TY - JOUR T1 - Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. JF - PLoS Genet Y1 - 2011 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Taylor, Kira A1 - Schumacher, Fredrick R A1 - Hindorff, Lucia A A1 - Ambite, José L A1 - Anderson, Garnet A1 - Best, Lyle G A1 - Brown-Gentry, Kristin A1 - Bůzková, Petra A1 - Carlson, Christopher S A1 - Cochran, Barbara A1 - Cole, Shelley A A1 - Devereux, Richard B A1 - Duggan, Dave A1 - Eaton, Charles B A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Haessler, Jeff A1 - Howard, Barbara V A1 - Johnson, Karen C A1 - Laston, Sandra A1 - Kolonel, Laurence N A1 - Lee, Elisa T A1 - MacCluer, Jean W A1 - Manolio, Teri A A1 - Pendergrass, Sarah A A1 - Quibrera, Miguel A1 - Shohet, Ralph V A1 - Wilkens, Lynne R A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Crawford, Dana C KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Continental Population Groups KW - Female KW - Gene Frequency KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Lipid Metabolism KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Male KW - Middle Aged KW - Molecular Epidemiology KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Triglycerides KW - Young Adult AB -

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.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738485?dopt=Abstract ER - TY - JOUR T1 - The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. JF - Am J Epidemiol Y1 - 2011 A1 - Matise, Tara C A1 - Ambite, Jose Luis A1 - Buyske, Steven A1 - Carlson, Christopher S A1 - Cole, Shelley A A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Heiss, Gerardo A1 - Kooperberg, Charles A1 - Marchand, Loic Le A1 - Manolio, Teri A A1 - North, Kari E A1 - Peters, Ulrike A1 - Ritchie, Marylyn D A1 - Hindorff, Lucia A A1 - Haines, Jonathan L KW - Epidemiologic Methods KW - Epidemiologic Research Design KW - Ethnic Groups KW - Genetic Association Studies KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Interinstitutional Relations KW - Multifactorial Inheritance KW - National Human Genome Research Institute (U.S.) KW - Phenotype KW - Pilot Projects KW - Research Design KW - Risk Factors KW - United States AB -

Genetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the "phenome-wide association study" approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser.

VL - 174 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21836165?dopt=Abstract ER - TY - JOUR T1 - Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium. JF - Diabetes Y1 - 2012 A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Spencer, Kylee L A1 - Bůzková, Petra A1 - Voruganti, V Saroja A1 - Wan, Peggy A1 - Haessler, Jeff A1 - Franceschini, Nora A1 - Monroe, Kristine R A1 - Howard, Barbara V A1 - Jackson, Rebecca D A1 - Florez, Jose C A1 - Kolonel, Laurence N A1 - Buyske, Steven A1 - Goodloe, Robert J A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Meigs, James B A1 - Waters, Kevin A1 - Mukamal, Kenneth J A1 - Pendergrass, Sarah A A1 - Shrader, Peter A1 - Wilkens, Lynne R A1 - Hindorff, Lucia A A1 - Ambite, Jose Luis A1 - North, Kari E A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - Le Marchand, Loïc A1 - Pankow, James S KW - Adult KW - Aged KW - Aged, 80 and over KW - Alleles KW - Diabetes Mellitus, Type 2 KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Metagenomics KW - Middle Aged KW - Population Groups KW - Risk KW - Risk Factors AB -

Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.

VL - 61 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22474029?dopt=Abstract ER - TY - JOUR T1 - Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. JF - PLoS One Y1 - 2012 A1 - Buyske, Steven A1 - Wu, Ying A1 - Carty, Cara L A1 - Cheng, Iona A1 - Assimes, Themistocles L A1 - Dumitrescu, Logan A1 - Hindorff, Lucia A A1 - Mitchell, Sabrina A1 - Ambite, Jose Luis A1 - Boerwinkle, Eric A1 - Bůzková, Petra A1 - Carlson, Chris S A1 - Cochran, Barbara A1 - Duggan, David A1 - Eaton, Charles B A1 - Fesinmeyer, Megan D A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Jenny, Nancy A1 - Kang, Hyun Min A1 - Kooperberg, Charles A1 - Lin, Yi A1 - Le Marchand, Loïc A1 - Matise, Tara C A1 - Robinson, Jennifer G A1 - Rodriguez, Carlos A1 - Schumacher, Fredrick R A1 - Voight, Benjamin F A1 - Young, Alicia A1 - Manolio, Teri A A1 - Mohlke, Karen L A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - North, Kari E KW - African Americans KW - Cardiovascular Diseases KW - Cholesterol Ester Transfer Proteins KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Chromosomes, Human KW - Cohort Studies KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Metabolic Diseases KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

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.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22539988?dopt=Abstract ER - TY - JOUR T1 - Fine-mapping and initial characterization of QT interval loci in African Americans. JF - PLoS Genet Y1 - 2012 A1 - Avery, Christy L A1 - Sethupathy, Praveen A1 - Buyske, Steven A1 - He, Qianchuan A1 - Lin, Dan-Yu A1 - Arking, Dan E A1 - Carty, Cara L A1 - Duggan, David A1 - Fesinmeyer, Megan D A1 - Hindorff, Lucia A A1 - Jeff, Janina M A1 - Klein, Liviu A1 - Patton, Kristen K A1 - Peters, Ulrike A1 - Shohet, Ralph V A1 - Sotoodehnia, Nona A1 - Young, Alicia M A1 - Kooperberg, Charles A1 - Haiman, Christopher A A1 - Mohlke, Karen L A1 - Whitsel, Eric A A1 - North, Kari E KW - African Americans KW - Aged KW - Computational Biology KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors KW - Tachycardia KW - United States AB -

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.

VL - 8 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22912591?dopt=Abstract ER - TY - JOUR T1 - Fine Mapping and Identification of BMI Loci in African Americans. JF - Am J Hum Genet Y1 - 2013 A1 - Gong, Jian A1 - Schumacher, Fredrick A1 - Lim, Unhee A1 - Hindorff, Lucia A A1 - Haessler, Jeff A1 - Buyske, Steven A1 - Carlson, Christopher S A1 - Rosse, Stephanie A1 - Bůzková, Petra A1 - Fornage, Myriam A1 - Gross, Myron A1 - Pankratz, Nathan A1 - Pankow, James S A1 - Schreiner, Pamela J A1 - Cooper, Richard A1 - Ehret, Georg A1 - Gu, C Charles A1 - Houston, Denise A1 - Irvin, Marguerite R A1 - Jackson, Rebecca A1 - Kuller, Lew A1 - Henderson, Brian A1 - Cheng, Iona A1 - Wilkens, Lynne A1 - Leppert, Mark A1 - Lewis, Cora E A1 - Li, Rongling A1 - Nguyen, Khanh-Dung H A1 - Goodloe, Robert A1 - Farber-Eger, Eric A1 - Boston, Jonathan A1 - Dilks, Holli H A1 - Ritchie, Marylyn D A1 - Fowke, Jay A1 - Pooler, Loreall A1 - Graff, Misa A1 - Fernandez-Rhodes, Lindsay A1 - Cochrane, Barbara A1 - Boerwinkle, Eric A1 - Kooperberg, Charles A1 - Matise, Tara C A1 - Le Marchand, Loïc A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - North, Kari E A1 - Peters, Ulrike KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

VL - 93 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24094743?dopt=Abstract ER - TY - JOUR T1 - Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. JF - PLoS Biol Y1 - 2013 A1 - Carlson, Christopher S A1 - Matise, Tara C A1 - North, Kari E A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Buyske, Steven A1 - Schumacher, Fredrick R A1 - Peters, Ulrike A1 - Franceschini, Nora A1 - Ritchie, Marylyn D A1 - Duggan, David J A1 - Spencer, Kylee L A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Thomas, Fridtjof A1 - Young, Alicia A1 - Carty, Cara A1 - Heiss, Gerardo A1 - Le Marchand, Loïc A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Kooperberg, Charles L KW - African Americans KW - Asian Americans KW - Body Mass Index KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Lipids KW - Metagenomics KW - Oceanic Ancestry Group KW - Polymorphism, Single Nucleotide AB -

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

VL - 11 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068893?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study. JF - Obesity (Silver Spring) Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - North, Kari E A1 - Ritchie, Marylyn D A1 - Lim, Unhee A1 - Franceschini, Nora A1 - Wilkens, Lynne R A1 - Gross, Myron D A1 - Bůzková, Petra A1 - Glenn, Kimberly A1 - Quibrera, P Miguel A1 - Fernandez-Rhodes, Lindsay A1 - Li, Qiong A1 - Fowke, Jay H A1 - Li, Rongling A1 - Carlson, Christopher S A1 - Prentice, Ross L A1 - Kuller, Lewis H A1 - Manson, JoAnn E A1 - Matise, Tara C A1 - Cole, Shelley A A1 - Chen, Christina T L A1 - Howard, Barbara V A1 - Kolonel, Laurence N A1 - Henderson, Brian E A1 - Monroe, Kristine R A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Buyske, Steven A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Peters, Ulrike KW - Alleles KW - Body Mass Index KW - Ethnic Groups KW - Gene Frequency KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Metagenomics KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

OBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.

DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI.

RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.

CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.

VL - 21 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23712987?dopt=Abstract ER - TY - JOUR T1 - Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - BMC Med Genet Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - Meigs, James B A1 - North, Kari E A1 - Schumacher, Fredrick R A1 - Bůzková, Petra A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Goodloe, Robert A1 - Spencer, Kylee L A1 - Voruganti, Venkata Saroja A1 - Howard, Barbara V A1 - Jackson, Rebecca A1 - Kolonel, Laurence N A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Monroe, Kristine R A1 - Mukamal, Kenneth A1 - Dilks, Holli H A1 - Pendergrass, Sarah A A1 - Nato, Andrew A1 - Wan, Peggy A1 - Wilkens, Lynne R A1 - Le Marchand, Loïc A1 - Ambite, Jose Luis A1 - Buyske, Steven A1 - Florez, Jose C A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Pankow, James S KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomics KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Transcription Factor 7-Like 2 Protein AB -

BACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.

METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.

RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.

CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24063630?dopt=Abstract ER - TY - JOUR T1 - The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study. JF - Diabetes Y1 - 2013 A1 - Graff, Mariaelisa A1 - Gordon-Larsen, Penny A1 - Lim, Unhee A1 - Fowke, Jay H A1 - Love, Shelly-Ann A1 - Fesinmeyer, Megan A1 - Wilkens, Lynne R A1 - Vertilus, Shawyntee A1 - Ritchie, Marilyn D A1 - Prentice, Ross L A1 - Pankow, Jim A1 - Monroe, Kristine A1 - Manson, JoAnn E A1 - Le Marchand, Loïc A1 - Kuller, Lewis H A1 - Kolonel, Laurence N A1 - Hong, Ching P A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Gross, Myron D A1 - Goodloe, Robert A1 - Franceschini, Nora A1 - Carlson, Christopher S A1 - Buyske, Steven A1 - Bůzková, Petra A1 - Hindorff, Lucia A A1 - Matise, Tara C A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - North, Kari E KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Body Mass Index KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Health Surveys KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins KW - United States KW - Young Adult AB -

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.

VL - 62 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23300277?dopt=Abstract ER - TY - JOUR T1 - Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. JF - BMC Genet Y1 - 2013 A1 - Taylor, Kira C A1 - Carty, Cara L A1 - Dumitrescu, Logan A1 - Bůzková, Petra A1 - Cole, Shelley A A1 - Hindorff, Lucia A1 - Schumacher, Fred R A1 - Wilkens, Lynne R A1 - Shohet, Ralph V A1 - Quibrera, P Miguel A1 - Johnson, Karen C A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Franceschini, Nora A1 - Eaton, Charles B A1 - Duggan, David J A1 - Cochran, Barbara A1 - Cheng, Iona A1 - Carlson, Chris S A1 - Brown-Gentry, Kristin A1 - Anderson, Garnet A1 - Ambite, Jose Luis A1 - Haiman, Christopher A1 - Le Marchand, Loïc A1 - Kooperberg, Charles A1 - Crawford, Dana C A1 - Buyske, Steven A1 - North, Kari E A1 - Fornage, Myriam KW - Female KW - Genetic Heterogeneity KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lipids KW - Male KW - Polymorphism, Single Nucleotide KW - Population Groups AB -

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.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23634756?dopt=Abstract ER - TY - JOUR T1 - No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population. JF - Hum Genet Y1 - 2013 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Franceschini, Nora A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Bůzková, Petra A1 - Schumacher, Fredrick R A1 - Eaton, Charles B A1 - Goodloe, Robert J A1 - Duggan, David J A1 - Haessler, Jeff A1 - Cochran, Barbara A1 - Henderson, Brian E A1 - Cheng, Iona A1 - Johnson, Karen C A1 - Carlson, Chris S A1 - Love, Shelly-Anne A1 - Brown-Gentry, Kristin A1 - Nato, Alejandro Q A1 - Quibrera, Miguel A1 - Shohet, Ralph V A1 - Ambite, Jose Luis A1 - Wilkens, Lynne R A1 - Le Marchand, Loïc A1 - Haiman, Christopher A A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Fornage, Myriam A1 - Crawford, Dana C KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Ethnic Groups KW - Female KW - Gene Frequency KW - Gene-Environment Interaction KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Lipid Metabolism KW - Male KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Smoking KW - Triglycerides KW - Young Adult AB -

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.

VL - 132 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24100633?dopt=Abstract ER - TY - JOUR T1 - 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. JF - Ann Hum Genet Y1 - 2013 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Franceschini, Nora A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Bůzková, Petra A1 - Schumacher, Fredrick R A1 - Eaton, Charles B A1 - Goodloe, Robert J A1 - Duggan, David J A1 - Haessler, Jeff A1 - Cochran, Barbara A1 - Henderson, Brian E A1 - Cheng, Iona A1 - Johnson, Karen C A1 - Carlson, Chris S A1 - Love, Shelly-Ann A1 - Brown-Gentry, Kristin A1 - Nato, Alejandro Q A1 - Quibrera, Miguel A1 - Anderson, Garnet A1 - Shohet, Ralph V A1 - Ambite, Jose Luis A1 - Wilkens, Lynne R A1 - Marchand, Loic Le A1 - Haiman, Christopher A A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Fornage, Myriam A1 - Crawford, Dana C KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Humans KW - Lipids KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors AB -

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.

VL - 77 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23808484?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. JF - PLoS Genet Y1 - 2013 A1 - Wu, Ying A1 - Waite, Lindsay L A1 - Jackson, Anne U A1 - Sheu, Wayne H-H A1 - Buyske, Steven A1 - Absher, Devin A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Carty, Cara L A1 - Cheng, Iona A1 - Cochran, Barbara A1 - Croteau-Chonka, Damien C A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Henderson, Brian E A1 - Hindorff, Lucia A A1 - Kim, Eric A1 - Kinnunen, Leena A1 - Komulainen, Pirjo A1 - Lee, Wen-Jane A1 - Le Marchand, Loïc A1 - Lin, Yi A1 - Lindström, Jaana A1 - Lingaas-Holmen, Oddgeir A1 - Mitchell, Sabrina L A1 - Narisu, Narisu A1 - Robinson, Jennifer G A1 - Schumacher, Fred A1 - Stančáková, Alena A1 - Sundvall, Jouko A1 - Sung, Yun-Ju A1 - Swift, Amy J A1 - Wang, Wen-Chang A1 - Wilkens, Lynne A1 - Wilsgaard, Tom A1 - Young, Alicia M A1 - Adair, Linda S A1 - Ballantyne, Christie M A1 - Bůzková, Petra A1 - Chakravarti, Aravinda A1 - Collins, Francis S A1 - Duggan, David A1 - Feranil, Alan B A1 - Ho, Low-Tone A1 - Hung, Yi-Jen A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Juang, Jyh-Ming J A1 - Kesäniemi, Antero Y A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lee, I-Te A1 - Leppert, Mark F A1 - Matise, Tara C A1 - Moilanen, Leena A1 - Njølstad, Inger A1 - Peters, Ulrike A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Rotter, Jerome I A1 - Saramies, Jouko A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - Wang, Tzung-Dau A1 - Boehnke, Michael A1 - Haiman, Christopher A A1 - Chen, Yii-der I A1 - Kooperberg, Charles A1 - Assimes, Themistocles L A1 - Crawford, Dana C A1 - Hsiung, Chao A A1 - North, Kari E A1 - Mohlke, Karen L KW - African Americans KW - Apolipoproteins A KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Proprotein Convertases KW - Serine Endopeptidases KW - Triglycerides AB -

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.

VL - 9 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23555291?dopt=Abstract ER - TY - JOUR T1 - Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. JF - Hum Mol Genet Y1 - 2016 A1 - Evans, Daniel S A1 - Avery, Christy L A1 - Nalls, Mike A A1 - Li, Guo A1 - Barnard, John A1 - Smith, Erin N A1 - Tanaka, Toshiko A1 - Butler, Anne M A1 - Buxbaum, Sarah G A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Berenson, Gerald S A1 - Bis, Joshua C A1 - Buyske, Steven A1 - Carty, Cara L A1 - Chen, Wei A1 - Chung, Mina K A1 - Cummings, Steven R A1 - Deo, Rajat A1 - Eaton, Charles B A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hindorff, Lucia A A1 - Hsueh, Wen-Chi A1 - Isaacs, Aaron A1 - Jamshidi, Yalda A1 - Kerr, Kathleen F A1 - Liu, Felix A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Magnani, Jared W A1 - Maher, Joseph F A1 - Mehra, Reena A1 - Meng, Yan A A1 - Musani, Solomon K A1 - Newton-Cheh, Christopher A1 - North, Kari E A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Schork, Nicholas J A1 - Shohet, Ralph V A1 - Singleton, Andrew B A1 - Smith, Jonathan D A1 - Soliman, Elsayed Z A1 - Srinivasan, Sathanur R A1 - Taylor, Herman A A1 - Van Wagoner, David R A1 - Wilson, James G A1 - Young, Taylor A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Ferrucci, Luigi A1 - Murray, Sarah S A1 - Tranah, Gregory J A1 - Whitsel, Eric A A1 - Reiner, Alex P A1 - Sotoodehnia, Nona AB -

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.

ER - TY - JOUR T1 - Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations. JF - Heart Rhythm Y1 - 2017 A1 - Avery, Christy L A1 - Wassel, Christina L A1 - Richard, Melissa A A1 - Highland, Heather M A1 - Bien, Stephanie A1 - Zubair, Niha A1 - Soliman, Elsayed Z A1 - Fornage, Myriam A1 - Bielinski, Suzette J A1 - Tao, Ran A1 - Seyerle, Amanda A A1 - Shah, Sanjiv J A1 - Lloyd-Jones, Donald M A1 - Buyske, Steven A1 - Rotter, Jerome I A1 - Post, Wendy S A1 - Rich, Stephen S A1 - Hindorff, Lucia A A1 - Jeff, Janina M A1 - Shohet, Ralph V A1 - Sotoodehnia, Nona A1 - Lin, Dan Yu A1 - Whitsel, Eric A A1 - Peters, Ulrike A1 - Haiman, Christopher A A1 - Crawford, Dana C A1 - Kooperberg, Charles A1 - North, Kari E AB -

BACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance.

OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry.

METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis.

RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10(-5)) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs.

CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.

VL - 14 IS - 4 ER - TY - JOUR T1 - Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. JF - Hum Genet Y1 - 2017 A1 - Fernandez-Rhodes, Lindsay A1 - Gong, Jian A1 - Haessler, Jeffrey A1 - Franceschini, Nora A1 - Graff, Mariaelisa A1 - Nishimura, Katherine K A1 - Wang, Yujie A1 - Highland, Heather M A1 - Yoneyama, Sachiko A1 - Bush, William S A1 - Goodloe, Robert A1 - Ritchie, Marylyn D A1 - Crawford, Dana A1 - Gross, Myron A1 - Fornage, Myriam A1 - Bůzková, Petra A1 - Tao, Ran A1 - Isasi, Carmen A1 - Avilés-Santa, Larissa A1 - Daviglus, Martha A1 - Mackey, Rachel H A1 - Houston, Denise A1 - Gu, C Charles A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Lim, Unhee A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Schumacher, Fredrick A1 - Wilkens, Lynne A1 - Lu, Yingchang A1 - Bottinger, Erwin P A1 - Loos, Ruth J L A1 - Sheu, Wayne H-H A1 - Guo, Xiuqing A1 - Lee, Wen-Jane A1 - Hai, Yang A1 - Hung, Yi-Jen A1 - Absher, Devin A1 - Wu, I-Chien A1 - Taylor, Kent D A1 - Lee, I-Te A1 - Liu, Yeheng A1 - Wang, Tzung-Dau A1 - Quertermous, Thomas A1 - Juang, Jyh-Ming J A1 - Rotter, Jerome I A1 - Assimes, Themistocles A1 - Hsiung, Chao A A1 - Chen, Yii-Der Ida A1 - Prentice, Ross A1 - Kuller, Lewis H A1 - Manson, JoAnn E A1 - Kooperberg, Charles A1 - Smokowski, Paul A1 - Robinson, Whitney R A1 - Gordon-Larsen, Penny A1 - Li, Rongling A1 - Hindorff, Lucia A1 - Buyske, Steven A1 - Matise, Tara C A1 - Peters, Ulrike A1 - North, Kari E KW - Body Mass Index KW - Ethnic Groups KW - Genetics, Population KW - Humans KW - Obesity AB -

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

VL - 136 IS - 6 ER - TY - JOUR T1 - Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. JF - Nat Med Y1 - 2022 A1 - Tcheandjieu, Catherine A1 - Zhu, Xiang A1 - Hilliard, Austin T A1 - Clarke, Shoa L A1 - Napolioni, Valerio A1 - Ma, Shining A1 - Lee, Kyung Min A1 - Fang, Huaying A1 - Chen, Fei A1 - Lu, Yingchang A1 - Tsao, Noah L A1 - Raghavan, Sridharan A1 - Koyama, Satoshi A1 - Gorman, Bryan R A1 - Vujkovic, Marijana A1 - Klarin, Derek A1 - Levin, Michael G A1 - Sinnott-Armstrong, Nasa A1 - Wojcik, Genevieve L A1 - Plomondon, Mary E A1 - Maddox, Thomas M A1 - Waldo, Stephen W A1 - Bick, Alexander G A1 - Pyarajan, Saiju A1 - Huang, Jie A1 - Song, Rebecca A1 - Ho, Yuk-Lam A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - Haessler, Jeffrey A1 - Loos, Ruth J F A1 - Do, Ron A1 - Verbanck, Marie A1 - Chaudhary, Kumardeep A1 - North, Kari E A1 - Avery, Christy L A1 - Graff, Mariaelisa A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Wilkens, Lynne R A1 - Bis, Joshua C A1 - Leonard, Hampton A1 - Shen, Botong A1 - Lange, Leslie A A1 - Giri, Ayush A1 - Dikilitas, Ozan A1 - Kullo, Iftikhar J A1 - Stanaway, Ian B A1 - Jarvik, Gail P A1 - Gordon, Adam S A1 - Hebbring, Scott A1 - Namjou, Bahram A1 - Kaufman, Kenneth M A1 - Ito, Kaoru A1 - Ishigaki, Kazuyoshi A1 - Kamatani, Yoichiro A1 - Verma, Shefali S A1 - Ritchie, Marylyn D A1 - Kember, Rachel L A1 - Baras, Aris A1 - Lotta, Luca A A1 - Kathiresan, Sekar A1 - Hauser, Elizabeth R A1 - Miller, Donald R A1 - Lee, Jennifer S A1 - Saleheen, Danish A1 - Reaven, Peter D A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Natarajan, Pradeep A1 - Huffman, Jennifer E A1 - Voight, Benjamin F A1 - Rader, Daniel J A1 - Chang, Kyong-Mi A1 - Lynch, Julie A A1 - Damrauer, Scott M A1 - Wilson, Peter W F A1 - Tang, Hua A1 - Sun, Yan V A1 - Tsao, Philip S A1 - O'Donnell, Christopher J A1 - Assimes, Themistocles L KW - Coronary Artery Disease KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

VL - 28 IS - 8 ER -