%0 Journal Article %J Thromb Haemost %D 2008 %T Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study. %A Carty, Cara L %A Cushman, Mary %A Jones, Daniel %A Lange, Leslie A %A Hindorff, Lucia A %A Rice, Kenneth %A Jenny, Nancy S %A Durda, J Peter %A Walston, Jeremy %A Carlson, Christopher S %A Nickerson, Debbie %A Tracy, Russell P %A Reiner, Alex P %K African Americans %K Age Factors %K Aged %K Brain Ischemia %K Cardiovascular Diseases %K Carotid Artery Diseases %K European Continental Ancestry Group %K Female %K Fibrinogen %K Gene Frequency %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Male %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Population Surveillance %K Proportional Hazards Models %K Prospective Studies %K Reproducibility of Results %K Risk Assessment %K Risk Factors %K Sex Factors %K Stroke %K United States %X

Elevated plasma fibrinogen is a risk factor for cardiovascular disease (CVD), but associations between fibrinogen single nucleotide polymorphisms (SNPs) and disease risk are inconsistent. We investigated whether common (> or = 5% minor allele frequency) variation in the fibrinogen genes (FGA, FGB, FGG) is associated with fibrinogen concentration, carotid artery intima-medial thickness (IMT) and risk of incident myocardial infarction (MI), ischemic stroke and CVD mortality in European- (EA) and African-descent (AA) adults (> or = 65 years) from the Cardiovascular Health Study. TagSNPs were genotyped in 3,969 EA and 719 AA free of MI or stroke at baseline. Race-specific models included multiple testing correction and adjustment for sex, age and site. Among EA, minor alleles of FGA3807, FGB1437 and FGG902 were associated with higher fibrinogen levels; whereas FGA251, FGA2224, FGA6534 and FGG10034 were associated with lower levels, p<0.004 for each. Strongest associations were seen for FGB1437; each additional copy of the minor allele was associated with 13 mg/dl (95%CI: 9-16) higher fibrinogen level. Similar trends in AA were not significant. Fibrinogen haplotypes were not significantly associated with internal or common carotid IMT. No associations with MI or CVD mortality were seen in EA, though FGB1038 and FGG902 were significantly associated with increased and decreased risk of stroke in men, respectively, as were related haplotypes. FGB1038 was also associated with CVD mortality in AA, HR = 1.9 (95%CI: 1.3-2.7). In conclusion, while fibrinogen genetic variation was strongly associated with fibrinogen levels, there was less evidence of association with the more complex outcomes of IMT and CVD events.

%B Thromb Haemost %V 99 %P 388-95 %8 2008 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/18278190?dopt=Abstract %R 10.1160/TH07-08-0523 %0 Journal Article %J J Atheroscler Thromb %D 2009 %T Association of genetic variation in serum amyloid-A with cardiovascular disease and interactions with IL6, IL1RN, IL1beta and TNF genes in the Cardiovascular Health Study. %A Carty, Cara L %A Heagerty, Patrick %A Heckbert, Susan R %A Enquobahrie, Daniel A %A Jarvik, Gail P %A Davis, Scott %A Tracy, Russell P %A Reiner, Alexander P %K Aged %K Cardiovascular Diseases %K Cholesterol, HDL %K Cytokines %K Female %K Gene Regulatory Networks %K Humans %K Inflammation Mediators %K Interleukin 1 Receptor Antagonist Protein %K Interleukin-1beta %K Interleukin-6 %K Male %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Serum Amyloid A Protein %K Tumor Necrosis Factor-alpha %K Tunica Intima %X

AIM: Since inflammation is an important contributor to atherosclerosis, gene variants mediating inflammation are of interest. We investigated gene variants in acute phase serum amyloid-A (SAA), a sensitive indicator of inflammatory activity, and their associations with cardiovascular disease (CVD) and HDL cholesterol. Interaction of the SAA genes with genetic variants of their regulators, IL-1, IL-6 and TNF-alpha in influencing CVD was also explored.

METHODS: SNPs characterizing common variation in the SAA1 and SAA2 genes were genotyped in European-(EA) and African-American (AA) participants (n=3969 and n=719) of the Cardiovascular Health Study. Using linear and Cox proportional hazards regression, we assessed associations of SNPs with baseline carotid artery intima-media thickness (cIMT) and risk of incident myocardial infarction, ischemic stroke, total CVD events or mortality during 14 years of follow-up.

RESULTS: No associations between SAA SNPs and outcomes were observed in EA, with the exception of total CVD events; each rs4638289 minor allele was associated with an increased risk in obese individuals, HR=1.2 (95%CI: 0.981.4; p=0.086) and decreased risk among non-obese, HR=0.9 (95%CI: 0.80.99; p=0.026). In AA, we observed modest associations between SAA SNPs and cIMT, potentially modified by HDL. SAA SNPs were also associated with lower HDL in EA and AA. Suggestive gene-gene interaction findings for cIMT in AA and CVD mortality in EA were not significant in subsequent model selection tests.

CONCLUSION: Associations of SAA SNPs with cIMT, HDL and total CVD events were identified, unadjusted for multiple testing. These findings should be regarded as hypothesis-generating until confirmed by other studies.

%B J Atheroscler Thromb %V 16 %P 419-30 %8 2009 Aug %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/19729864?dopt=Abstract %0 Journal Article %J Ann Hum Genet %D 2010 %T Interaction between fibrinogen and IL-6 genetic variants and associations with cardiovascular disease risk in the Cardiovascular Health Study. %A Carty, Cara L %A Heagerty, Patrick %A Heckbert, Susan R %A Jarvik, Gail P %A Lange, Leslie A %A Cushman, Mary %A Tracy, Russell P %A Reiner, Alexander P %K Aged %K Cardiovascular Diseases %K Carotid Arteries %K Female %K Fibrinogen %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Interleukin-6 %K Male %K Models, Biological %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Risk %K Stroke %X

The inflammatory cytokine interleukin-6 (IL-6) is a main regulator of fibrinogen synthesis, though its interaction with fibrinogen genes (FGA, FGB, FGG) and subsequent impact on cardiovascular disease (CVD) risk is not well-studied. We investigated joint associations of fibrinogen and IL6 tagSNPs with fibrinogen concentrations, carotid intima-media thickness, and myocardial infarction or ischemic stroke in 3900 European-American Cardiovascular Health Study participants. To identify combinations of genetic main effects and interactions associated with outcomes, we used logic regression. We also evaluated whether the relationship between fibrinogen SNPs and fibrinogen level varied by IL-6 level using linear regression models with multiplicative interaction terms. Combinations of fibrinogen and IL6 SNPs were significantly associated with fibrinogen level (p < 0.005), but not with other outcomes. Fibrinogen levels were higher in individuals having FGB1437 (rs1800790) and lacking FGA6534 (rs6050) minor alleles; these SNPs interacted with IL6 rs1800796 to influence fibrinogen level. Marginally significant (p= 0.03) interactions between IL-6 level and FGA and FGG promoter SNPs associated with fibrinogen levels were detected. We identified potential gene-gene interactions influencing fibrinogen levels. Although IL-6 responsive binding sites are present in fibrinogen gene promoter regions, we did not find strong evidence of interaction between fibrinogen SNPs and IL6 SNPs or levels influencing CVD.

%B Ann Hum Genet %V 74 %P 1-10 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20059469?dopt=Abstract %R 10.1111/j.1469-1809.2009.00551.x %0 Journal Article %J PLoS Genet %D 2011 %T Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. %A Dumitrescu, Logan %A Carty, Cara L %A Taylor, Kira %A Schumacher, Fredrick R %A Hindorff, Lucia A %A Ambite, José L %A Anderson, Garnet %A Best, Lyle G %A Brown-Gentry, Kristin %A Bůzková, Petra %A Carlson, Christopher S %A Cochran, Barbara %A Cole, Shelley A %A Devereux, Richard B %A Duggan, Dave %A Eaton, Charles B %A Fornage, Myriam %A Franceschini, Nora %A Haessler, Jeff %A Howard, Barbara V %A Johnson, Karen C %A Laston, Sandra %A Kolonel, Laurence N %A Lee, Elisa T %A MacCluer, Jean W %A Manolio, Teri A %A Pendergrass, Sarah A %A Quibrera, Miguel %A Shohet, Ralph V %A Wilkens, Lynne R %A Haiman, Christopher A %A Le Marchand, Loïc %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Crawford, Dana C %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Continental Population Groups %K Female %K Gene Frequency %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Lipid Metabolism %K Lipoproteins, HDL %K Lipoproteins, LDL %K Male %K Middle Aged %K Molecular Epidemiology %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Triglycerides %K Young Adult %X

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

%B PLoS Genet %V 7 %P e1002138 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21738485?dopt=Abstract %R 10.1371/journal.pgen.1002138 %0 Journal Article %J Stroke %D 2011 %T Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study. %A Elkind, Mitchell S V %A Carty, Cara L %A O'Meara, Ellen S %A Lumley, Thomas %A Lefkowitz, David %A Kronmal, Richard A %A Longstreth, W T %K Bacterial Infections %K Brain Ischemia %K Cardiology %K Cohort Studies %K Cross-Over Studies %K Female %K Follow-Up Studies %K Hospitalization %K Humans %K Male %K Odds Ratio %K Proportional Hazards Models %K Regression Analysis %K Risk %K Stroke %K Time Factors %X

BACKGROUND AND PURPOSE: Little is known about the acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with the short-term risk of stroke.

METHODS: The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days before an incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years before stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by conditional logistic regression. Confirmatory analyses assessed hazard ratios of stroke from Cox regression models, with hospitalization for infection as a time-varying exposure.

RESULTS: During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without a baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days before stroke, OR=3.4 (95% CI, 1.8 to 6.5). The point estimates of risks were higher when we examined shorter intervals: for 30 days, OR=7.3 (95% CI, 1.9 to 40.9), and for 14 days, OR=8.0 (95% CI, 1.7 to 77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted hazard ratio=2.4 (95% CI, 1.6 to 3.4).

CONCLUSIONS: Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.

%B Stroke %V 42 %P 1851-6 %8 2011 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21546476?dopt=Abstract %R 10.1161/STROKEAHA.110.608588 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Associations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study. %A Carty, Cara L %A Bůzková, Petra %A Fornage, Myriam %A Franceschini, Nora %A Cole, Shelley %A Heiss, Gerardo %A Hindorff, Lucia A %A Howard, Barbara V %A Mann, Sue %A Martin, Lisa W %A Zhang, Ying %A Matise, Tara C %A Prentice, Ross %A Reiner, Alexander P %A Kooperberg, Charles %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Female %K Genetics, Population %K Genome-Wide Association Study %K Genomics %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Triglycerides %X

BACKGROUND: Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.

METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomics and Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were significantly associated with [corrected] IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.

CONCLUSIONS: Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.

%B Circ Cardiovasc Genet %V 5 %P 210-6 %8 2012 Apr 01 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22403240?dopt=Abstract %R 10.1161/CIRCGENETICS.111.962191 %0 Journal Article %J PLoS One %D 2012 %T Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. %A Buyske, Steven %A Wu, Ying %A Carty, Cara L %A Cheng, Iona %A Assimes, Themistocles L %A Dumitrescu, Logan %A Hindorff, Lucia A %A Mitchell, Sabrina %A Ambite, Jose Luis %A Boerwinkle, Eric %A Bůzková, Petra %A Carlson, Chris S %A Cochran, Barbara %A Duggan, David %A Eaton, Charles B %A Fesinmeyer, Megan D %A Franceschini, Nora %A Haessler, Jeffrey %A Jenny, Nancy %A Kang, Hyun Min %A Kooperberg, Charles %A Lin, Yi %A Le Marchand, Loïc %A Matise, Tara C %A Robinson, Jennifer G %A Rodriguez, Carlos %A Schumacher, Fredrick R %A Voight, Benjamin F %A Young, Alicia %A Manolio, Teri A %A Mohlke, Karen L %A Haiman, Christopher A %A Peters, Ulrike %A Crawford, Dana C %A North, Kari E %K African Americans %K Cardiovascular Diseases %K Cholesterol Ester Transfer Proteins %K Cholesterol, HDL %K Cholesterol, LDL %K Chromosomes, Human %K Cohort Studies %K Gene Frequency %K Genome-Wide Association Study %K Genotype %K Humans %K Metabolic Diseases %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.

%B PLoS One %V 7 %P e35651 %8 2012 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22539988?dopt=Abstract %R 10.1371/journal.pone.0035651 %0 Journal Article %J PLoS Genet %D 2012 %T Fine-mapping and initial characterization of QT interval loci in African Americans. %A Avery, Christy L %A Sethupathy, Praveen %A Buyske, Steven %A He, Qianchuan %A Lin, Dan-Yu %A Arking, Dan E %A Carty, Cara L %A Duggan, David %A Fesinmeyer, Megan D %A Hindorff, Lucia A %A Jeff, Janina M %A Klein, Liviu %A Patton, Kristen K %A Peters, Ulrike %A Shohet, Ralph V %A Sotoodehnia, Nona %A Young, Alicia M %A Kooperberg, Charles %A Haiman, Christopher A %A Mohlke, Karen L %A Whitsel, Eric A %A North, Kari E %K African Americans %K Aged %K Computational Biology %K Electrocardiography %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Metagenomics %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %K Tachycardia %K United States %X

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'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≤1.20×10(-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≤1.37×10(-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.

%B PLoS Genet %V 8 %P e1002870 %8 2012 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/22912591?dopt=Abstract %R 10.1371/journal.pgen.1002870 %0 Journal Article %J BMC Genet %D 2013 %T Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. %A Taylor, Kira C %A Carty, Cara L %A Dumitrescu, Logan %A Bůzková, Petra %A Cole, Shelley A %A Hindorff, Lucia %A Schumacher, Fred R %A Wilkens, Lynne R %A Shohet, Ralph V %A Quibrera, P Miguel %A Johnson, Karen C %A Henderson, Brian E %A Haessler, Jeff %A Franceschini, Nora %A Eaton, Charles B %A Duggan, David J %A Cochran, Barbara %A Cheng, Iona %A Carlson, Chris S %A Brown-Gentry, Kristin %A Anderson, Garnet %A Ambite, Jose Luis %A Haiman, Christopher %A Le Marchand, Loïc %A Kooperberg, Charles %A Crawford, Dana C %A Buyske, Steven %A North, Kari E %A Fornage, Myriam %K Female %K Genetic Heterogeneity %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Polymorphism, Single Nucleotide %K Population Groups %X

BACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.

CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.

%B BMC Genet %V 14 %P 33 %8 2013 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/23634756?dopt=Abstract %R 10.1186/1471-2156-14-33 %0 Journal Article %J Hum Genet %D 2013 %T No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population. %A Dumitrescu, Logan %A Carty, Cara L %A Franceschini, Nora %A Hindorff, Lucia A %A Cole, Shelley A %A Bůzková, Petra %A Schumacher, Fredrick R %A Eaton, Charles B %A Goodloe, Robert J %A Duggan, David J %A Haessler, Jeff %A Cochran, Barbara %A Henderson, Brian E %A Cheng, Iona %A Johnson, Karen C %A Carlson, Chris S %A Love, Shelly-Anne %A Brown-Gentry, Kristin %A Nato, Alejandro Q %A Quibrera, Miguel %A Shohet, Ralph V %A Ambite, Jose Luis %A Wilkens, Lynne R %A Le Marchand, Loïc %A Haiman, Christopher A %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Fornage, Myriam %A Crawford, Dana C %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Ethnic Groups %K Female %K Gene Frequency %K Gene-Environment Interaction %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Male %K Polymorphism, Single Nucleotide %K Prevalence %K Smoking %K Triglycerides %K Young Adult %X

Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.

%B Hum Genet %V 132 %P 1427-31 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24100633?dopt=Abstract %R 10.1007/s00439-013-1375-3 %0 Journal Article %J Ann Hum Genet %D 2013 %T Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Dumitrescu, Logan %A Carty, Cara L %A Franceschini, Nora %A Hindorff, Lucia A %A Cole, Shelley A %A Bůzková, Petra %A Schumacher, Fredrick R %A Eaton, Charles B %A Goodloe, Robert J %A Duggan, David J %A Haessler, Jeff %A Cochran, Barbara %A Henderson, Brian E %A Cheng, Iona %A Johnson, Karen C %A Carlson, Chris S %A Love, Shelly-Ann %A Brown-Gentry, Kristin %A Nato, Alejandro Q %A Quibrera, Miguel %A Anderson, Garnet %A Shohet, Ralph V %A Ambite, Jose Luis %A Wilkens, Lynne R %A Marchand, Loic Le %A Haiman, Christopher A %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Fornage, Myriam %A Crawford, Dana C %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %X

Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.

%B Ann Hum Genet %V 77 %P 416-25 %8 2013 Sep %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23808484?dopt=Abstract %R 10.1111/ahg.12027 %0 Journal Article %J PLoS Genet %D 2013 %T Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. %A Wu, Ying %A Waite, Lindsay L %A Jackson, Anne U %A Sheu, Wayne H-H %A Buyske, Steven %A Absher, Devin %A Arnett, Donna K %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Carty, Cara L %A Cheng, Iona %A Cochran, Barbara %A Croteau-Chonka, Damien C %A Dumitrescu, Logan %A Eaton, Charles B %A Franceschini, Nora %A Guo, Xiuqing %A Henderson, Brian E %A Hindorff, Lucia A %A Kim, Eric %A Kinnunen, Leena %A Komulainen, Pirjo %A Lee, Wen-Jane %A Le Marchand, Loïc %A Lin, Yi %A Lindström, Jaana %A Lingaas-Holmen, Oddgeir %A Mitchell, Sabrina L %A Narisu, Narisu %A Robinson, Jennifer G %A Schumacher, Fred %A Stančáková, Alena %A Sundvall, Jouko %A Sung, Yun-Ju %A Swift, Amy J %A Wang, Wen-Chang %A Wilkens, Lynne %A Wilsgaard, Tom %A Young, Alicia M %A Adair, Linda S %A Ballantyne, Christie M %A Bůzková, Petra %A Chakravarti, Aravinda %A Collins, Francis S %A Duggan, David %A Feranil, Alan B %A Ho, Low-Tone %A Hung, Yi-Jen %A Hunt, Steven C %A Hveem, Kristian %A Juang, Jyh-Ming J %A Kesäniemi, Antero Y %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lee, I-Te %A Leppert, Mark F %A Matise, Tara C %A Moilanen, Leena %A Njølstad, Inger %A Peters, Ulrike %A Quertermous, Thomas %A Rauramaa, Rainer %A Rotter, Jerome I %A Saramies, Jouko %A Tuomilehto, Jaakko %A Uusitupa, Matti %A Wang, Tzung-Dau %A Boehnke, Michael %A Haiman, Christopher A %A Chen, Yii-der I %A Kooperberg, Charles %A Assimes, Themistocles L %A Crawford, Dana C %A Hsiung, Chao A %A North, Kari E %A Mohlke, Karen L %K African Americans %K Apolipoproteins A %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Genome-Wide Association Study %K Humans %K Lipoproteins, HDL %K Lipoproteins, LDL %K Proprotein Convertases %K Serine Endopeptidases %K Triglycerides %X

Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

%B PLoS Genet %V 9 %P e1003379 %8 2013 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23555291?dopt=Abstract %R 10.1371/journal.pgen.1003379 %0 Journal Article %J Epidemiology %D 2014 %T Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. %A Seyerle, Amanda A %A Young, Alicia M %A Jeff, Janina M %A Melton, Phillip E %A Jorgensen, Neal W %A Lin, Yi %A Carty, Cara L %A Deelman, Ewa %A Heckbert, Susan R %A Hindorff, Lucia A %A Jackson, Rebecca D %A Martin, Lisa W %A Okin, Peter M %A Perez, Marco V %A Psaty, Bruce M %A Soliman, Elsayed Z %A Whitsel, Eric A %A North, Kari E %A Laston, Sandra %A Kooperberg, Charles %A Avery, Christy L %K Aged %K Continental Population Groups %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %X

BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.

METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.

RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.

CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

%B Epidemiology %V 25 %P 790-8 %8 2014 Nov %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25166880?dopt=Abstract %R 10.1097/EDE.0000000000000168 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study. %A Kocarnik, Jonathan M %A Pendergrass, Sarah A %A Carty, Cara L %A Pankow, James S %A Schumacher, Fredrick R %A Cheng, Iona %A Durda, Peter %A Ambite, Jose Luis %A Deelman, Ewa %A Cook, Nancy R %A Liu, Simin %A Wactawski-Wende, Jean %A Hutter, Carolyn %A Brown-Gentry, Kristin %A Wilson, Sarah %A Best, Lyle G %A Pankratz, Nathan %A Hong, Ching-Ping %A Cole, Shelley A %A Voruganti, V Saroja %A Bůzková, Petra %A Jorgensen, Neal W %A Jenny, Nancy S %A Wilkens, Lynne R %A Haiman, Christopher A %A Kolonel, Laurence N %A LaCroix, Andrea %A North, Kari %A Jackson, Rebecca %A Le Marchand, Loïc %A Hindorff, Lucia A %A Crawford, Dana C %A Gross, Myron %A Peters, Ulrike %K Adult %K African Continental Ancestry Group %K Aged %K Asian Continental Ancestry Group %K C-Reactive Protein %K Female %K Genetic Variation %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Indians, North American %K Inflammation %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K United States %K Young Adult %X

BACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.

METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).

CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.

%B Circ Cardiovasc Genet %V 7 %P 178-88 %8 2014 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24622110?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000173 %0 Journal Article %J Stroke %D 2015 %T Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. %A Carty, Cara L %A Keene, Keith L %A Cheng, Yu-Ching %A Meschia, James F %A Chen, Wei-Min %A Nalls, Mike %A Bis, Joshua C %A Kittner, Steven J %A Rich, Stephen S %A Tajuddin, Salman %A Zonderman, Alan B %A Evans, Michele K %A Langefeld, Carl D %A Gottesman, Rebecca %A Mosley, Thomas H %A Shahar, Eyal %A Woo, Daniel %A Yaffe, Kristine %A Liu, Yongmei %A Sale, Michèle M %A Dichgans, Martin %A Malik, Rainer %A Longstreth, W T %A Mitchell, Braxton D %A Psaty, Bruce M %A Kooperberg, Charles %A Reiner, Alexander %A Worrall, Bradford B %A Fornage, Myriam %K African Americans %K Case-Control Studies %K Cohort Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.

METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.

RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.

CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

%B Stroke %V 46 %P 2063-8 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26089329?dopt=Abstract %R 10.1161/STROKEAHA.115.009044 %0 Journal Article %J JAMA Neurol %D 2015 %T Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. %A Auer, Paul L %A Nalls, Mike %A Meschia, James F %A Worrall, Bradford B %A Longstreth, W T %A Seshadri, Sudha %A Kooperberg, Charles %A Burger, Kathleen M %A Carlson, Christopher S %A Carty, Cara L %A Chen, Wei-Min %A Cupples, L Adrienne %A DeStefano, Anita L %A Fornage, Myriam %A Hardy, John %A Hsu, Li %A Jackson, Rebecca D %A Jarvik, Gail P %A Kim, Daniel S %A Lakshminarayan, Kamakshi %A Lange, Leslie A %A Manichaikul, Ani %A Quinlan, Aaron R %A Singleton, Andrew B %A Thornton, Timothy A %A Nickerson, Deborah A %A Peters, Ulrike %A Rich, Stephen S %K Aged %K Brain Ischemia %K Exome %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Muscle Proteins %K National Heart, Lung, and Blood Institute (U.S.) %K Nuclear Proteins %K Open Reading Frames %K Palmitoyl-CoA Hydrolase %K Stroke %K United States %X

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

%B JAMA Neurol %V 72 %P 781-8 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/25961151?dopt=Abstract %R 10.1001/jamaneurol.2015.0582 %0 Journal Article %J Hum Mol Genet %D 2016 %T Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. %A Evans, Daniel S %A Avery, Christy L %A Nalls, Mike A %A Li, Guo %A Barnard, John %A Smith, Erin N %A Tanaka, Toshiko %A Butler, Anne M %A Buxbaum, Sarah G %A Alonso, Alvaro %A Arking, Dan E %A Berenson, Gerald S %A Bis, Joshua C %A Buyske, Steven %A Carty, Cara L %A Chen, Wei %A Chung, Mina K %A Cummings, Steven R %A Deo, Rajat %A Eaton, Charles B %A Fox, Ervin R %A Heckbert, Susan R %A Heiss, Gerardo %A Hindorff, Lucia A %A Hsueh, Wen-Chi %A Isaacs, Aaron %A Jamshidi, Yalda %A Kerr, Kathleen F %A Liu, Felix %A Liu, Yongmei %A Lohman, Kurt K %A Magnani, Jared W %A Maher, Joseph F %A Mehra, Reena %A Meng, Yan A %A Musani, Solomon K %A Newton-Cheh, Christopher %A North, Kari E %A Psaty, Bruce M %A Redline, Susan %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Shohet, Ralph V %A Singleton, Andrew B %A Smith, Jonathan D %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Taylor, Herman A %A Van Wagoner, David R %A Wilson, James G %A Young, Taylor %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Evans, Michele K %A Ferrucci, Luigi %A Murray, Sarah S %A Tranah, Gregory J %A Whitsel, Eric A %A Reiner, Alex P %A Sotoodehnia, Nona %X

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 × 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 × 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 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 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 × 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.

%B Hum Mol Genet %8 2016 Aug 29 %G eng %R 10.1093/hmg/ddw284 %0 Journal Article %J PLoS One %D 2016 %T Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. %A Dehghan, Abbas %A Bis, Joshua C %A White, Charles C %A Smith, Albert Vernon %A Morrison, Alanna C %A Cupples, L Adrienne %A Trompet, Stella %A Chasman, Daniel I %A Lumley, Thomas %A Völker, Uwe %A Buckley, Brendan M %A Ding, Jingzhong %A Jensen, Majken K %A Folsom, Aaron R %A Kritchevsky, Stephen B %A Girman, Cynthia J %A Ford, Ian %A Dörr, Marcus %A Salomaa, Veikko %A Uitterlinden, André G %A Eiriksdottir, Gudny %A Vasan, Ramachandran S %A Franceschini, Nora %A Carty, Cara L %A Virtamo, Jarmo %A Demissie, Serkalem %A Amouyel, Philippe %A Arveiler, Dominique %A Heckbert, Susan R %A Ferrieres, Jean %A Ducimetiere, Pierre %A Smith, Nicholas L %A Wang, Ying A %A Siscovick, David S %A Rice, Kenneth M %A Wiklund, Per-Gunnar %A Taylor, Kent D %A Evans, Alun %A Kee, Frank %A Rotter, Jerome I %A Karvanen, Juha %A Kuulasmaa, Kari %A Heiss, Gerardo %A Kraft, Peter %A Launer, Lenore J %A Hofman, Albert %A Markus, Marcello R P %A Rose, Lynda M %A Silander, Kaisa %A Wagner, Peter %A Benjamin, Emelia J %A Lohman, Kurt %A Stott, David J %A Rivadeneira, Fernando %A Harris, Tamara B %A Levy, Daniel %A Liu, Yongmei %A Rimm, Eric B %A Jukema, J Wouter %A Völzke, Henry %A Ridker, Paul M %A Blankenberg, Stefan %A Franco, Oscar H %A Gudnason, Vilmundur %A Psaty, Bruce M %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Aged %K Cohort Studies %K Cooperative Behavior %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

%B PLoS One %V 11 %P e0144997 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract %R 10.1371/journal.pone.0144997 %0 Journal Article %J Exp Gerontol %D 2017 %T Leisure-time physical activity and leukocyte telomere length among older women. %A Shadyab, Aladdin H %A Lamonte, Michael J %A Kooperberg, Charles %A Reiner, Alexander P %A Carty, Cara L %A Manini, Todd M %A Hou, Lifang %A Di, Chongzhi %A Macera, Caroline A %A Gallo, Linda C %A Shaffer, Richard A %A Jain, Sonia %A LaCroix, Andrea Z %X

BACKGROUND: Shortened leukocyte telomere length (LTL), a purported marker of cellular aging, is associated with morbidity and mortality. However, the association of physical activity, a modifiable lifestyle behavior, with LTL has not been adequately studied among older adults.

METHODS: In this cross-sectional study, we examined associations of various intensity levels of leisure-time physical activity with LTL among 1476 older white and African American women from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health study. Self-reported physical activity was assessed by questionnaire, and LTL was measured by Southern blot. The association between physical activity and LTL was evaluated using multiple linear regression models adjusted for demographic characteristics, lifestyle behaviors, and health-related variables.

RESULTS: Women were on average aged 79.2 (standard deviation 6.7) years old. In the final model adjusted for age, race/ethnicity, education, marital status, smoking, alcohol, body mass index, a history of chronic diseases, and hormone therapy use, LTL was on average 110 (95% confidence interval, 20-190) base pairs longer among women in the highest (≥17.00MET-hours/week) compared with the lowest (<1.25MET-hours/week) level of total leisure-time physical activity (P for trend=0.02). Higher levels of moderate-to-vigorous physical activity (P for trend=0.04) and faster walking speed (P for trend=0.03) were also associated with longer LTL in the fully-adjusted models.

CONCLUSION: Older women participating in greater amounts of total leisure-time physical activity and moderate-to-vigorous physical activity had longer LTL.

%B Exp Gerontol %V 95 %P 141-147 %8 2017 Sep %G eng %R 10.1016/j.exger.2017.05.019 %0 Journal Article %J Hum Mol Genet %D 2018 %T Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Kocarnik, Jonathan M %A Richard, Melissa %A Graff, Misa %A Haessler, Jeffrey %A Bien, Stephanie %A Carlson, Chris %A Carty, Cara L %A Reiner, Alexander P %A Avery, Christy L %A Ballantyne, Christie M %A LaCroix, Andrea Z %A Assimes, Themistocles L %A Barbalic, Maja %A Pankratz, Nathan %A Tang, Weihong %A Tao, Ran %A Chen, Dongquan %A Talavera, Gregory A %A Daviglus, Martha L %A Chirinos-Medina, Diana A %A Pereira, Rocio %A Nishimura, Katie %A Bůzková, Petra %A Best, Lyle G %A Ambite, Jose Luis %A Cheng, Iona %A Crawford, Dana C %A Hindorff, Lucia A %A Fornage, Myriam %A Heiss, Gerardo %A North, Kari E %A Haiman, Christopher A %A Peters, Ulrike %A Le Marchand, Loïc %A Kooperberg, Charles %X

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

%B Hum Mol Genet %V 27 %P 2940-2953 %8 2018 Aug 15 %G eng %N 16 %R 10.1093/hmg/ddy211 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A den Hoed, Marcel %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Bis, Joshua C %A Pastinen, Tomi %A Ruusalepp, Arno %A Schadt, Eric E %A Koplev, Simon %A Björkegren, Johan L M %A Codoni, Veronica %A Civelek, Mete %A Smith, Nicholas L %A Trégouët, David A %A Christophersen, Ingrid E %A Roselli, Carolina %A Lubitz, Steven A %A Ellinor, Patrick T %A Tai, E Shyong %A Kooner, Jaspal S %A Kato, Norihiro %A He, Jiang %A van der Harst, Pim %A Elliott, Paul %A Chambers, John C %A Takeuchi, Fumihiko %A Johnson, Andrew D %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A Hoed, Marcel den %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Amin, Najaf %A Aparicio, Hugo S %A Arnett, Donna K %A Attia, John %A Beiser, Alexa S %A Berr, Claudine %A Buring, Julie E %A Bustamante, Mariana %A Caso, Valeria %A Cheng, Yu-Ching %A Choi, Seung Hoan %A Chowhan, Ayesha %A Cullell, Natalia %A Dartigues, Jean-François %A Delavaran, Hossein %A Delgado, Pilar %A Dörr, Marcus %A Engström, Gunnar %A Ford, Ian %A Gurpreet, Wander S %A Hamsten, Anders %A Heitsch, Laura %A Hozawa, Atsushi %A Ibanez, Laura %A Ilinca, Andreea %A Ingelsson, Martin %A Iwasaki, Motoki %A Jackson, Rebecca D %A Jood, Katarina %A Jousilahti, Pekka %A Kaffashian, Sara %A Kalra, Lalit %A Kamouchi, Masahiro %A Kitazono, Takanari %A Kjartansson, Olafur %A Kloss, Manja %A Koudstaal, Peter J %A Krupinski, Jerzy %A Labovitz, Daniel L %A Laurie, Cathy C %A Levi, Christopher R %A Li, Linxin %A Lind, Lars %A Lindgren, Cecilia M %A Lioutas, Vasileios %A Liu, Yong Mei %A Lopez, Oscar L %A Makoto, Hirata %A Martinez-Majander, Nicolas %A Matsuda, Koichi %A Minegishi, Naoko %A Montaner, Joan %A Morris, Andrew P %A Muiño, Elena %A Müller-Nurasyid, Martina %A Norrving, Bo %A Ogishima, Soichi %A Parati, Eugenio A %A Peddareddygari, Leema Reddy %A Pedersen, Nancy L %A Pera, Joanna %A Perola, Markus %A Pezzini, Alessandro %A Pileggi, Silvana %A Rabionet, Raquel %A Riba-Llena, Iolanda %A Ribasés, Marta %A Romero, Jose R %A Roquer, Jaume %A Rudd, Anthony G %A Sarin, Antti-Pekka %A Sarju, Ralhan %A Sarnowski, Chloe %A Sasaki, Makoto %A Satizabal, Claudia L %A Satoh, Mamoru %A Sattar, Naveed %A Sawada, Norie %A Sibolt, Gerli %A Sigurdsson, Ásgeir %A Smith, Albert %A Sobue, Kenji %A Soriano-Tárraga, Carolina %A Stanne, Tara %A Stine, O Colin %A Stott, David J %A Strauch, Konstantin %A Takai, Takako %A Tanaka, Hideo %A Tanno, Kozo %A Teumer, Alexander %A Tomppo, Liisa %A Torres-Aguila, Nuria P %A Touze, Emmanuel %A Tsugane, Shoichiro %A Uitterlinden, André G %A Valdimarsson, Einar M %A van der Lee, Sven J %A Völzke, Henry %A Wakai, Kenji %A Weir, David %A Williams, Stephen R %A Wolfe, Charles D A %A Wong, Quenna %A Xu, Huichun %A Yamaji, Taiki %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %X

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

%B Nat Genet %V 50 %P 524-537 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0058-3