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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.

Dumitrescu L, Carty CL, Franceschini N, Hindorff LA, Cole SA, Bůžková P, Schumacher FR, Eaton CB, Goodloe RJ, Duggan DJ, Haessler J, Cochran B, Henderson BE, Cheng I, Johnson KC, Carlson CS, Love SA, Brown-Gentry K, Nato AQ, Quibrera M, Anderson G, Shohet RV, Ambite JL, Wilkens LR, Marchand LL, Haiman CA, Buyske S, Kooperberg C, North KE, Fornage M, Crawford DC
Ann Hum Genet. 2013 77 (5): 416-25

PMID: 23808484 · PMCID: PMC3796061 · DOI:10.1111/ahg.12027

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.

© 2013 John Wiley & Sons Ltd/University College London.

MeSH Terms (14)

Adult Aged European Continental Ancestry Group Female Genetic Association Studies Genome-Wide Association Study Humans Lipids Male Middle Aged Polymorphism, Single Nucleotide Quantitative Trait, Heritable Quantitative Trait Loci Risk Factors

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