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

Abstract

Summary Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) 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 post-menopausal). 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, I2=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.

Linkage analysis incorporating gene–age interactions identifies seven novel lipid loci: The Family Blood Pressure Program

“…We also identified ten known lipid lociwith interactions that lacked even suggestive evidence without interactions, showing the impact that age-dependent effects may have on the consistency of results across populations. Other investigations have reported gene-age interactions in three of our known QTLs [6, 11, 13], lending some credibility to the results from our modeling method. Known loci on chromosomes 1p33, 2q14.1, and 6p22.3 contained SNPs (in PCSK9 [11], INSIG2 [13], and an intergenic region[6], respectively)that yielded nominal evidence (p-value<0.05) of age interactions in prior lipid investigations.…”

Genome-wide association study of circulating interleukin 6 levels identifies novel loci

“…Also, conventionally increasing sample sizes without correction for population substructures may raise heterogeneity within populations ( 72 ), likely concealing the SNPs that affect particular subgroups. Future specific studies should counter the widely held assumption of unconditional risk alleles of complex traits and focus on the importance of studying more homogenous subgroups to, for example, investigate the age-dependent effect of genetic variants ( 73 , 74 ). Here, while further exploring the pleiotropic effect of IL-6-related variants, we identified phenotypes differentially regulated by diverse variants in the 1q21 locus.…”

Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults

“…[6][7][8][9] In earlier analyses in the GLACIER Study, we showed that whereas some of the 157 loci robustly associated with cross-sectional lipid concentrations 2,3 also convey robust effects on long-term changes in lipids, most loci do not. 8 Thus, discovering loci related to long-term changes in blood lipids, and not merely focusing on variants that are known to bear cross-sectional associations, 10 might be informative for the early identification of persons at high risk of atherosclerotic heart disease; such studies might also yield leads for targeted prevention, as loci that predict changes with age might do so owing to interactions with ageing-related risk factors or cumulative environmental exposures. 7…”