@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 {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 {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 {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} }