Blair H and Smith, J Gustav and Smith, Jonathan D and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Stricker, Bruno H and Sun, Albert and Sun, Han and Svendsen, Jesper H and Tanaka, Toshihiro and Tanriverdi, Kahraman and Taylor, Kent D and Teder-Laving, Maris and Teumer, Alexander and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Tucker, Nathan R and Tveit, Arnljot and Uitterlinden, Andr{\'e} G and van der Harst, Pim and Van Gelder, Isabelle C and Van Wagoner, David R and Verweij, Niek and Vlachopoulou, Efthymia and V{\"o}lker, Uwe and Wang, Biqi and Weeke, Peter E and Weijs, Bob and Weiss, Raul and Weiss, Stefan and Wells, Quinn S and Wiggins, Kerri L and Wong, Jorge A and Woo, Daniel and Worrall, Bradford B and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Lubitz, Steven A and Lunetta, Kathryn L and Ellinor, Patrick T} } @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 {7815, title = {PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jul 25}, pages = {2904}, abstract = {

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04766-9}, author = {van Setten, Jessica and Brody, Jennifer A and Jamshidi, Yalda and Swenson, Brenton R and Butler, Anne M and Campbell, Harry and Del Greco, Fabiola M and Evans, Daniel S and Gibson, Quince and Gudbjartsson, Daniel F and Kerr, Kathleen F and Krijthe, Bouwe P and Lyytik{\"a}inen, Leo-Pekka and M{\"u}ller, Christian and M{\"u}ller-Nurasyid, Martina and Nolte, Ilja M and Padmanabhan, Sandosh and Ritchie, Marylyn D and Robino, Antonietta and Smith, Albert V and Steri, Maristella and Tanaka, Toshiko and Teumer, Alexander and Trompet, Stella and Ulivi, Sheila and Verweij, Niek and Yin, Xiaoyan and Arnar, David O and Asselbergs, Folkert W and Bader, Joel S and Barnard, John and Bis, Josh and Blankenberg, Stefan and Boerwinkle, Eric and Bradford, Yuki and Buckley, Brendan M and Chung, Mina K and Crawford, Dana and den Hoed, Marcel and Denny, Josh C and Dominiczak, Anna F and Ehret, Georg B and Eijgelsheim, Mark and Ellinor, Patrick T and Felix, Stephan B and Franco, Oscar H and Franke, Lude and Harris, Tamara B and Holm, Hilma and Ilaria, Gandin and Iorio, Annamaria and K{\"a}h{\"o}nen, Mika and Kolcic, Ivana and Kors, Jan A and Lakatta, Edward G and Launer, Lenore J and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lubitz, Steven A and Macfarlane, Peter W and Magnani, Jared W and Leach, Irene Mateo and Meitinger, Thomas and Mitchell, Braxton D and M{\"u}nzel, Thomas and Papanicolaou, George J and Peters, Annette and Pfeufer, Arne and Pramstaller, Peter P and Raitakari, Olli T and Rotter, Jerome I and Rudan, Igor and Samani, Nilesh J and Schlessinger, David and Silva Aldana, Claudia T and Sinner, Moritz F and Smith, Jonathan D and Snieder, Harold and Soliman, Elsayed Z and Spector, Timothy D and Stott, David J and Strauch, Konstantin and Tarasov, Kirill V and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Jan Westra, Harm and Wild, Philipp S and Zeller, Tanja and Alonso, Alvaro and Avery, Christy L and Bandinelli, Stefania and Benjamin, Emelia J and Cucca, Francesco and D{\"o}rr, Marcus and Ferrucci, Luigi and Gasparini, Paolo and Gudnason, Vilmundur and Hayward, Caroline and Heckbert, Susan R and Hicks, Andrew A and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and Lehtim{\"a}ki, Terho and Liu, Yongmei and Munroe, Patricia B and Parsa, Afshin and Polasek, Ozren and Psaty, Bruce M and Roden, Dan M and Schnabel, Renate B and Sinagra, Gianfranco and Stefansson, Kari and Stricker, Bruno H and van der Harst, Pim and van Duijn, Cornelia M and Wilson, James F and Gharib, Sina A and de Bakker, Paul I W and Isaacs, Aaron and Arking, Dan E and Sotoodehnia, Nona} } @article {7788, title = {Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 May 29}, pages = {2098}, abstract = {

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 {\texttimes} 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3\% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04362-x}, author = {Davies, Gail and Lam, Max and Harris, Sarah E and Trampush, Joey W and Luciano, Michelle and Hill, W David and Hagenaars, Saskia P and Ritchie, Stuart J and Marioni, Riccardo E and Fawns-Ritchie, Chloe and Liewald, David C M and Okely, Judith A and Ahola-Olli, Ari V and Barnes, Catriona L K and Bertram, Lars and Bis, Joshua C and Burdick, Katherine E and Christoforou, Andrea and DeRosse, Pamela and Djurovic, Srdjan and Espeseth, Thomas and Giakoumaki, Stella and Giddaluru, Sudheer and Gustavson, Daniel E and Hayward, Caroline and Hofer, Edith and Ikram, M Arfan and Karlsson, Robert and Knowles, Emma and Lahti, Jari and Leber, Markus and Li, Shuo and Mather, Karen A and Melle, Ingrid and Morris, Derek and Oldmeadow, Christopher and Palviainen, Teemu and Payton, Antony and Pazoki, Raha and Petrovic, Katja and Reynolds, Chandra A and Sargurupremraj, Muralidharan and Scholz, Markus and Smith, Jennifer A and Smith, Albert V and Terzikhan, Natalie and Thalamuthu, Anbupalam and Trompet, Stella and van der Lee, Sven J and Ware, Erin B and Windham, B Gwen and Wright, Margaret J and Yang, Jingyun and Yu, Jin and Ames, David and Amin, Najaf and Amouyel, Philippe and Andreassen, Ole A and Armstrong, Nicola J and Assareh, Amelia A and Attia, John R and Attix, Deborah and Avramopoulos, Dimitrios and Bennett, David A and B{\"o}hmer, Anne C and Boyle, Patricia A and Brodaty, Henry and Campbell, Harry and Cannon, Tyrone D and Cirulli, Elizabeth T and Congdon, Eliza and Conley, Emily Drabant and Corley, Janie and Cox, Simon R and Dale, Anders M and Dehghan, Abbas and Dick, Danielle and Dickinson, Dwight and Eriksson, Johan G and Evangelou, Evangelos and Faul, Jessica D and Ford, Ian and Freimer, Nelson A and Gao, He and Giegling, Ina and Gillespie, Nathan A and Gordon, Scott D and Gottesman, Rebecca F and Griswold, Michael E and Gudnason, Vilmundur and Harris, Tamara B and Hartmann, Annette M and Hatzimanolis, Alex and Heiss, Gerardo and Holliday, Elizabeth G and Joshi, Peter K and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and Karlsson, Ida and Kleineidam, Luca and Knopman, David S and Kochan, Nicole A and Konte, Bettina and Kwok, John B and Le Hellard, Stephanie and Lee, Teresa and Lehtim{\"a}ki, Terho and Li, Shu-Chen and Liu, Tian and Koini, Marisa and London, Edythe and Longstreth, Will T and Lopez, Oscar L and Loukola, Anu and Luck, Tobias and Lundervold, Astri J and Lundquist, Anders and Lyytik{\"a}inen, Leo-Pekka and Martin, Nicholas G and Montgomery, Grant W and Murray, Alison D and Need, Anna C and Noordam, Raymond and Nyberg, Lars and Ollier, William and Papenberg, Goran and Pattie, Alison and Polasek, Ozren and Poldrack, Russell A and Psaty, Bruce M and Reppermund, Simone and Riedel-Heller, Steffi G and Rose, Richard J and Rotter, Jerome I and Roussos, Panos and Rovio, Suvi P and Saba, Yasaman and Sabb, Fred W and Sachdev, Perminder S and Satizabal, Claudia L and Schmid, Matthias and Scott, Rodney J and Scult, Matthew A and Simino, Jeannette and Slagboom, P Eline and Smyrnis, Nikolaos and Soumar{\'e}, A{\"\i}cha and Stefanis, Nikos C and Stott, David J and Straub, Richard E and Sundet, Kjetil and Taylor, Adele M and Taylor, Kent D and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andre and Vitart, Veronique and Voineskos, Aristotle N and Kaprio, Jaakko and Wagner, Michael and Wagner, Holger and Weinhold, Leonie and Wen, K Hoyan and Widen, Elisabeth and Yang, Qiong and Zhao, Wei and Adams, Hieab H H and Arking, Dan E and Bilder, Robert M and Bitsios, Panos and Boerwinkle, Eric and Chiba-Falek, Ornit and Corvin, Aiden and De Jager, Philip L and Debette, Stephanie and Donohoe, Gary and Elliott, Paul and Fitzpatrick, Annette L and Gill, Michael and Glahn, David C and H{\"a}gg, Sara and Hansell, Narelle K and Hariri, Ahmad R and Ikram, M Kamran and Jukema, J Wouter and Vuoksimaa, Eero and Keller, Matthew C and Kremen, William S and Launer, Lenore and Lindenberger, Ulman and Palotie, Aarno and Pedersen, Nancy L and Pendleton, Neil and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Raitakari, Olli T and Ramirez, Alfredo and Reinvang, Ivar and Rudan, Igor and Schmidt, Reinhold and Schmidt, Helena and Schofield, Peter W and Schofield, Peter R and Starr, John M and Steen, Vidar M and Trollor, Julian N and Turner, Steven T and van Duijn, Cornelia M and Villringer, Arno and Weinberger, Daniel R and Weir, David R and Wilson, James F and Malhotra, Anil and McIntosh, Andrew M and Gale, Catharine R and Seshadri, Sudha and Mosley, Thomas H and Bressler, Jan and Lencz, Todd and Deary, Ian J} } @article {7681, title = {Trans-ethnic Evaluation Identifies Novel Low Frequency Loci Associated with 25-Hydroxyvitamin D Concentrations.}, journal = {J Clin Endocrinol Metab}, year = {2018}, month = {2018 Jan 09}, abstract = {

Context: Vitamin D inadequacy is common in the adult population of the United States. While the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known in Hispanic or African ancestry populations.

Objective: The TRANSCEN-D (TRANS-ethniC Evaluation of vitamiN D GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D (25(OH)D) concentrations from the meta-analyses of European ancestry (SUNLIGHT) and to identify novel genetic variants related to vitamin D concentrations in African and Hispanic ancestries.

Design: Ancestry-specific (Hispanic and African) and trans-ethnic (Hispanic, African and European) meta-analyses were performed using the METAL software.

Patients or Other Participants: In total, 8,541 African-American and 3,485 Hispanic-American (from North America) participants from twelve cohorts, and 16,124 European participants from SUNLIGHT were included in the study.

Main Outcome Measure(s): Blood concentrations of 25(OH)D were measured for all participants.

Results: Ancestry-specific analyses in African and Hispanic Americans replicated SNPs in GC (2 and 4 SNPs, respectively). A potentially novel SNP (rs79666294) near the KIF4B gene was identified in the African-American cohort. Trans-ethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the trans-ethnic analyses revealed novel SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.

Conclusions: Ancestry-specific and trans-ethnic GWAS of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed novel findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism require further investigation.

}, issn = {1945-7197}, doi = {10.1210/jc.2017-01802}, author = {Hong, Jaeyoung and Hatchell, Kathryn E and Bradfield, Jonathan P and Andrew, Bjonnes and Alessandra, Chesi and Chao-Qiang, Lai and Langefeld, Carl D and Lu, Lingyi and Lu, Yingchang and Lutsey, Pamela L and Musani, Solomon K and Nalls, Mike A and Robinson-Cohen, Cassianne and Roizen, Jeffery D and Saxena, Richa and Tucker, Katherine L and Ziegler, Julie T and Arking, Dan E and Bis, Joshua C and Boerwinkle, Eric and Bottinger, Erwin P and Bowden, Donald W and Gilsanz, Vincente and Houston, Denise K and Kalkwarf, Heidi J and Kelly, Andrea and Lappe, Joan M and Liu, Yongmei and Michos, Erin D and Oberfield, Sharon E and Palmer, Nicholette D and Rotter, Jerome I and Sapkota, Bishwa and Shepherd, John A and Wilson, James G and Basu, Saonli and de Boer, Ian H and Divers, Jasmin and Freedman, Barry I and Grant, Struan F A and Hakanarson, Hakon and Harris, Tamara B and Kestenbaum, Bryan R and Kritchevsky, Stephen B and Loos, Ruth J F and Norris, Jill M and Norwood, Arnita F and Ordovas, Jose M and Pankow, James S and Psaty, Bruce M and Sanhgera, Dharambir K and Wagenknecht, Lynne E and Zemel, Babette S and Meigs, James and Dupuis, Jos{\'e}e and Florez, Jose C and Wang, Thomas and Liu, Ching-Ti and Engelman, Corinne D and Billings, Liana K} } @article {7973, title = {Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study.}, journal = {JAMA Cardiol}, year = {2019}, month = {2019 Jan 23}, abstract = {

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.

Objective: To evaluate the potential direct involvement of thyroid traits on AF.

Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.

Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.

Main Outcomes and Measures: Prevalent and incident AF.

Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7\%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95\% CI, 1.09-2.20; P = .02; I2 = 76\%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95\% CI, 1.41-5.54; P = .003; I2 = 64\%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95\% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95\% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95\% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95\% CI, 1.08-1.63; P = .006), 0.88 (95\% CI, 0.84-0.92; P < .001), and 0.94 (95\% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95\% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).

Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2018.4635}, author = {Ellervik, Christina and Roselli, Carolina and Christophersen, Ingrid E and Alonso, Alvaro and Pietzner, Maik and Sitlani, Collen M and Trompet, Stella and Arking, Dan E and Geelhoed, Bastiaan and Guo, Xiuqing and Kleber, Marcus E and Lin, Henry J and Lin, Honghuang and Macfarlane, Peter and Selvin, Elizabeth and Shaffer, Christian and Smith, Albert V and Verweij, Niek and Weiss, Stefan and Cappola, Anne R and D{\"o}rr, Marcus and Gudnason, Vilmundur and Heckbert, Susan and Mooijaart, Simon and M{\"a}rz, Winfried and Psaty, Bruce M and Ridker, Paul M and Roden, Dan and Stott, David J and V{\"o}lzke, Henry and Benjamin, Emelia J and Delgado, Graciela and Ellinor, Patrick and Homuth, Georg and K{\"o}ttgen, Anna and Jukema, Johan W and Lubitz, Steven A and Mora, Samia and Rienstra, Michiel and Rotter, Jerome I and Shoemaker, M Benjamin and Sotoodehnia, Nona and Taylor, Kent D and van der Harst, Pim and Albert, Christine M and Chasman, Daniel I} } @article {7970, title = {Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.}, journal = {Am J Epidemiol}, year = {2019}, month = {2019 Jan 29}, abstract = {

An individual{\textquoteright}s lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P~<~1~{\texttimes}~10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P~<~5~{\texttimes}~10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

}, issn = {1476-6256}, doi = {10.1093/aje/kwz005}, author = {de Vries, Paul S and Brown, Michael R and Bentley, Amy R and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Schwander, Karen and Kraja, Aldi T and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Deng, Xuan and Dorajoo, Rajkumar and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Evangelou, Evangelos and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Lee, Joseph H and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Riaz, Muhammad 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 Wang, Yajuan and Ware, Erin B 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 Ballantyne, Christie and Boerwinkle, Eric and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Connell, John M and de Faire, Ulf and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Ding, Jingzhong and Dominiczak, Anna F and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Ghanbari, Mohsen and Giulianini, Franco and Grabe, Hans J and Grove, Megan L and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Howard, Barbara V and Ikram, M Arfan and Jacobs, David R and Johnson, Craig and Jonas, Jost Bruno and Kammerer, Candace M and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Koistinen, Heikki A and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Steve 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 Lemaitre, Rozenn N and Li, Yize and Liang, Jingjing and Liu, Jianjun and Liu, Kiang and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Mosley, Thomas H and Mukamal, Kenneth J and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and Sotoodehnia, Nona and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Reiner, Alex P and Rice, Treva K and Rich, Stephen S and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Blair H and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tan, Nicholas and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Vuckovic, Dragana and Waldenberger, Melanie and Wang, Lihua and Wang, Yujie and Wang, Zhe and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K 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 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 Horta, Bernardo L and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Penninx, Brenda and Pereira, Alexandre C and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Zheng, Wei and Elliott, Paul and North, Kari E and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Liu, Ching-Ti and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Kardia, Sharon L R and Zhu, Xiaofeng and Rotimi, Charles N and Mook-Kanamori, Dennis O and Fornage, Myriam 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 Liu, Jingmin and Rotter, Jerome I and Gauderman, W James and Province, Michael A and Munroe, Patricia B and Rice, Kenneth and Chasman, Daniel I and Cupples, L Adrienne and Rao, Dabeeru C and Morrison, Alanna C} } @article {8005, title = {Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Apr}, pages = {636-648}, abstract = {

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0378-y}, author = {Bentley, Amy R and Sung, Yun J and Brown, Michael R and Winkler, Thomas W and Kraja, Aldi T and Ntalla, Ioanna and Schwander, Karen and Chasman, Daniel I and Lim, Elise and Deng, Xuan and Guo, Xiuqing and Liu, Jingmin and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Baker, Jenna and Chen, Guanjie and Aschard, Hugues and Bartz, Traci M and Ding, Jingzhong and Dorajoo, Rajkumar and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Zhao, Wei and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Hung, Yi-Jen and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Leander, Karin and Lin, Keng-Hung and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Prins, Bram and Riaz, Muhammad and Robino, Antonietta and Said, M Abdullah and Schupf, Nicole 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 Wang, Tzung-Dau and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Xiang, Yong-Bing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Adeyemo, Adebowale and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Arzumanyan, Zorayr and Aung, Tin and Ballantyne, Christie and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Broeckel, Ulrich and Brown, Morris and Cade, Brian E and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Christensen, Kaare and Concas, Maria Pina and Connell, John M and de Las Fuentes, Lisa and de Silva, H Janaka and de Vries, Paul S and Doumatey, Ayo and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Floyd, James S and Forouhi, Nita G and Forrester, Terrence and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gharib, Sina A and Gigante, Bruna and Giulianini, Franco and Grabe, Hans J and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Ikram, M Arfan and Jia, Yucheng and Joehanes, Roby and Johnson, Craig and Jonas, Jost Bruno and Justice, Anne E and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Kolcic, Ivana and Kooperberg, Charles 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 Liang, Jingjing and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Kiang and Loh, Marie and Lohman, Kurt K and Louie, Tin and Luzzi, Anna and M{\"a}gi, Reedik and Mahajan, Anubha and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Morris, Andrew P and Murray, Alison D and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Papanicolau, George J and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raitakari, Olli T and Reiner, Alex P and Renstrom, Frida and Rice, Treva K and Rich, Stephen S and Robinson, Jennifer G and Rose, Lynda M and Rosendaal, Frits R and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario 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 Tiemeier, Henning and Turner, Stephen T and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Heming and Wang, Lan and Wang, Lihua and Wei, Wen Bin and Williams, Christine A and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Young, Kristin and Yu, Caizheng and Yuan, Jian-Min and Zhou, Jie and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Cooper, Richard S and de Faire, Ulf and Deary, Ian J and Elliott, Paul 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 Horta, Bernardo L and Juang, Jyh-Ming Jimmy and Kamatani, Yoichiro and Kammerer, Candace M and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Laurie, Cathy C and Lee, I-Te and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Pereira, Alexandre C and Rauramaa, Rainer and Redline, Susan and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Jun-Sing and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zeggini, Eleftheria and Zheng, Wei and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Mook-Kanamori, Dennis O and Fornage, Myriam and Province, Michael A 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 Loos, Ruth J F and Franceschini, Nora and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Rao, Dabeeru C and Rotimi, Charles N and Cupples, L Adrienne} } @article {8008, title = {NT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure.}, journal = {J Am Heart Assoc}, volume = {8}, year = {2019}, month = {2019 Apr 02}, pages = {e010868}, abstract = {

Background Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12~418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40\% higher than blacks; 95\% CI , 29-53; ARIC : 39\% higher; 95\% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95\% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95\% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2\%; 95\% CI , 23.2-69.2\%; ARIC : 24.6\%; 95\% CI , 14.8-39.6\%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95\% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95\% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed.

}, issn = {2047-9980}, doi = {10.1161/JAHA.118.010868}, author = {Whitman, Isaac R and Vittinghoff, Eric and deFilippi, Christopher R and Gottdiener, John S and Alonso, Alvaro and Psaty, Bruce M and Heckbert, Susan R and Hoogeveen, Ron C and Arking, Dan E and Selvin, Elizabeth and Chen, Lin Y and Dewland, Thomas A and Marcus, Gregory M} } @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 {8480, title = {Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.}, journal = {Genome Med}, volume = {12}, year = {2020}, month = {2020 Sep 28}, pages = {84}, abstract = {

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.

METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.

RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 {\texttimes} 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 {\texttimes} 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 {\texttimes} 10), as well as the TFAM knockout methylation (P =~4.41 {\texttimes} 10) and expression (P =~4.30 {\texttimes} 10) studies.

CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

}, issn = {1756-994X}, doi = {10.1186/s13073-020-00778-7}, author = {Castellani, Christina A and Longchamps, Ryan J and Sumpter, Jason A and Newcomb, Charles E and Lane, John A and Grove, Megan L and Bressler, Jan and Brody, Jennifer A and Floyd, James S and Bartz, Traci M and Taylor, Kent D and Wang, Penglong and Tin, Adrienne and Coresh, Josef and Pankow, James S and Fornage, Myriam and Guallar, Eliseo and O{\textquoteright}Rourke, Brian and Pankratz, Nathan and Liu, Chunyu and Levy, Daniel and Sotoodehnia, Nona and Boerwinkle, Eric and Arking, Dan E} } @article {8368, title = {Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 May 21}, pages = {2542}, abstract = {

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5\% to 62.6\%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

}, issn = {2041-1723}, doi = {10.1038/s41467-020-15706-x}, author = {Ntalla, Ioanna and Weng, Lu-Chen and Cartwright, James H and Hall, Amelia Weber and Sveinbjornsson, Gardar and Tucker, Nathan R and Choi, Seung Hoan and Chaffin, Mark D and Roselli, Carolina and Barnes, Michael R and Mifsud, Borbala and Warren, Helen R and Hayward, Caroline and Marten, Jonathan and Cranley, James J and Concas, Maria Pina and Gasparini, Paolo and Boutin, Thibaud and Kolcic, Ivana and Polasek, Ozren and Rudan, Igor and Araujo, Nathalia M and Lima-Costa, Maria Fernanda and Ribeiro, Antonio Luiz P and Souza, Renan P and Tarazona-Santos, Eduardo and Giedraitis, Vilmantas and Ingelsson, Erik and Mahajan, Anubha and Morris, Andrew P and del Greco M, Fabiola and Foco, Luisa and G{\"o}gele, Martin and Hicks, Andrew A and Cook, James P and Lind, Lars and Lindgren, Cecilia M and Sundstr{\"o}m, Johan and Nelson, Christopher P and Riaz, Muhammad B and Samani, Nilesh J and Sinagra, Gianfranco and Ulivi, Sheila and K{\"a}h{\"o}nen, Mika and Mishra, Pashupati P and Mononen, Nina and Nikus, Kjell and Caulfield, Mark J and Dominiczak, Anna and Padmanabhan, Sandosh and Montasser, May E and O{\textquoteright}Connell, Jeff R and Ryan, Kathleen and Shuldiner, Alan R and Aeschbacher, Stefanie and Conen, David and Risch, Lorenz and Th{\'e}riault, S{\'e}bastien and Hutri-K{\"a}h{\"o}nen, Nina and Lehtim{\"a}ki, Terho and Lyytik{\"a}inen, Leo-Pekka and Raitakari, Olli T and Barnes, Catriona L K and Campbell, Harry and Joshi, Peter K and Wilson, James F and Isaacs, Aaron and Kors, Jan A and van Duijn, Cornelia M and Huang, Paul L and Gudnason, Vilmundur and Harris, Tamara B and Launer, Lenore J and Smith, Albert V and Bottinger, Erwin P and Loos, Ruth J F and Nadkarni, Girish N and Preuss, Michael H and Correa, Adolfo and Mei, Hao and Wilson, James and Meitinger, Thomas and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Waldenberger, Melanie and Mangino, Massimo and Spector, Timothy D and Rienstra, Michiel and van de Vegte, Yordi J and van der Harst, Pim and Verweij, Niek and K{\"a}{\"a}b, Stefan and Schramm, Katharina and Sinner, Moritz F and Strauch, Konstantin and Cutler, Michael J and Fatkin, Diane and London, Barry and Olesen, Morten and Roden, Dan M and Benjamin Shoemaker, M and Gustav Smith, J and Biggs, Mary L and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Rice, Kenneth and Sotoodehnia, Nona and De Grandi, Alessandro and Fuchsberger, Christian and Pattaro, Cristian and Pramstaller, Peter P and Ford, Ian and Wouter Jukema, J and Macfarlane, Peter W and Trompet, Stella and D{\"o}rr, Marcus and Felix, Stephan B and V{\"o}lker, Uwe and Weiss, Stefan and Havulinna, Aki S and Jula, Antti and S{\"a}{\"a}ksj{\"a}rvi, Katri and Salomaa, Veikko and Guo, Xiuqing and Heckbert, Susan R and Lin, Henry J and Rotter, Jerome I and Taylor, Kent D and Yao, Jie and de Mutsert, Ren{\'e}e and Maan, Arie C and Mook-Kanamori, Dennis O and Noordam, Raymond and Cucca, Francesco and Ding, Jun and Lakatta, Edward G and Qian, Yong and Tarasov, Kirill V and Levy, Daniel and Lin, Honghuang and Newton-Cheh, Christopher H and Lunetta, Kathryn L and Murray, Alison D and Porteous, David J and Smith, Blair H and Stricker, Bruno H and Uitterlinden, Andre and van den Berg, Marten E and Haessler, Jeffrey and Jackson, Rebecca D and Kooperberg, Charles and Peters, Ulrike and Reiner, Alexander P and Whitsel, Eric A and Alonso, Alvaro and Arking, Dan E and Boerwinkle, Eric and Ehret, Georg B and Soliman, Elsayed Z and Avery, Christy L and Gogarten, Stephanie M and Kerr, Kathleen F and Laurie, Cathy C and Seyerle, Amanda A and Stilp, Adrienne and Assa, Solmaz and Abdullah Said, M and Yldau van der Ende, M and Lambiase, Pier D and Orini, Michele and Ramirez, Julia and Van Duijvenboden, Stefan and Arnar, David O and Gudbjartsson, Daniel F and Holm, Hilma and Sulem, Patrick and Thorleifsson, Gudmar and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Benjamin, Emelia J and Tinker, Andrew and Stefansson, Kari and Ellinor, Patrick T and Jamshidi, Yalda and Lubitz, Steven A and Munroe, Patricia B} } @article {8997, title = {Association of mitochondrial DNA copy number with cardiometabolic diseases.}, journal = {Cell Genom}, volume = {1}, year = {2021}, month = {2021 Oct 13}, abstract = {

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 {\texttimes} 10) among older participants (>=65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 {\texttimes} 10), hypertension ( = 2.8 {\texttimes} 10), diabetes ( = 3.6 {\texttimes} 10), and hyperlipidemia ( = 6.3 {\texttimes} 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

}, issn = {2666-979X}, doi = {10.1016/j.xgen.2021.100006}, author = {Liu, Xue and Longchamps, Ryan J and Wiggins, Kerri L and Raffield, Laura M and Bielak, Lawrence F and Zhao, Wei and Pitsillides, Achilleas and Blackwell, Thomas W and Yao, Jie and Guo, Xiuqing and Kurniansyah, Nuzulul and Thyagarajan, Bharat and Pankratz, Nathan and Rich, Stephen S and Taylor, Kent D and Peyser, Patricia A and Heckbert, Susan R and Seshadri, Sudha and Cupples, L Adrienne and Boerwinkle, Eric and Grove, Megan L and Larson, Nicholas B and Smith, Jennifer A and Vasan, Ramachandran S and Sofer, Tamar and Fitzpatrick, Annette L and Fornage, Myriam and Ding, Jun and Correa, Adolfo and Abecasis, Goncalo and Psaty, Bruce M and Wilson, James G and Levy, Daniel and Rotter, Jerome I and Bis, Joshua C and Satizabal, Claudia L and Arking, Dan E and Liu, Chunyu} } @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 {9005, title = {Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.}, journal = {HGG Adv}, volume = {2}, year = {2021}, month = {2021 Jan 14}, abstract = {

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

}, issn = {2666-2477}, doi = {10.1016/j.xhgg.2020.100013}, author = {Sun, Daokun and Richard, Melissa and Musani, Solomon K and Sung, Yun Ju and Winkler, Thomas W and Schwander, Karen and Chai, Jin Fang and Guo, Xiuqing and Kilpel{\"a}inen, Tuomas O and Vojinovic, Dina and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Brown, Michael R and Chitrala, Kumaraswamy and Hartwig, Fernando P and Horimoto, Andrea R V R and Liu, Yongmei and Manning, Alisa K and Noordam, Raymond and Smith, Albert V and Harris, Sarah E and Kuhnel, Brigitte and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Rauramaa, Rainer and van der Most, Peter J and Wang, Rujia and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Arking, Dan E and Arnett, Donna K and Barac, Ana and Boerwinkle, Eric and Broeckel, Ulrich and Chakravarti, Aravinda and Chen, Yii-Der Ida and Cupples, L Adrienne and Davigulus, Martha L and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Vries, Paul S and Delaney, Joseph A C and Roux, Ana V Diez and D{\"o}rr, Marcus and Faul, Jessica D and Fretts, Amanda M and Gallo, Linda C and Grabe, Hans J{\"o}rgen and Gu, C Charles and Harris, Tamara B and Hartman, Catharina C A and Heikkinen, Sami and Ikram, M Arfan and Isasi, Carmen and Johnson, W Craig and Jonas, Jost Bruno and Kaplan, Robert C and Komulainen, Pirjo and Krieger, Jose E and Levy, Daniel and Liu, Jianjun and Lohman, Kurt and Luik, Annemarie I and Martin, Lisa W and Meitinger, Thomas and Milaneschi, Yuri and O{\textquoteright}Connell, Jeff R and Palmas, Walter R and Peters, Annette and Peyser, Patricia A and Pulkki-R{\r a}back, Laura and Raffel, Leslie J and Reiner, Alex P and Rice, Kenneth and Robinson, Jennifer G and Rosendaal, Frits R and Schmidt, Carsten Oliver and Schreiner, Pamela J and Schwettmann, Lars and Shikany, James M and Shu, Xiao-Ou and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Sotoodehnia, Nona and Strauch, Konstantin and Tai, E Shyong and Taylor, Kent and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Waldenberger, Melanie and Wee, Hwee-Lin and Wei, Wen-Bin and Wilson, Gregory and Xuan, Deng and Yao, Jie and Zeng, Donglin and Zhao, Wei and Zhu, Xiaofeng and Zonderman, Alan B and Becker, Diane M and Deary, Ian J and Gieger, Christian and Lakka, Timo A and Lehtim{\"a}ki, Terho and North, Kari E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Snieder, Harold and Wang, Ya-Xing and Weir, David R and Zheng, Wei and Evans, Michele K and Gauderman, W James and Gudnason, Vilmundur and Horta, Bernardo L and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Morrison, Alanna C and Pereira, Alexandre C and Psaty, Bruce M and Amin, Najaf and Fox, Ervin R and Kooperberg, Charles and Sim, Xueling and Bierut, Laura and Rotter, Jerome I and Kardia, Sharon L R and Franceschini, Nora and Rao, Dabeeru C and Fornage, Myriam} } @article {8714, title = {Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.}, journal = {Mol Psychiatry}, year = {2021}, month = {2021 Apr 15}, abstract = {

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 {\texttimes} 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 {\texttimes} 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 {\texttimes} 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

}, issn = {1476-5578}, doi = {10.1038/s41380-021-01087-0}, author = {Wang, Heming and Noordam, Raymond and Cade, Brian E and Schwander, Karen and Winkler, Thomas W and Lee, Jiwon and Sung, Yun Ju and Bentley, Amy R and Manning, Alisa K and Aschard, Hugues and Kilpel{\"a}inen, Tuomas O and Ilkov, Marjan and Brown, Michael R and Horimoto, Andrea R and Richard, Melissa and Bartz, Traci M and Vojinovic, Dina and Lim, Elise and Nierenberg, Jovia L and Liu, Yongmei and Chitrala, Kumaraswamynaidu and Rankinen, Tuomo and Musani, Solomon K and Franceschini, Nora and Rauramaa, Rainer and Alver, Maris and Zee, Phyllis C and Harris, Sarah E and van der Most, Peter J and Nolte, Ilja M and Munroe, Patricia B and Palmer, Nicholette D and Kuhnel, Brigitte and Weiss, Stefan and Wen, Wanqing and Hall, Kelly A and Lyytik{\"a}inen, Leo-Pekka and O{\textquoteright}Connell, Jeff and Eiriksdottir, Gudny and Launer, Lenore J and de Vries, Paul S and Arking, Dan E and Chen, Han and Boerwinkle, Eric and Krieger, Jose E and Schreiner, Pamela J and Sidney, Stephen and Shikany, James M and Rice, Kenneth and Chen, Yii-Der Ida and Gharib, Sina A and Bis, Joshua C and Luik, Annemarie I and Ikram, M Arfan and Uitterlinden, Andr{\'e} G and Amin, Najaf and Xu, Hanfei and Levy, Daniel and He, Jiang and Lohman, Kurt K and Zonderman, Alan B and Rice, Treva K and Sims, Mario and Wilson, Gregory and Sofer, Tamar and Rich, Stephen S and Palmas, Walter and Yao, Jie and Guo, Xiuqing and Rotter, Jerome I and Biermasz, Nienke R and Mook-Kanamori, Dennis O and Martin, Lisa W and Barac, Ana and Wallace, Robert B and Gottlieb, Daniel J and Komulainen, Pirjo and Heikkinen, Sami and M{\"a}gi, Reedik and Milani, Lili and Metspalu, Andres and Starr, John M and Milaneschi, Yuri and Waken, R J and Gao, Chuan and Waldenberger, Melanie and Peters, Annette and Strauch, Konstantin and Meitinger, Thomas and Roenneberg, Till and V{\"o}lker, Uwe and D{\"o}rr, Marcus and Shu, Xiao-Ou and Mukherjee, Sutapa and Hillman, David R and K{\"a}h{\"o}nen, Mika and Wagenknecht, Lynne E and Gieger, Christian and Grabe, Hans J and Zheng, Wei and Palmer, Lyle J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Morrison, Alanna C and Pereira, Alexandre C and Fornage, Myriam and Psaty, Bruce M and van Duijn, Cornelia M and Liu, Ching-Ti and Kelly, Tanika N and Evans, Michele K and Bouchard, Claude and Fox, Ervin R and Kooperberg, Charles and Zhu, Xiaofeng and Lakka, Timo A and Esko, T{\~o}nu and North, Kari E and Deary, Ian J and Snieder, Harold and Penninx, Brenda W J H and Gauderman, W James and Rao, Dabeeru C and Redline, Susan and van Heemst, Diana} } @article {8666, title = {Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.}, journal = {Nature}, volume = {590}, year = {2021}, month = {2021 02}, pages = {290-299}, abstract = {

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

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03205-y}, author = {Taliun, Daniel and Harris, Daniel N and Kessler, Michael D and Carlson, Jedidiah and Szpiech, Zachary A and Torres, Raul and Taliun, Sarah A Gagliano and Corvelo, Andr{\'e} and Gogarten, Stephanie M and Kang, Hyun Min and Pitsillides, Achilleas N and LeFaive, Jonathon and Lee, Seung-Been and Tian, Xiaowen and Browning, Brian L and Das, Sayantan and Emde, Anne-Katrin and Clarke, Wayne E and Loesch, Douglas P and Shetty, Amol C and Blackwell, Thomas W and Smith, Albert V and Wong, Quenna and Liu, Xiaoming and Conomos, Matthew P and Bobo, Dean M and Aguet, Francois and Albert, Christine and Alonso, Alvaro and Ardlie, Kristin G and Arking, Dan E and Aslibekyan, Stella and Auer, Paul L and Barnard, John and Barr, R Graham and Barwick, Lucas and Becker, Lewis C and Beer, Rebecca L and Benjamin, Emelia J and Bielak, Lawrence F and Blangero, John and Boehnke, Michael and Bowden, Donald W and Brody, Jennifer A and Burchard, Esteban G and Cade, Brian E and Casella, James F and Chalazan, Brandon and Chasman, Daniel I and Chen, Yii-Der Ida and Cho, Michael H and Choi, Seung Hoan and Chung, Mina K and Clish, Clary B and Correa, Adolfo and Curran, Joanne E and Custer, Brian and Darbar, Dawood and Daya, Michelle and de Andrade, Mariza and DeMeo, Dawn L and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Eng, Celeste and Fatkin, Diane and Fingerlin, Tasha and Forer, Lukas and Fornage, Myriam and Franceschini, Nora and Fuchsberger, Christian and Fullerton, Stephanie M and Germer, Soren and Gladwin, Mark T and Gottlieb, Daniel J and Guo, Xiuqing and Hall, Michael E and He, Jiang and Heard-Costa, Nancy L and Heckbert, Susan R and Irvin, Marguerite R and Johnsen, Jill M and Johnson, Andrew D and Kaplan, Robert and Kardia, Sharon L R and Kelly, Tanika and Kelly, Shannon and Kenny, Eimear E and Kiel, Douglas P and Klemmer, Robert and Konkle, Barbara A and Kooperberg, Charles and K{\"o}ttgen, Anna and Lange, Leslie A and Lasky-Su, Jessica and Levy, Daniel and Lin, Xihong and Lin, Keng-Han and Liu, Chunyu and Loos, Ruth J F and Garman, Lori and Gerszten, Robert and Lubitz, Steven A and Lunetta, Kathryn L and Mak, Angel C Y and Manichaikul, Ani and Manning, Alisa K and Mathias, Rasika A and McManus, David D and McGarvey, Stephen T and Meigs, James B and Meyers, Deborah A and Mikulla, Julie L and Minear, Mollie A and Mitchell, Braxton D and Mohanty, Sanghamitra and Montasser, May E and Montgomery, Courtney and Morrison, Alanna C and Murabito, Joanne M and Natale, Andrea and Natarajan, Pradeep and Nelson, Sarah C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pankratz, Nathan and Peloso, Gina M and Peyser, Patricia A and Pleiness, Jacob and Post, Wendy S and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Roden, Dan and Rotter, Jerome I and Ruczinski, Ingo and Sarnowski, Chloe and Schoenherr, Sebastian and Schwartz, David A and Seo, Jeong-Sun and Seshadri, Sudha and Sheehan, Vivien A and Sheu, Wayne H and Shoemaker, M Benjamin and Smith, Nicholas L and Smith, Jennifer A and Sotoodehnia, Nona and Stilp, Adrienne M and Tang, Weihong and Taylor, Kent D and Telen, Marilyn and Thornton, Timothy A and Tracy, Russell P and Van Den Berg, David J and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Vrieze, Scott and Weeks, Daniel E and Weir, Bruce S and Weiss, Scott T and Weng, Lu-Chen and Willer, Cristen J and Zhang, Yingze and Zhao, Xutong and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Boerwinkle, Eric and Gabriel, Stacey and Gibbs, Richard and Rice, Kenneth M and Rich, Stephen S and Silverman, Edwin K and Qasba, Pankaj and Gan, Weiniu and Papanicolaou, George J and Nickerson, Deborah A and Browning, Sharon R and Zody, Michael C and Z{\"o}llner, Sebastian and Wilson, James G and Cupples, L Adrienne and Laurie, Cathy C and Jaquish, Cashell E and Hernandez, Ryan D and O{\textquoteright}Connor, Timothy D and Abecasis, Goncalo R} } @article {9038, title = {Monogenic and Polygenic Contributions to QTc Prolongation in the Population.}, journal = {Circulation}, year = {2022}, month = {2022 Apr 07}, abstract = {

Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95\% CI 1.3 -1.5; p-value=1.1{\texttimes}10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7\% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4\% monogenic, 21\% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.121.057261}, author = {Nauffal, Victor and Morrill, Valerie N and Jurgens, Sean J and Choi, Seung Hoan and Hall, Amelia W and Weng, Lu-Chen and Halford, Jennifer L and Austin-Tse, Christina and Haggerty, Christopher M and Harris, Stephanie L and Wong, Eugene K and Alonso, Alvaro and Arking, Dan E and Benjamin, Emelia J and Boerwinkle, Eric and Min, Yuan-I and Correa, Adolfo and Fornwalt, Brandon K and Heckbert, Susan R and Kooperberg, Charles and Lin, Henry J and Loos, Ruth J F and Rice, Kenneth M and Gupta, Namrata and Blackwell, Thomas W and Mitchell, Braxton D and Morrison, Alanna C and Psaty, Bruce M and Post, Wendy S and Redline, Susan and Rehm, Heidi L and Rich, Stephen S and Rotter, Jerome I and Soliman, Elsayed Z and Sotoodehnia, Nona and Lunetta, Kathryn L and Ellinor, Patrick T and Lubitz, Steven A} } @article {9502, title = {Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.}, journal = {J Am Heart Assoc}, year = {2023}, month = {2023 Oct 07}, pages = {e029090}, abstract = {

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95\% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029090}, author = {Liu, Xue and Sun, Xianbang and Zhang, Yuankai and Jiang, Wenqing and Lai, Meng and Wiggins, Kerri L and Raffield, Laura M and Bielak, Lawrence F and Zhao, Wei and Pitsillides, Achilleas and Haessler, Jeffrey and Zheng, Yinan and Blackwell, Thomas W and Yao, Jie and Guo, Xiuqing and Qian, Yong and Thyagarajan, Bharat and Pankratz, Nathan and Rich, Stephen S and Taylor, Kent D and Peyser, Patricia A and Heckbert, Susan R and Seshadri, Sudha and Boerwinkle, Eric and Grove, Megan L and Larson, Nicholas B and Smith, Jennifer A and Vasan, Ramachandran S and Fitzpatrick, Annette L and Fornage, Myriam and Ding, Jun and Carson, April P and Abecasis, Goncalo and Dupuis, Jos{\'e}e and Reiner, Alexander and Kooperberg, Charles and Hou, Lifang and Psaty, Bruce M and Wilson, James G and Levy, Daniel and Rotter, Jerome I and Bis, Joshua C and Satizabal, Claudia L and Arking, Dan E and Liu, Chunyu} } @article {9323, title = {Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.}, journal = {Neurology}, year = {2023}, month = {2023 Mar 16}, abstract = {

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer{\textquoteright}s disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within {\textpm}5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. >=60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57\% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95\% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000207157}, author = {Zhang, Yuankai and Liu, Xue and Wiggins, Kerri L and Kurniansyah, Nuzulul and Guo, Xiuqing and Rodrigue, Amanda L and Zhao, Wei and Yanek, Lisa R and Ratliff, Scott M and Pitsillides, Achilleas and Aguirre Pati{\~n}o, Juan Sebastian and Sofer, Tamar and Arking, Dan E and Austin, Thomas R and Beiser, Alexa S and Blangero, John and Boerwinkle, Eric and Bressler, Jan and Curran, Joanne E and Hou, Lifang and Hughes, Timothy M and Kardia, Sharon L and Launer, Lenore and Levy, Daniel and Mosley, Tom H and Nasrallah, Ilya M and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Tarraf, Wassim and Gonz{\'a}lez, Kevin A and Ramachandran, Vasan and Yaffe, Kristine and Nyquist, Paul A and Psaty, Bruce M and DeCarli, Charles S and Smith, Jennifer A and Glahn, David C and Gonz{\'a}lez, Hector M and Bis, Joshua C and Fornage, Myriam and Heckbert, Susan R and Fitzpatrick, Annette L and Liu, Chunyu and Satizabal, Claudia L} } @article {9386, title = {Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.}, journal = {medRxiv}, year = {2023}, month = {2023 May 17}, abstract = {

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as and and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95\% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95\% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than (HR: 1.49, 95\% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non- CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95\% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in -CHIP mice. Kidney macrophage infiltration was markedly increased in -CHIP mice and -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

}, doi = {10.1101/2023.05.16.23290051}, author = {Vlasschaert, Caitlyn and Robinson-Cohen, Cassianne and Kestenbaum, Bryan and Silver, Samuel A and Chen, Jian-Chun and Akwo, Elvis and Bhatraju, Pavan K and Zhang, Ming-Zhi and Cao, Shirong and Jiang, Ming and Wang, Yinqiu and Niu, Aolei and Siew, Edward and Kramer, Holly J and K{\"o}ttgen, Anna and Franceschini, Nora and Psaty, Bruce M and Tracy, Russell P and Alonso, Alvaro and Arking, Dan E and Coresh, Josef and Ballantyne, Christie M and Boerwinkle, Eric and Grams, Morgan and Lanktree, Matthew B and Rauh, Michael J and Harris, Raymond C and Bick, Alexander G} } @article {9535, title = {Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1235337}, abstract = {

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 {\texttimes} 10) and suggestive ( < 1 {\texttimes} 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1235337}, author = {de Las Fuentes, Lisa and Schwander, Karen L and Brown, Michael R and Bentley, Amy R and Winkler, Thomas W and Sung, Yun Ju and Munroe, Patricia B and Miller, Clint L and Aschard, Hugo and Aslibekyan, Stella and Bartz, Traci M and Bielak, Lawrence F and Chai, Jin Fang and Cheng, Ching-Yu and Dorajoo, Rajkumar and Feitosa, Mary F and Guo, Xiuqing and Hartwig, Fernando P and Horimoto, Andrea and Kolcic, Ivana and Lim, Elise and Liu, Yongmei and Manning, Alisa K and Marten, Jonathan and Musani, Solomon K and Noordam, Raymond and Padmanabhan, Sandosh and Rankinen, Tuomo and Richard, Melissa A and Ridker, Paul M and Smith, Albert V and Vojinovic, Dina and Zonderman, Alan B and Alver, Maris and Boissel, Mathilde and Christensen, Kaare and Freedman, Barry I and Gao, Chuan and Giulianini, Franco 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 Robino, Antonietta and Sofer, Tamar and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhan, Yiqiang and Amin, Najaf and Arking, Dan E and Ballantyne, Christie and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Chai, Xiaoran and Chen, Yii-Der Ida and Chen, Xu and Chitrala, Kumaraswamy Naidu and Concas, Maria Pina and de Faire, Ulf and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Do, Ahn and Faul, Jessica D and Fisher, Virginia and Floyd, James S and Forrester, Terrence and Friedlander, Yechiel and Girotto, Giorgia and Gu, C Charles and Hallmans, G{\"o}ran and Heikkinen, Sami and Heng, Chew-Kiat and Homuth, Georg and Hunt, Steven and Ikram, M Arfan and Jacobs, David R and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Langefeld, Carl D and Liang, Jingjing and Liu, Kiang and Liu, Jianjun and Lohman, Kurt and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Milaneschi, Yuri and Nauck, Matthias and Nelson, Christopher P and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pereira, Alexandre C and Perls, Thomas and Peters, Annette and Polasek, Ozren and Raitakari, Olli T and Rice, Kenneth and Rice, Treva K and Rich, Stephen S and Sabanayagam, Charumathi and Schreiner, Pamela J and Shu, Xiao-Ou and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Tai, E Shyong and Taylor, Kent D and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Ya-Xing and Wei, Wen-Bin and Wilson, Gregory and Xuan, Deng and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Becker, Diane M and Bonnefond, Am{\'e}lie and Bowden, Donald W and Cooper, Richard S and Deary, Ian J and Divers, Jasmin and Esko, T{\~o}nu and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Jonas, Jost B and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and North, Kari E and Ntalla, Ioanna and Penninx, Brenda and Samani, Nilesh J and Snieder, Harold and Spedicati, Beatrice and van der Harst, Pim and V{\"o}lzke, Henry and Wagenknecht, Lynne E and Weir, David R and Wojczynski, Mary K and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Chasman, Daniel I and Evans, Michele K and Fox, Ervin R and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kardia, Sharon L R and Krieger, Jose Eduardo and Mook-Kanamori, Dennis O and Peyser, Patricia A and Province, Michael M and Psaty, Bruce M and Rudan, Igor and Sim, Xueling and Smith, Blair H and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Arnett, Donna K and Rao, Dabeeru C and Gauderman, James and Liu, Ching-Ti and Morrison, Alanna C and Rotter, Jerome I and Fornage, Myriam} } @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 {9791, title = {Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization.}, journal = {Wellcome Open Res}, volume = {8}, year = {2023}, month = {2023}, pages = {483}, abstract = {

BACKGROUND: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways.

METHODS: To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses.

RESULTS: Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology.

CONCLUSIONS: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

}, issn = {2398-502X}, doi = {10.12688/wellcomeopenres.18754.1}, author = {Willems, Sara M and Ng, Natasha H J and Fernandez, Juan and Fine, Rebecca S and Wheeler, Eleanor and Wessel, Jennifer and Kitajima, Hidetoshi and Marenne, Gaelle and Sim, Xueling and Yaghootkar, Hanieh and Wang, Shuai and Chen, Sai and Chen, Yuning and Chen, Yii-Der Ida and Grarup, Niels and Li-Gao, Ruifang and Varga, Tibor V and Asimit, Jennifer L and Feng, Shuang and Strawbridge, Rona J and Kleinbrink, Erica L and Ahluwalia, Tarunveer S and An, Ping and Appel, Emil V and Arking, Dan E and Auvinen, Juha and Bielak, Lawrence F and Bihlmeyer, Nathan A and Bork-Jensen, Jette and Brody, Jennifer A and Campbell, Archie and Chu, Audrey Y and Davies, Gail and Demirkan, Ayse and Floyd, James S and Giulianini, Franco and Guo, Xiuqing and Gustafsson, Stefan and Jackson, Anne U and Jakobsdottir, Johanna and Jarvelin, Marjo-Riitta and Jensen, Richard A and Kanoni, Stavroula and Keinanen-Kiukaanniemi, Sirkka and Li, Man and Lu, Yingchang and Luan, Jian{\textquoteright}an and Manning, Alisa K and Marten, Jonathan and Meidtner, Karina and Mook-Kanamori, Dennis O and Muka, Taulant and Pistis, Giorgio and Prins, Bram and Rice, Kenneth M and Sanna, Serena and Smith, Albert Vernon and Smith, Jennifer A and Southam, Lorraine and Stringham, Heather M and Tragante, Vinicius and van der Laan, Sander W and Warren, Helen R and Yao, Jie and Yiorkas, Andrianos M and Zhang, Weihua and Zhao, Wei and Graff, Mariaelisa and Highland, Heather M and Justice, Anne E and Marouli, Eirini and Medina-G{\'o}mez, Carolina and Afaq, Saima and Alhejily, Wesam A and Amin, Najaf and Asselbergs, Folkert W and Bonnycastle, Lori L and Bots, Michiel L and Brandslund, Ivan and Chen, Ji and Danesh, John and de Mutsert, Ren{\'e}e and Dehghan, Abbas and Ebeling, Tapani and Elliott, Paul and Farmaki, Aliki-Eleni and Faul, Jessica D and Franks, Paul W and Franks, Steve and Fritsche, Andreas and Gjesing, Anette P and Goodarzi, Mark O and Gudnason, Vilmundur and Hallmans, G{\"o}ran and Harris, Tamara B and Herzig, Karl-Heinz and Hivert, Marie-France and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and Jousilahti, Pekka and Kajantie, Eero and Karaleftheri, Maria and Kardia, Sharon L R and Kinnunen, Leena and Koistinen, Heikki A and Komulainen, Pirjo and Kovacs, Peter and Kuusisto, Johanna and Laakso, Markku and Lange, Leslie A and Launer, Lenore J and Leong, Aaron and Lindstr{\"o}m, Jaana and Manning Fox, Jocelyn E and M{\"a}nnist{\"o}, Satu and Maruthur, Nisa M and Moilanen, Leena and Mulas, Antonella and Nalls, Mike A and Neville, Matthew and Pankow, James S and Pattie, Alison and Petersen, Eva R B and Puolijoki, Hannu and Rasheed, Asif and Redmond, Paul and Renstrom, Frida and Roden, Michael and Saleheen, Danish and Saltevo, Juha and Savonen, Kai and Sebert, Sylvain and Skaaby, Tea and Small, Kerrin S and Stan{\v c}{\'a}kov{\'a}, Alena and Stokholm, Jakob and Strauch, Konstantin and Tai, E-Shyong and Taylor, Kent D and Thuesen, Betina H and T{\"o}njes, Anke and Tsafantakis, Emmanouil and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Uusitupa, Matti and V{\"a}{\"a}r{\"a}sm{\"a}ki, Marja and Vaartjes, Ilonca and Zoledziewska, Magdalena and Abecasis, Goncalo and Balkau, Beverley and Bisgaard, Hans and Blakemore, Alexandra I and Bl{\"u}her, Matthias and Boeing, Heiner and Boerwinkle, Eric and B{\o}nnelykke, Klaus and Bottinger, Erwin P and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Cheng, Ching-Yu and Collins, Francis S and Coresh, Josef and Cucca, Francesco and de Borst, Gert J and Deary, Ian J and Dedoussis, George and Deloukas, Panos and den Ruijter, Hester M and Dupuis, Jos{\'e}e and Evans, Michele K and Ferrannini, Ele and Franco, Oscar H and Grallert, Harald and Hansen, Torben and Hattersley, Andrew T and Hayward, Caroline and Hirschhorn, Joel N and Ikram, Arfan and Ingelsson, Erik and Karpe, Fredrik and Kaw, Kay-Tee and Kiess, Wieland and Kooner, Jaspal S and K{\"o}rner, Antje and Lakka, Timo and Langenberg, Claudia and Lind, Lars and Lindgren, Cecilia M and Linneberg, Allan and Lipovich, Leonard and Liu, Ching-Ti and Liu, Jun and Liu, Yongmei and Loos, Ruth J F and MacDonald, Patrick E and Mohlke, Karen L and Morris, Andrew D and Munroe, Patricia B and Murray, Alison and Padmanabhan, Sandosh and Palmer, Colin N A and Pasterkamp, Gerard and Pedersen, Oluf and Peyser, Patricia A and Polasek, Ozren and Porteous, David and Province, Michael A and Psaty, Bruce M and Rauramaa, Rainer and Ridker, Paul M and Rolandsson, Olov and Rorsman, Patrik and Rosendaal, Frits R and Rudan, Igor and Salomaa, Veikko and Schulze, Matthias B and Sladek, Robert and Smith, Blair H and Spector, Timothy D and Starr, John M and Stumvoll, Michael and van Duijn, Cornelia M and Walker, Mark and Wareham, Nick J and Weir, David R and Wilson, James G and Wong, Tien Yin and Zeggini, Eleftheria and Zonderman, Alan B and Rotter, Jerome I and Morris, Andrew P and Boehnke, Michael and Florez, Jose C and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Scott, Robert A and Gloyn, Anna L and Barroso, In{\^e}s} } @article {9580, title = {Association analysis of mitochondrial DNA heteroplasmic variants: methods and application.}, journal = {medRxiv}, year = {2024}, month = {2024 Jan 13}, abstract = {

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5\% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31\% of African Ancestry, mean age of 62, with 58\% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

}, doi = {10.1101/2024.01.12.24301233}, author = {Sun, Xianbang and Bulekova, Katia and Yang, Jian and Lai, Meng and Pitsillides, Achilleas N and Liu, Xue and Zhang, Yuankai and Guo, Xiuqing and Yong, Qian and Raffield, Laura M and Rotter, Jerome I and Rich, Stephen S and Abecasis, Goncalo and Carson, April P and Vasan, Ramachandran S and Bis, Joshua C and Psaty, Bruce M and Boerwinkle, Eric and Fitzpatrick, Annette L and Satizabal, Claudia L and Arking, Dan E and Ding, Jun and Levy, Daniel and Liu, Chunyu} } @article {9740, title = {Circulating Blood Plasma Profiling Reveals Proteomic Signature and a Causal Role for SVEP1 in Sudden Cardiac Death.}, journal = {Circ Genom Precis Med}, year = {2024}, month = {2024 Sep 05}, pages = {e004494}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.123.004494}, author = {Duong, ThuyVy and Austin, Thomas R and Brody, Jennifer A and Shojaie, Ali and Battle, Alexis and Bader, Joel S and Hong, Yun Soo and Ballantyne, Christie M and Coresh, Josef and Gerszten, Robert E and Tracy, Russell P and Psaty, Bruce M and Sotoodehnia, Nona and Arking, Dan E} } @article {9870, title = {The impact of common and rare genetic variants on bradyarrhythmia development.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Jan}, pages = {53-64}, abstract = {

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

}, keywords = {Bradycardia, Cardiac Conduction System Disease, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Pacemaker, Artificial, Phenotype, Polymorphism, Single Nucleotide, Sick Sinus Syndrome}, issn = {1546-1718}, doi = {10.1038/s41588-024-01978-2}, author = {Weng, Lu-Chen and R{\"a}m{\"o}, Joel T and Jurgens, Sean J and Khurshid, Shaan and Chaffin, Mark and Hall, Amelia Weber and Morrill, Valerie N and Wang, Xin and Nauffal, Victor and Sun, Yan V and Beer, Dominik and Lee, Simon and Nadkarni, Girish N and Duong, ThuyVy and Wang, Biqi and Czuba, Tomasz and Austin, Thomas R and Yoneda, Zachary T and Friedman, Daniel J and Clayton, Anne and Hyman, Matthew C and Judy, Renae L and Skanes, Allan C and Orland, Kate M and Treu, Timothy M and Oetjens, Matthew T and Alonso, Alvaro and Soliman, Elsayed Z and Lin, Honghuang and Lunetta, Kathryn L and van der Pals, Jesper and Issa, Tariq Z and Nafissi, Navid A and May, Heidi T and Leong-Sit, Peter and Roselli, Carolina and Choi, Seung Hoan and Khan, Habib R and Knight, Stacey and Karlsson Linn{\'e}r, Richard and Bezzina, Connie R and Ripatti, Samuli and Heckbert, Susan R and Gaziano, J Michael and Loos, Ruth J F and Psaty, Bruce M and Smith, J Gustav and Benjamin, Emelia J and Arking, Dan E and Rader, Daniel J and Shah, Svati H and Roden, Dan M and Damrauer, Scott M and Eckhardt, Lee L and Roberts, Jason D and Cutler, Michael J and Shoemaker, M Benjamin and Haggerty, Christopher M and Cho, Kelly and Palotie, Aarno and Wilson, Peter W F and Ellinor, Patrick T and Lubitz, Steven A} } @article {9914, title = {Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Mar}, pages = {539-547}, abstract = {

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

}, keywords = {Atrial Fibrillation, Chromatin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-024-02072-3}, author = {Roselli, Carolina and Surakka, Ida and Olesen, Morten S and Sveinbjornsson, Gardar and Marston, Nicholas A and Choi, Seung Hoan and Holm, Hilma and Chaffin, Mark and Gudbjartsson, Daniel and Hill, Matthew C and Aegisdottir, Hildur and Albert, Christine M and Alonso, Alvaro and Anderson, Christopher D and Arking, Dan E and Arnar, David O and Barnard, John and Benjamin, Emelia J and Braunwald, Eugene and Brumpton, Ben and Campbell, Archie and Chami, Nathalie and Chasman, Daniel I and Cho, Kelly and Choi, Eue-Keun and Christophersen, Ingrid E and Chung, Mina K and Conen, David and Crijns, Harry J and Cutler, Michael J and Czuba, Tomasz and Damrauer, Scott M and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton and Duong, ThuyVy and Erikstrup, Christian and Esko, T{\~o}nu and Fatkin, Diane and Faul, Jessica D and Ferreira, Manuel and Freitag, Daniel F and Ganesh, Santhi K and Gaziano, J Michael and Geelhoed, Bastiaan and Ghouse, Jonas and Gieger, Christian and Giulianini, Franco and Graham, Sarah E and Gudnason, Vilmundur and Guo, Xiuqing and Haggerty, Christopher and Hayward, Caroline and Heckbert, Susan R and Hveem, Kristian and Ito, Kaoru and Johnson, Renee and Jukema, J Wouter and Jurgens, Sean J and K{\"a}{\"a}b, Stefan and Kane, John P and Kany, Shinwan and Kardia, Sharon L R and Kavousi, Maryam and Khurshid, Shaan and Kamanu, Frederick K and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Komuro, Issei and Krieger, Jose E and Launer, Lenore J and Li, Dadong and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lotta, Luca and Lubitz, Steven A and Lunetta, Kathryn L and Macfarlane, Peter W and Magnusson, Patrik K E and Malik, Rainer and Mantineo, Helene and Marcus, Gregory M and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Melloni, Giorgio E M and Meyre, Pascal B and Miyazawa, Kazuo and Mohanty, Sanghamitra and Monfort, Laia M and M{\"u}ller-Nurasyid, Martina and Nafissi, Navid A and Natale, Andrea and Nazarian, Saman and Ostrowski, Sisse R and Pak, Hui-Nam and Pang, Shichao and Pedersen, Ole B and Pedersen, Nancy L and Pereira, Alexandre C and Pirruccello, James P and Preuss, Michael and Psaty, Bruce M and Pullinger, Clive R and Rader, Daniel J and R{\"a}m{\"o}, Joel T and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rotter, Jerome I and Sabatine, Marc S and Schunkert, Heribert and Shah, Svati H and Shim, Jaemin and Shoemaker, M Benjamin and Simonson, Bridget and Sinner, Moritz F and Smit, Roelof A J and Smith, Jennifer A and Smith, Nicholas L and Smith, J Gustav and Soliman, Elsayed Z and S{\o}rensen, Erik and Sotoodehnia, Nona and Strbian, Daniel and Stricker, Bruno H and Teder-Laving, Maris and Sun, Yan V and Th{\'e}riault, S{\'e}bastien and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Tveit, Arnljot and van der Harst, Pim and van Meurs, Joyce and Wang, Biqi and Weiss, Stefan and Wells, Quinn S and Weng, Lu-Chen and Wilson, Peter W and Xiao, Ling and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Zhao, Wei and Zhou, Xiang and Z{\"o}llner, Sebastian and Ruff, Christian T and Bundgaard, Henning and Willer, Cristen and Stefansson, Kari and Ellinor, Patrick T} } @article {9907, title = {Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Mar}, pages = {548-562}, abstract = {

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.

}, keywords = {Atrial Fibrillation, Case-Control Studies, Exome Sequencing, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Myocytes, Cardiac, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-025-02074-9}, author = {Choi, Seung Hoan and Jurgens, Sean J and Xiao, Ling and Hill, Matthew C and Haggerty, Christopher M and Sveinbj{\"o}rnsson, Gar{\dh}ar and Morrill, Valerie N and Marston, Nicholas A and Weng, Lu-Chen and Pirruccello, James P and Arnar, David O and Gudbjartsson, Daniel Fannar and Mantineo, Helene and von Falkenhausen, Aenne S and Natale, Andrea and Tveit, Arnljot and Geelhoed, Bastiaan and Roselli, Carolina and Van Wagoner, David R and Darbar, Dawood and Haase, Doreen and Soliman, Elsayed Z and Davogustto, Giovanni E and Jun, Goo and Calkins, Hugh and Anderson, Jeffrey L and Brody, Jennifer A and Halford, Jennifer L and Barnard, John and Hokanson, John E and Smith, Jonathan D and Bis, Joshua C and Young, Kendra and Johnson, Linda S B and Risch, Lorenz and Gula, Lorne J and Kwee, Lydia Coulter and Chaffin, Mark D and K{\"u}hne, Michael and Preuss, Michael and Gupta, Namrata and Nafissi, Navid A and Smith, Nicholas L and Nilsson, Peter M and van der Harst, Pim and Wells, Quinn S and Judy, Renae L and Schnabel, Renate B and Johnson, Renee and Smit, Roelof A J and Gabriel, Stacey and Knight, Stacey and Furukawa, Tetsushi and Blackwell, Thomas W and Nauffal, Victor and Wang, Xin and Min, Yuan-I and Yoneda, Zachary T and Laksman, Zachary W M and Bezzina, Connie R and Alonso, Alvaro and Psaty, Bruce M and Albert, Christine M and Arking, Dan E and Roden, Dan M and Chasman, Daniel I and Rader, Daniel J and Conen, David and McManus, David D and Fatkin, Diane and Benjamin, Emelia J and Boerwinkle, Eric and Marcus, Gregory M and Christophersen, Ingrid E and Smith, J Gustav and Roberts, Jason D and Raffield, Laura M and Shoemaker, M Benjamin and Cho, Michael H and Cutler, Michael J and Rienstra, Michiel and Chung, Mina K and S Olesen, Morten and Sinner, Moritz F and Sotoodehnia, Nona and Kirchhof, Paulus and Loos, Ruth J F and Nazarian, Saman and Mohanty, Sanghamitra and Damrauer, Scott M and K{\"a}{\"a}b, Stefan and Heckbert, Susan R and Redline, Susan and Shah, Svati H and Tanaka, Toshihiro and Ebana, Yusuke and Holm, Hilma and Stefansson, Kari and Ruff, Christian T and Sabatine, Marc S and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} }