@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 {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 {6627, title = {Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study.}, journal = {BMC Genet}, volume = {14}, year = {2013}, month = {2013}, pages = {33}, abstract = {

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

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

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

}, keywords = {Female, Genetic Heterogeneity, Genome, Human, Genome-Wide Association Study, Humans, Lipids, Male, Polymorphism, Single Nucleotide, Population Groups}, issn = {1471-2156}, doi = {10.1186/1471-2156-14-33}, author = {Taylor, Kira C and Carty, Cara L and Dumitrescu, Logan and B{\r u}zkov{\'a}, Petra and Cole, Shelley A and Hindorff, Lucia and Schumacher, Fred R and Wilkens, Lynne R and Shohet, Ralph V and Quibrera, P Miguel and Johnson, Karen C and Henderson, Brian E and Haessler, Jeff and Franceschini, Nora and Eaton, Charles B and Duggan, David J and Cochran, Barbara and Cheng, Iona and Carlson, Chris S and Brown-Gentry, Kristin and Anderson, Garnet and Ambite, Jose Luis and Haiman, Christopher and Le Marchand, Lo{\"\i}c and Kooperberg, Charles and Crawford, Dana C and Buyske, Steven and North, Kari E and Fornage, Myriam} } @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} }