@article {711, title = {Angiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events.}, journal = {Am J Hypertens}, volume = {15}, year = {2002}, month = {2002 Dec}, pages = {1050-6}, abstract = {

BACKGROUND: The angiotensin II type 1 receptor A1166C polymorphism has been associated with increased risks of hypertension and myocardial infarction in several small studies. We examined the association between this polymorphism and new-onset hypertension, blood pressure (BP) control, and incident cardiovascular events in a large population-based cohort of older adults.

METHODS: Eight hundred self-identified African Americans and 1,371 randomly selected white participants in the Cardiovascular Health Study were genotyped. The median duration of follow-up was 8.1 years.

RESULTS: The A1166C polymorphism was not associated with new-onset hypertension, with BP control, or with incident cardiovascular events in the overall population. In white participants, the CC genotype was associated with higher baseline systolic BP and pulse pressure, compared to the AC or AA genotype. In whites with treated hypertension at baseline, compared to the AA genotype, the CC genotype was associated with increased risks of incident congestive heart failure (hazard ratio = 2.5, 95\% confidence interval [CI] 1.3-4.9) and incident ischemic stroke (hazard ratio = 2.6, 95\% CI 1.1-6.0). These associations were not observed among white participants without treated hypertension, but the interaction of genotype with treated hypertension on ischemic stroke and heart failure was only marginally significant.

CONCLUSIONS: On the whole, in this large cohort of older adults, the A1166C polymorphism was not associated with BP control or incident cardiovascular events. The subgroup findings in treated hypertensives need to be confirmed in additional studies.

}, keywords = {African Continental Ancestry Group, Aged, Blood Pressure, Cardiovascular Diseases, European Continental Ancestry Group, Female, Gene Frequency, Humans, Hypertension, Male, Polymorphism, Genetic, Receptor, Angiotensin, Type 1, Receptors, Angiotensin, United States}, issn = {0895-7061}, doi = {10.1016/s0895-7061(02)03063-7}, author = {Hindorff, Lucia A and Heckbert, Susan R and Tracy, Russell and Tang, Zhonghua and Psaty, Bruce M and Edwards, Karen L and Siscovick, David S and Kronmal, Richard A and Nazar-Stewart, Valle} } @article {733, title = {Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly.}, journal = {Circulation}, volume = {107}, year = {2003}, month = {2003 Apr 22}, pages = {2021-4}, abstract = {

BACKGROUND: Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study.

METHODS AND RESULTS: A total of 808 black and 4441 white participants (mean age, 73 years) were genotyped for the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenergic receptor. There were 702 incident coronary events, 438 ischemic strokes, and 1136 combined cardiovascular events during 7 to 10 years of follow-up. Allele frequencies differed by race but not by age or hypertension status. Glu27 carriers had a lower risk of coronary events than Gln27 homozygotes (hazard ratio, 0.82; 95\% CI, 0.70 to 0.95), and there was a suggestion of decreased risk among Gly16 carriers compared with Arg16 homozygotes (hazard ratio, 0.88; 95\% CI, 0.72 to 1.07). There was no association of beta2-adrenergic receptor genotype with ischemic stroke or combined cardiovascular events.

CONCLUSIONS: The Glu27 allele of the beta2-adrenergic receptor was associated with a lower risk of incident coronary events in this elderly population.

}, keywords = {African Continental Ancestry Group, Aged, Alleles, Brain Ischemia, Cardiovascular Diseases, Cohort Studies, Comorbidity, Coronary Disease, European Continental Ancestry Group, Follow-Up Studies, Gene Frequency, Humans, Incidence, Linkage Disequilibrium, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Risk Assessment, Stroke, United States}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000065231.07729.92}, author = {Heckbert, Susan R and Hindorff, Lucia A and Edwards, Karen L and Psaty, Bruce M and Lumley, Thomas and Siscovick, David S and Tang, Zhonghua and Durda, J Peter and Kronmal, Richard A and Tracy, Russell P} } @article {825, title = {beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study.}, journal = {Am J Hypertens}, volume = {18}, year = {2005}, month = {2005 Mar}, pages = {392-7}, abstract = {

BACKGROUND: Common Arg16Gly and Gln27Glu polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) have been associated with hypertension and coronary disease. This analysis of older adults in the Cardiovascular Health Study examined whether these polymorphisms were associated with blood pressure (BP), subclinical atherosclerosis, and, among treated hypertensive individuals, differences in coronary disease risk according to antihypertensive drug class.

METHODS: Altogether, 5249 participants (4441 white and 808 African American, median follow-up time 10.2 years) were genotyped for both polymorphisms. Ankle-arm index (AAI), carotid intima-media thickness (IMT), and brachial flow-mediated dilation were measured cross-sectionally. All estimates were adjusted for ethnicity.

RESULTS: Relative to Gln27 homozygotes, carrying the Glu27 allele was not associated with new-onset hypertension (hazard ratio [HR] = 1.01, 95\% confidence interval [CI] = 0.87 to 1.16), BP control (odds ratio [OR] = 0.97, 95\% CI = 0.89 to 1.06), AAI (mean difference 0.0042 +/- 0.0052), carotid IMT (mean difference 0.0044 +/- 0.02 mm), or brachial flow-mediated dilation (mean difference in baseline diameter -0.028 +/- 0.036 mm; the most marked of three measures). Among treated hypertensive individuals, coronary disease risk was similar in Glu27 carriers relative to Gln27 homozygotes in subgroups defined by use of beta-blockers (HR = 1.09, 95\% CI = 0.64 to 1.87) or other antihypertensive medications (HR = 1.00, 95\% CI = 0.78 to 1.28). Results were similar for the Arg16Gly polymorphism.

CONCLUSIONS: The association of beta(2)AR genotype with coronary disease previously reported in this older adult population is not likely to be explained by BP levels, subclinical atherosclerosis, or antihypertensive treatment. Other measures of vascular response, gene-gene or gene-environment interactions, or characteristics developing earlier in life may mediate the association between beta(2)AR genotype and coronary disease and merit further research.

}, keywords = {African Americans, Antihypertensive Agents, Arteriosclerosis, Coronary Artery Disease, European Continental Ancestry Group, Female, Genotype, Homozygote, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Risk Factors}, issn = {0895-7061}, doi = {10.1016/j.amjhyper.2004.10.014}, author = {Hindorff, Lucia A and Heckbert, Susan R and Psaty, Bruce M and Lumley, Thomas and Siscovick, David S and Herrington, David M and Edwards, Karen L and Tracy, Russell P} } @article {932, title = {Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events.}, journal = {JAMA}, volume = {296}, year = {2006}, month = {2006 Dec 13}, pages = {2703-11}, abstract = {

CONTEXT: C-reactive protein (CRP) is an inflammation protein that may play a role in the pathogenesis of cardiovascular disease (CVD).

OBJECTIVE: To assess whether polymorphisms in the CRP gene are associated with plasma CRP, carotid intima-media thickness (CIMT), and CVD events.

DESIGN, SETTING, AND PARTICIPANTS: In the prospective, population-based Cardiovascular Health Study, 4 tag single-nucleotide polymorphisms (SNPs) (1919A/T, 2667G/C, 3872G/A, 5237A/G) were genotyped in 3941 white (European American) participants and 5 tag SNPs (addition of 790A/T) were genotyped in 700 black (African American) participants, aged 65 years or older, all of whom were without myocardial infarction (MI) or stroke before study entry. Median follow-up was 13 years (1989-2003).

MAIN OUTCOME MEASURES: Baseline CIMT; occurrence of MI, stroke, and CVD mortality during follow-up.

RESULTS: In white participants, 461 incident MIs, 491 incident strokes, and 490 CVD-related deaths occurred; in black participants, 67 incident MIs, 78 incident strokes, and 75 CVD-related deaths occurred. The 1919T and 790T alleles were associated with higher CRP levels in white and black participants, respectively. The 3872A allele was associated with lower CRP levels in both populations, and the 2667C allele was associated with lower CRP levels in white participants only. There was no association between CIMT and any CRP gene polymorphism in either population. In white participants, the 1919T allele was associated with increased risk of stroke for TT vs AA (hazard ratio [HR], 1.40; 95\% confidence interval [CI], 1.06-1.87) and for CVD mortality (HR, 1.40; 95\% CI, 1.10-1.90). In black participants, homozygosity for the 790T allele was associated with a 4-fold increased risk of MI compared with homozygosity for the 790A allele (95\% CI, 1.58-10.53). The minor alleles of the 2 SNPs associated with lower plasma CRP concentration in white participants (2667C and 3872A) were associated with decreased risk of CVD mortality.

CONCLUSIONS: Genetic variation in the CRP gene is associated with plasma CRP levels and CVD risk in older adults.

}, keywords = {African Continental Ancestry Group, Aged, C-Reactive Protein, Cardiovascular Diseases, Carotid Arteries, European Continental Ancestry Group, Female, Genotype, Humans, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk, Stroke, Tunica Intima}, issn = {1538-3598}, doi = {10.1001/jama.296.22.2703}, author = {Lange, Leslie A and Carlson, Christopher S and Hindorff, Lucia A and Lange, Ethan M and Walston, Jeremy and Durda, J Peter and Cushman, Mary and Bis, Joshua C and Zeng, Donglin and Lin, Danyu and Kuller, Lewis H and Nickerson, Deborah A and Psaty, Bruce M and Tracy, Russell P and Reiner, Alexander P} } @article {1019, title = {Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study.}, journal = {Thromb Haemost}, volume = {99}, year = {2008}, month = {2008 Feb}, pages = {388-95}, abstract = {

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.

}, keywords = {African Americans, Age Factors, Aged, Brain Ischemia, Cardiovascular Diseases, Carotid Artery Diseases, European Continental Ancestry Group, Female, Fibrinogen, Gene Frequency, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Population Surveillance, Proportional Hazards Models, Prospective Studies, Reproducibility of Results, Risk Assessment, Risk Factors, Sex Factors, Stroke, United States}, issn = {0340-6245}, doi = {10.1160/TH07-08-0523}, author = {Carty, Cara L and Cushman, Mary and Jones, Daniel and Lange, Leslie A and Hindorff, Lucia A and Rice, Kenneth and Jenny, Nancy S and Durda, J Peter and Walston, Jeremy and Carlson, Christopher S and Nickerson, Debbie and Tracy, Russell P and Reiner, Alex P} } @article {986, title = {Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {197}, year = {2008}, month = {2008 Apr}, pages = {922-30}, abstract = {

Common polymorphisms in the CRP gene are associated with plasma CRP levels in population-based studies, but associations with age-related events are uncertain. A previous study of CRP haplotypes in older adults was broadened to include longevity and cause-specific mortality (all-cause, noncardiovascular (non-CV), and cardiovascular (CV)). Common haplotypes were inferred from four tagSNPs in 4512 whites and five tagSNPs in 812 blacks from the Cardiovascular Health Study, a longitudinal cohort of adults over age 65. Exploratory analyses addressed early versus late mortality. CRP haplotypes were not associated with all-cause mortality or longevity overall in either population, but associations with all-cause mortality differed during early and late periods. In blacks, the haplotype tagged by 3872A (rs1205) was associated with increased risk of non-CV mortality, relative to other haplotypes (adjusted hazard ratio for each additional copy: 1.42, 95\% CI: 1.07, 1.87). Relative to other haplotypes, this haplotype was associated with decreased risk of early but not decreased risk of late CV mortality in blacks; among whites, a haplotype tagged by 2667C (rs1800947) gave similar but nonsignificant findings. If confirmed, CRP genetic variants may be weakly associated with CV and non-CV mortality in older adults, particularly in self-identified blacks.

}, keywords = {African Americans, Aged, C-Reactive Protein, Cardiovascular Diseases, Cause of Death, Cohort Studies, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Linear Models, Longevity, Male, Polymorphism, Single Nucleotide, Proportional Hazards Models, United States}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2007.08.012}, author = {Hindorff, Lucia A and Rice, Kenneth M and Lange, Leslie A and Diehr, Paula and Halder, Indrani and Walston, Jeremy and Kwok, Pui and Ziv, Elad and Nievergelt, Caroline and Cummings, Steven R and Newman, Anne B and Tracy, Russell P and Psaty, Bruce M and Reiner, Alexander P} } @article {1347, title = {Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.}, journal = {Circ Cardiovasc Genet}, volume = {4}, year = {2011}, month = {2011 Dec}, pages = {661-72}, abstract = {

BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.

METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 {\texttimes} 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 {\texttimes} 10(-6)), MTHFD1L (rs6922269, P=5.1 {\texttimes} 10(-10)), APOE (rs429358; P=2.7{\texttimes}10(-18)), ZNF627 (rs4804611; P=5.0 {\texttimes} 10(-8)), CXCL12 (rs501120; P=1.4 {\texttimes} 10(-6)) and LPL (rs268; P=2.7 {\texttimes} 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.

CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

}, keywords = {Aged, Aged, 80 and over, Continental Population Groups, Coronary Disease, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.111.960096}, author = {Franceschini, Nora and Carty, Cara and B{\r u}zkov{\'a}, Petra and Reiner, Alex P and Garrett, Tiana and Lin, Yi and V{\"o}ckler, Jens-S and Hindorff, Lucia A and Cole, Shelley A and Boerwinkle, Eric and Lin, Dan-Yu and Bookman, Ebony and Best, Lyle G and Bella, Jonathan N and Eaton, Charles and Greenland, Philip and Jenny, Nancy and North, Kari E and Taverna, Darin and Young, Alicia M and Deelman, Ewa and Kooperberg, Charles and Psaty, Bruce and Heiss, Gerardo} } @article {1303, title = {Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002138}, abstract = {

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.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Continental Population Groups, Female, Gene Frequency, Genetics, Population, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Lipid Metabolism, Lipoproteins, HDL, Lipoproteins, LDL, Male, Middle Aged, Molecular Epidemiology, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Triglycerides, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002138}, author = {Dumitrescu, Logan and Carty, Cara L and Taylor, Kira and Schumacher, Fredrick R and Hindorff, Lucia A and Ambite, Jos{\'e} L and Anderson, Garnet and Best, Lyle G and Brown-Gentry, Kristin and B{\r u}zkov{\'a}, Petra and Carlson, Christopher S and Cochran, Barbara and Cole, Shelley A and Devereux, Richard B and Duggan, Dave and Eaton, Charles B and Fornage, Myriam and Franceschini, Nora and Haessler, Jeff and Howard, Barbara V and Johnson, Karen C and Laston, Sandra and Kolonel, Laurence N and Lee, Elisa T and MacCluer, Jean W and Manolio, Teri A and Pendergrass, Sarah A and Quibrera, Miguel and Shohet, Ralph V and Wilkens, Lynne R and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Buyske, Steven and Kooperberg, Charles and North, Kari E and Crawford, Dana C} } @article {1313, title = {The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study.}, journal = {Am J Epidemiol}, volume = {174}, year = {2011}, month = {2011 Oct 01}, pages = {849-59}, abstract = {

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{\textquoteright}s Database of Genotypes and Phenotypes and made available via a custom browser.

}, keywords = {Epidemiologic Methods, Epidemiologic Research Design, Ethnic Groups, Genetic Association Studies, Genetics, Population, Genome-Wide Association Study, Humans, Interinstitutional Relations, Multifactorial Inheritance, National Human Genome Research Institute (U.S.), Phenotype, Pilot Projects, Research Design, Risk Factors, United States}, issn = {1476-6256}, doi = {10.1093/aje/kwr160}, author = {Matise, Tara C and Ambite, Jose Luis and Buyske, Steven and Carlson, Christopher S and Cole, Shelley A and Crawford, Dana C and Haiman, Christopher A and Heiss, Gerardo and Kooperberg, Charles and Marchand, Loic Le and Manolio, Teri A and North, Kari E and Peters, Ulrike and Ritchie, Marylyn D and Hindorff, Lucia A and Haines, Jonathan L} } @article {1345, title = {A phenomics-based strategy identifies loci on APOC1, BRAP, and PLCG1 associated with metabolic syndrome phenotype domains.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Oct}, pages = {e1002322}, abstract = {

Despite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Association Resource Consortium participants to identify loci associated with the clustering of metabolic phenotypes. Six phenotype domains (atherogenic dyslipidemia, vascular dysfunction, vascular inflammation, pro-thrombotic state, central obesity, and elevated plasma glucose) encompassing 19 quantitative traits were examined. Principal components analysis was used to reduce the dimension of each domain such that >55\% of the trait variance was represented within each domain. We then applied a statistically efficient and computational feasible multivariate approach that related eight principal components from the six domains to 250,000 imputed SNPs using an additive genetic model and including demographic covariates. In European Americans, we identified 606 genome-wide significant SNPs representing 19 loci. Many of these loci were associated with only one trait domain, were consistent with results in African Americans, and overlapped with published findings, for instance central obesity and FTO. However, our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. These pleiotropic loci may help characterize metabolic dysregulation and identify targets for intervention.

}, keywords = {African Americans, Apolipoprotein C-I, Blood Glucose, Dyslipidemias, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genome, Human, Humans, Metabolic Syndrome, Obesity, Abdominal, Phenotype, Phospholipase C gamma, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Ubiquitin-Protein Ligases, Vascular Diseases}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002322}, author = {Avery, Christy L and He, Qianchuan and North, Kari E and Ambite, Jos{\'e} L and Boerwinkle, Eric and Fornage, Myriam and Hindorff, Lucia A and Kooperberg, Charles and Meigs, James B and Pankow, James S and Pendergrass, Sarah A and Psaty, Bruce M and Ritchie, Marylyn D and Rotter, Jerome I and Taylor, Kent D and Wilkens, Lynne R and Heiss, Gerardo and Lin, Dan Yu} } @article {1371, title = {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.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Apr 01}, pages = {210-6}, abstract = {

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.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Female, Genetics, Population, Genome-Wide Association Study, Genomics, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Triglycerides}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.111.962191}, author = {Carty, Cara L and B{\r u}zkov{\'a}, Petra and Fornage, Myriam and Franceschini, Nora and Cole, Shelley and Heiss, Gerardo and Hindorff, Lucia A and Howard, Barbara V and Mann, Sue and Martin, Lisa W and Zhang, Ying and Matise, Tara C and Prentice, Ross and Reiner, Alexander P and Kooperberg, Charles} } @article {6633, title = {Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium.}, journal = {Diabetes}, volume = {61}, year = {2012}, month = {2012 Jun}, pages = {1642-7}, abstract = {

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.

}, keywords = {Adult, Aged, Aged, 80 and over, Alleles, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Metagenomics, Middle Aged, Population Groups, Risk, Risk Factors}, issn = {1939-327X}, doi = {10.2337/db11-1296}, author = {Haiman, Christopher A and Fesinmeyer, Megan D and Spencer, Kylee L and B{\r u}zkov{\'a}, Petra and Voruganti, V Saroja and Wan, Peggy and Haessler, Jeff and Franceschini, Nora and Monroe, Kristine R and Howard, Barbara V and Jackson, Rebecca D and Florez, Jose C and Kolonel, Laurence N and Buyske, Steven and Goodloe, Robert J and Liu, Simin and Manson, JoAnn E and Meigs, James B and Waters, Kevin and Mukamal, Kenneth J and Pendergrass, Sarah A and Shrader, Peter and Wilkens, Lynne R and Hindorff, Lucia A and Ambite, Jose Luis and North, Kari E and Peters, Ulrike and Crawford, Dana C and Le Marchand, Lo{\"\i}c and Pankow, James S} } @article {6634, title = {Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e35651}, abstract = {

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 {\texttimes} 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 {\texttimes} 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.

}, keywords = {African Americans, Cardiovascular Diseases, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Cholesterol, LDL, Chromosomes, Human, Cohort Studies, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Metabolic Diseases, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1932-6203}, doi = {10.1371/journal.pone.0035651}, author = {Buyske, Steven and Wu, Ying and Carty, Cara L and Cheng, Iona and Assimes, Themistocles L and Dumitrescu, Logan and Hindorff, Lucia A and Mitchell, Sabrina and Ambite, Jose Luis and Boerwinkle, Eric and B{\r u}zkov{\'a}, Petra and Carlson, Chris S and Cochran, Barbara and Duggan, David and Eaton, Charles B and Fesinmeyer, Megan D and Franceschini, Nora and Haessler, Jeffrey and Jenny, Nancy and Kang, Hyun Min and Kooperberg, Charles and Lin, Yi and Le Marchand, Lo{\"\i}c and Matise, Tara C and Robinson, Jennifer G and Rodriguez, Carlos and Schumacher, Fredrick R and Voight, Benjamin F and Young, Alicia and Manolio, Teri A and Mohlke, Karen L and Haiman, Christopher A and Peters, Ulrike and Crawford, Dana C and North, Kari E} } @article {6083, title = {Fine-mapping and initial characterization of QT interval loci in African Americans.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002870}, abstract = {

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

}, keywords = {African Americans, Aged, Computational Biology, Electrocardiography, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Metagenomics, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Risk Factors, Tachycardia, United States}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002870}, author = {Avery, Christy L and Sethupathy, Praveen and Buyske, Steven and He, Qianchuan and Lin, Dan-Yu and Arking, Dan E and Carty, Cara L and Duggan, David and Fesinmeyer, Megan D and Hindorff, Lucia A and Jeff, Janina M and Klein, Liviu and Patton, Kristen K and Peters, Ulrike and Shohet, Ralph V and Sotoodehnia, Nona and Young, Alicia M and Kooperberg, Charles and Haiman, Christopher A and Mohlke, Karen L and Whitsel, Eric A and North, Kari E} } @article {6065, title = {Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study.}, journal = {BMC Med Genet}, volume = {14}, year = {2013}, month = {2013 Jan 11}, pages = {6}, abstract = {

BACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.

METHODS: As part of the {\textquoteright}Population Architecture using Genomics and Epidemiology (PAGE){\textquoteright} Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.

RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08).

CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.

CLINICAL TRIAL REGISTRATION: NCT00000611.

}, keywords = {Adolescent, Adult, African Americans, Aged, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Mass Index, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Humans, Male, Membrane Proteins, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Proteins, Risk Factors, Smoking, Young Adult}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-6}, author = {Fesinmeyer, Megan D and North, Kari E and Lim, Unhee and B{\r u}zkov{\'a}, Petra and Crawford, Dana C and Haessler, Jeffrey and Gross, Myron D and Fowke, Jay H and Goodloe, Robert and Love, Shelley-Ann and Graff, Misa and Carlson, Christopher S and Kuller, Lewis H and Matise, Tara C and Hong, Ching-Ping and Henderson, Brian E and Allen, Melissa and Rohde, Rebecca R and Mayo, Ping and Schnetz-Boutaud, Nathalie and Monroe, Kristine R and Ritchie, Marylyn D and Prentice, Ross L and Kolonel, Lawrence N and Manson, JoAnn E and Pankow, James and Hindorff, Lucia A and Franceschini, Nora and Wilkens, Lynne R and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Peters, Ulrike} } @article {6626, title = {Fine Mapping and Identification of BMI Loci in African Americans.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Oct 3}, pages = {661-71}, abstract = {

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~{\texttimes} 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~{\texttimes} 10(-8)) and DHX34 (rs4802349, p = 1.2~{\texttimes} 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.

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Body Mass Index, Female, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.08.012}, author = {Gong, Jian and Schumacher, Fredrick and Lim, Unhee and Hindorff, Lucia A and Haessler, Jeff and Buyske, Steven and Carlson, Christopher S and Rosse, Stephanie and B{\r u}zkov{\'a}, Petra and Fornage, Myriam and Gross, Myron and Pankratz, Nathan and Pankow, James S and Schreiner, Pamela J and Cooper, Richard and Ehret, Georg and Gu, C Charles and Houston, Denise and Irvin, Marguerite R and Jackson, Rebecca and Kuller, Lew and Henderson, Brian and Cheng, Iona and Wilkens, Lynne and Leppert, Mark and Lewis, Cora E and Li, Rongling and Nguyen, Khanh-Dung H and Goodloe, Robert and Farber-Eger, Eric and Boston, Jonathan and Dilks, Holli H and Ritchie, Marylyn D and Fowke, Jay and Pooler, Loreall and Graff, Misa and Fernandez-Rhodes, Lindsay and Cochrane, Barbara and Boerwinkle, Eric and Kooperberg, Charles and Matise, Tara C and Le Marchand, Lo{\"\i}c and Crawford, Dana C and Haiman, Christopher A and North, Kari E and Peters, Ulrike} } @article {6289, title = {Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.}, journal = {PLoS Biol}, volume = {11}, year = {2013}, month = {2013 Sep}, pages = {e1001661}, abstract = {

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.

}, keywords = {African Americans, Asian Americans, Body Mass Index, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Hispanic Americans, Humans, Indians, North American, Lipids, Metagenomics, Oceanic Ancestry Group, Polymorphism, Single Nucleotide}, issn = {1545-7885}, doi = {10.1371/journal.pbio.1001661}, author = {Carlson, Christopher S and Matise, Tara C and North, Kari E and Haiman, Christopher A and Fesinmeyer, Megan D and Buyske, Steven and Schumacher, Fredrick R and Peters, Ulrike and Franceschini, Nora and Ritchie, Marylyn D and Duggan, David J and Spencer, Kylee L and Dumitrescu, Logan and Eaton, Charles B and Thomas, Fridtjof and Young, Alicia and Carty, Cara and Heiss, Gerardo and Le Marchand, Lo{\"\i}c and Crawford, Dana C and Hindorff, Lucia A and Kooperberg, Charles L} } @article {6631, title = {Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study.}, journal = {Obesity (Silver Spring)}, volume = {21}, year = {2013}, month = {2013 Apr}, pages = {835-46}, abstract = {

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.

}, keywords = {Alleles, Body Mass Index, Ethnic Groups, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Metagenomics, Obesity, Phenotype, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1930-739X}, doi = {10.1002/oby.20268}, author = {Fesinmeyer, Megan D and North, Kari E and Ritchie, Marylyn D and Lim, Unhee and Franceschini, Nora and Wilkens, Lynne R and Gross, Myron D and B{\r u}zkov{\'a}, Petra and Glenn, Kimberly and Quibrera, P Miguel and Fernandez-Rhodes, Lindsay and Li, Qiong and Fowke, Jay H and Li, Rongling and Carlson, Christopher S and Prentice, Ross L and Kuller, Lewis H and Manson, JoAnn E and Matise, Tara C and Cole, Shelley A and Chen, Christina T L and Howard, Barbara V and Kolonel, Laurence N and Henderson, Brian E and Monroe, Kristine R and Crawford, Dana C and Hindorff, Lucia A and Buyske, Steven and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Peters, Ulrike} } @article {6290, title = {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.}, journal = {BMC Med Genet}, volume = {14}, year = {2013}, month = {2013 Sep 25}, pages = {98}, abstract = {

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 {\textquoteright}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 {\texttimes} 10-15), versus 3/9 in AA (p= 0.03 to 6 {\texttimes} 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.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, African Americans, Aged, Alleles, Asian Continental Ancestry Group, Blood Glucose, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Genomics, Hispanic Americans, Humans, Indians, North American, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Transcription Factor 7-Like 2 Protein}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-98}, author = {Fesinmeyer, Megan D and Meigs, James B and North, Kari E and Schumacher, Fredrick R and B{\r u}zkov{\'a}, Petra and Franceschini, Nora and Haessler, Jeffrey and Goodloe, Robert and Spencer, Kylee L and Voruganti, Venkata Saroja and Howard, Barbara V and Jackson, Rebecca and Kolonel, Laurence N and Liu, Simin and Manson, JoAnn E and Monroe, Kristine R and Mukamal, Kenneth and Dilks, Holli H and Pendergrass, Sarah A and Nato, Andrew and Wan, Peggy and Wilkens, Lynne R and Le Marchand, Lo{\"\i}c and Ambite, Jose Luis and Buyske, Steven and Florez, Jose C and Crawford, Dana C and Hindorff, Lucia A and Haiman, Christopher A and Peters, Ulrike and Pankow, James S} } @article {6630, title = {The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study.}, journal = {Diabetes}, volume = {62}, year = {2013}, month = {2013 May}, pages = {1763-7}, abstract = {

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/m{\texttwosuperior}, 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.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Aging, Body Mass Index, Cohort Studies, Cross-Sectional Studies, European Continental Ancestry Group, Female, Genetic Association Studies, Health Surveys, Humans, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Proteins, United States, Young Adult}, issn = {1939-327X}, doi = {10.2337/db12-0863}, author = {Graff, Mariaelisa and Gordon-Larsen, Penny and Lim, Unhee and Fowke, Jay H and Love, Shelly-Ann and Fesinmeyer, Megan and Wilkens, Lynne R and Vertilus, Shawyntee and Ritchie, Marilyn D and Prentice, Ross L and Pankow, Jim and Monroe, Kristine and Manson, JoAnn E and Le Marchand, Lo{\"\i}c and Kuller, Lewis H and Kolonel, Laurence N and Hong, Ching P and Henderson, Brian E and Haessler, Jeff and Gross, Myron D and Goodloe, Robert and Franceschini, Nora and Carlson, Christopher S and Buyske, Steven and B{\r u}zkov{\'a}, Petra and Hindorff, Lucia A and Matise, Tara C and Crawford, Dana C and Haiman, Christopher A and Peters, Ulrike and North, Kari E} } @article {6292, title = {No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population.}, journal = {Hum Genet}, volume = {132}, year = {2013}, month = {2013 Dec}, pages = {1427-31}, abstract = {

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 {\texttimes} smoking interactions.

}, keywords = {Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Ethnic Groups, Female, Gene Frequency, Gene-Environment Interaction, Genetics, Population, Genome-Wide Association Study, Humans, Lipid Metabolism, Male, Polymorphism, Single Nucleotide, Prevalence, Smoking, Triglycerides, Young Adult}, issn = {1432-1203}, doi = {10.1007/s00439-013-1375-3}, author = {Dumitrescu, Logan and Carty, Cara L and Franceschini, Nora and Hindorff, Lucia A and Cole, Shelley A and B{\r u}zkov{\'a}, Petra and Schumacher, Fredrick R and Eaton, Charles B and Goodloe, Robert J and Duggan, David J and Haessler, Jeff and Cochran, Barbara and Henderson, Brian E and Cheng, Iona and Johnson, Karen C and Carlson, Chris S and Love, Shelly-Anne and Brown-Gentry, Kristin and Nato, Alejandro Q and Quibrera, Miguel and Shohet, Ralph V and Ambite, Jose Luis and Wilkens, Lynne R and Le Marchand, Lo{\"\i}c and Haiman, Christopher A and Buyske, Steven and Kooperberg, Charles and North, Kari E and Fornage, Myriam and Crawford, Dana C} } @article {6111, title = {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.}, journal = {Ann Hum Genet}, volume = {77}, year = {2013}, month = {2013 Sep}, pages = {416-25}, abstract = {

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.

}, keywords = {Adult, Aged, European Continental Ancestry Group, Female, Genetic Association Studies, Genome-Wide Association Study, Humans, Lipids, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Risk Factors}, issn = {1469-1809}, doi = {10.1111/ahg.12027}, author = {Dumitrescu, Logan and Carty, Cara L and Franceschini, Nora and Hindorff, Lucia A and Cole, Shelley A and B{\r u}zkov{\'a}, Petra and Schumacher, Fredrick R and Eaton, Charles B and Goodloe, Robert J and Duggan, David J and Haessler, Jeff and Cochran, Barbara and Henderson, Brian E and Cheng, Iona and Johnson, Karen C and Carlson, Chris S and Love, Shelly-Ann and Brown-Gentry, Kristin and Nato, Alejandro Q and Quibrera, Miguel and Anderson, Garnet and Shohet, Ralph V and Ambite, Jose Luis and Wilkens, Lynne R and Marchand, Loic Le and Haiman, Christopher A and Buyske, Steven and Kooperberg, Charles and North, Kari E and Fornage, Myriam and Crawford, Dana C} } @article {6628, title = {A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003171}, abstract = {

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 {\texttimes} 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, African Americans, Aged, Aged, 80 and over, Alleles, Body Mass Index, Chromosome Mapping, Continental Population Groups, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Metagenomics, Middle Aged, Obesity, Proteins}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003171}, author = {Peters, Ulrike and North, Kari E and Sethupathy, Praveen and Buyske, Steve and Haessler, Jeff and Jiao, Shuo and Fesinmeyer, Megan D and Jackson, Rebecca D and Kuller, Lew H and Rajkovic, Aleksandar and Lim, Unhee and Cheng, Iona and Schumacher, Fred and Wilkens, Lynne and Li, Rongling and Monda, Keri and Ehret, Georg and Nguyen, Khanh-Dung H and Cooper, Richard and Lewis, Cora E and Leppert, Mark and Irvin, Marguerite R and Gu, C Charles and Houston, Denise and B{\r u}zkov{\'a}, Petra and Ritchie, Marylyn and Matise, Tara C and Le Marchand, Lo{\"\i}c and Hindorff, Lucia A and Crawford, Dana C and Haiman, Christopher A and Kooperberg, Charles} } @article {6629, title = {Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013 Mar}, pages = {e1003379}, abstract = {

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 {\texttimes} 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.

}, keywords = {African Americans, Apolipoproteins A, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Proprotein Convertases, Serine Endopeptidases, Triglycerides}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003379}, author = {Wu, Ying and Waite, Lindsay L and Jackson, Anne U and Sheu, Wayne H-H and Buyske, Steven and Absher, Devin and Arnett, Donna K and Boerwinkle, Eric and Bonnycastle, Lori L and Carty, Cara L and Cheng, Iona and Cochran, Barbara and Croteau-Chonka, Damien C and Dumitrescu, Logan and Eaton, Charles B and Franceschini, Nora and Guo, Xiuqing and Henderson, Brian E and Hindorff, Lucia A and Kim, Eric and Kinnunen, Leena and Komulainen, Pirjo and Lee, Wen-Jane and Le Marchand, Lo{\"\i}c and Lin, Yi and Lindstr{\"o}m, Jaana and Lingaas-Holmen, Oddgeir and Mitchell, Sabrina L and Narisu, Narisu and Robinson, Jennifer G and Schumacher, Fred and Stan{\v c}{\'a}kov{\'a}, Alena and Sundvall, Jouko and Sung, Yun-Ju and Swift, Amy J and Wang, Wen-Chang and Wilkens, Lynne and Wilsgaard, Tom and Young, Alicia M and Adair, Linda S and Ballantyne, Christie M and B{\r u}zkov{\'a}, Petra and Chakravarti, Aravinda and Collins, Francis S and Duggan, David and Feranil, Alan B and Ho, Low-Tone and Hung, Yi-Jen and Hunt, Steven C and Hveem, Kristian and Juang, Jyh-Ming J and Kes{\"a}niemi, Antero Y and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lee, I-Te and Leppert, Mark F and Matise, Tara C and Moilanen, Leena and Nj{\o}lstad, Inger and Peters, Ulrike and Quertermous, Thomas and Rauramaa, Rainer and Rotter, Jerome I and Saramies, Jouko and Tuomilehto, Jaakko and Uusitupa, Matti and Wang, Tzung-Dau and Boehnke, Michael and Haiman, Christopher A and Chen, Yii-der I and Kooperberg, Charles and Assimes, Themistocles L and Crawford, Dana C and Hsiung, Chao A and North, Kari E and Mohlke, Karen L} } @article {6598, title = {Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval.}, journal = {Epidemiology}, volume = {25}, year = {2014}, month = {2014 Nov}, pages = {790-8}, abstract = {

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{\textquoteright}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.

}, keywords = {Aged, Continental Population Groups, Electrocardiography, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Long QT Syndrome, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Risk Factors}, issn = {1531-5487}, doi = {10.1097/EDE.0000000000000168}, author = {Seyerle, Amanda A and Young, Alicia M and Jeff, Janina M and Melton, Phillip E and Jorgensen, Neal W and Lin, Yi and Carty, Cara L and Deelman, Ewa and Heckbert, Susan R and Hindorff, Lucia A and Jackson, Rebecca D and Martin, Lisa W and Okin, Peter M and Perez, Marco V and Psaty, Bruce M and Soliman, Elsayed Z and Whitsel, Eric A and North, Kari E and Laston, Sandra and Kooperberg, Charles and Avery, Christy L} } @article {7019, title = {Genetic determinants of age-related macular degeneration in diverse populations from the PAGE study.}, journal = {Invest Ophthalmol Vis Sci}, volume = {55}, year = {2014}, month = {2014 Sep 9}, pages = {6839-50}, abstract = {

PURPOSE: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci.

METHODS: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05{\texttimes}10(-8) and P=6.36{\texttimes}10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing.

CONCLUSIONS: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.

}, keywords = {Adult, Aged, Aged, 80 and over, Complement Factor H, DNA, Ethnic Groups, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Macular Degeneration, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Prevalence, Prospective Studies, Proteins, Risk Factors, United States}, issn = {1552-5783}, doi = {10.1167/iovs.14-14246}, author = {Restrepo, Nicole A and Spencer, Kylee L and Goodloe, Robert and Garrett, Tiana A and Heiss, Gerardo and B{\r u}zkov{\'a}, Petra and Jorgensen, Neal and Jensen, Richard A and Matise, Tara C and Hindorff, Lucia A and Klein, Barbara E K and Klein, Ronald and Wong, Tien Y and Cheng, Ching-Yu and Cornes, Belinda K and Tai, E-Shyong and Ritchie, Marylyn D and Haines, Jonathan L and Crawford, Dana C} } @article {6360, title = {Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Apr}, pages = {178-88}, abstract = {

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{\texttimes}10(-3) for replication, P<2.0{\texttimes}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{\texttimes}10(-6)) and rs646776 (P=3.1{\texttimes}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.

}, keywords = {Adult, African Continental Ancestry Group, Aged, Asian Continental Ancestry Group, C-Reactive Protein, Female, Genetic Variation, Genome-Wide Association Study, Hispanic Americans, Humans, Indians, North American, Inflammation, Male, Middle Aged, Polymorphism, Single Nucleotide, United States, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000173}, author = {Kocarnik, Jonathan M and Pendergrass, Sarah A and Carty, Cara L and Pankow, James S and Schumacher, Fredrick R and Cheng, Iona and Durda, Peter and Ambite, Jose Luis and Deelman, Ewa and Cook, Nancy R and Liu, Simin and Wactawski-Wende, Jean and Hutter, Carolyn and Brown-Gentry, Kristin and Wilson, Sarah and Best, Lyle G and Pankratz, Nathan and Hong, Ching-Ping and Cole, Shelley A and Voruganti, V Saroja and B{\r u}zkov{\'a}, Petra and Jorgensen, Neal W and Jenny, Nancy S and Wilkens, Lynne R and Haiman, Christopher A and Kolonel, Laurence N and LaCroix, Andrea and North, Kari and Jackson, Rebecca and Le Marchand, Lo{\"\i}c and Hindorff, Lucia A and Crawford, Dana C and Gross, Myron and Peters, Ulrike} } @article {7259, title = {Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.}, journal = {Hum Mol Genet}, year = {2016}, month = {2016 Aug 29}, abstract = {

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

}, issn = {1460-2083}, doi = {10.1093/hmg/ddw284}, author = {Evans, Daniel S and Avery, Christy L and Nalls, Mike A and Li, Guo and Barnard, John and Smith, Erin N and Tanaka, Toshiko and Butler, Anne M and Buxbaum, Sarah G and Alonso, Alvaro and Arking, Dan E and Berenson, Gerald S and Bis, Joshua C and Buyske, Steven and Carty, Cara L and Chen, Wei and Chung, Mina K and Cummings, Steven R and Deo, Rajat and Eaton, Charles B and Fox, Ervin R and Heckbert, Susan R and Heiss, Gerardo and Hindorff, Lucia A and Hsueh, Wen-Chi and Isaacs, Aaron and Jamshidi, Yalda and Kerr, Kathleen F and Liu, Felix and Liu, Yongmei and Lohman, Kurt K and Magnani, Jared W and Maher, Joseph F and Mehra, Reena and Meng, Yan A and Musani, Solomon K and Newton-Cheh, Christopher and North, Kari E and Psaty, Bruce M and Redline, Susan and Rotter, Jerome I and Schnabel, Renate B and Schork, Nicholas J and Shohet, Ralph V and Singleton, Andrew B and Smith, Jonathan D and Soliman, Elsayed Z and Srinivasan, Sathanur R and Taylor, Herman A and Van Wagoner, David R and Wilson, James G and Young, Taylor and Zhang, Zhu-Ming and Zonderman, Alan B and Evans, Michele K and Ferrucci, Luigi and Murray, Sarah S and Tranah, Gregory J and Whitsel, Eric A and Reiner, Alex P and Sotoodehnia, Nona} } @article {7463, title = {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.}, journal = {Heart Rhythm}, volume = {14}, year = {2017}, month = {2017 Apr}, pages = {572-580}, abstract = {

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{\texttimes}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.

}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2016.12.021}, author = {Avery, Christy L and Wassel, Christina L and Richard, Melissa A and Highland, Heather M and Bien, Stephanie and Zubair, Niha and Soliman, Elsayed Z and Fornage, Myriam and Bielinski, Suzette J and Tao, Ran and Seyerle, Amanda A and Shah, Sanjiv J and Lloyd-Jones, Donald M and Buyske, Steven and Rotter, Jerome I and Post, Wendy S and Rich, Stephen S and Hindorff, Lucia A and Jeff, Janina M and Shohet, Ralph V and Sotoodehnia, Nona and Lin, Dan Yu and Whitsel, Eric A and Peters, Ulrike and Haiman, Christopher A and Crawford, Dana C and Kooperberg, Charles and North, Kari E} } @article {7798, title = {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.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 Aug 15}, pages = {2940-2953}, abstract = {

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.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddy211}, author = {Kocarnik, Jonathan M and Richard, Melissa and Graff, Misa and Haessler, Jeffrey and Bien, Stephanie and Carlson, Chris and Carty, Cara L and Reiner, Alexander P and Avery, Christy L and Ballantyne, Christie M and LaCroix, Andrea Z and Assimes, Themistocles L and Barbalic, Maja and Pankratz, Nathan and Tang, Weihong and Tao, Ran and Chen, Dongquan and Talavera, Gregory A and Daviglus, Martha L and Chirinos-Medina, Diana A and Pereira, Rocio and Nishimura, Katie and B{\r u}zkov{\'a}, Petra and Best, Lyle G and Ambite, Jose Luis and Cheng, Iona and Crawford, Dana C and Hindorff, Lucia A and Fornage, Myriam and Heiss, Gerardo and North, Kari E and Haiman, Christopher A and Peters, Ulrike and Le Marchand, Lo{\"\i}c and Kooperberg, Charles} } @article {7793, title = {Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study.}, journal = {Am J Hematol}, year = {2018}, month = {2018 Jun 15}, abstract = {

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson{\textquoteright}s r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.

}, issn = {1096-8652}, doi = {10.1002/ajh.25161}, author = {Jo Hodonsky, Chani and Schurmann, Claudia and Schick, Ursula M and Kocarnik, Jonathan and Tao, Ran and van Rooij, Frank Ja and Wassel, Christina and Buyske, Steve and Fornage, Myriam and Hindorff, Lucia A and Floyd, James S and Ganesh, Santhi K and Lin, Dan-Yu and North, Kari E and Reiner, Alex P and Loos, Ruth Jf and Kooperberg, Charles and Avery, Christy L} }