Abstract 13051: Unbiased Estimate of Heritability of CAD Before and After Adjustment for Traditional Risk Factors in Five NHLBI Cohorts
Introduction: The relative contribution of traditional risk factors (TRFs) to the genesis of CAD remains uncertain. Cohort studies report a high population attributable risk for TRFs, but only a third of the GWAS loci for CAD mediate risk through TRFs. Furthermore, these loci explain a small fraction of the overall heritability of CAD based on twin studies making it unclear whether these patterns will persist and whether estimates from twin studies are inflated.
Hypothesis: Unbiased estimates of narrow sense heritability (h2) of CAD using contemporary analytic techniques applied to very distantly related individuals prior to and after adjustment of TRFs have not yet been reported. We hypothesized that such estimates would confirm a high heritability of CAD and that a substantial proportion of the genetic variance would be independent of TRFs.
Methods: We used ~7 million genome wide imputed single nucleotide polymorphisms (SNPs) and a mixed linear model implemented in Genome-wide Complex Trait Analysis to estimate the h2 of CAD from genomic relatedness among participants of five prospective NHLBI cohorts - ARIC, CHS, FHS, MESA, and WHI. To guard against bias from differences in minor allele frequencies (MAF) as well as region-specific heterogeneity in linkage disequilibrium (LD) between variants used in our analyses and causal variants, we used MAF and LD stratified multicomponent genetic restricted maximum likelihood. We ran 2 models assuming a population prevalence of 8%. The first model was not adjusted for any covariates and the second was adjusted for all TRFs as well as use of antihypertensive and statin drugs.
Results: We analyzed a total of 23,522 participants including 3520 that developed incident clinical CAD during follow up. CAD h2 was 39% (±3.1%) in our unadjusted model and 32% (±3.2%) in our fully adjusted model. A large majority (~95%) of the heritability in both models was derived from common SNPs with MAF >1%.
Conclusions: CAD is a moderately heritable trait with a large fraction of its genetic variance being a result of processes unrelated to TRFs. Prior family based estimates of the h2 of CAD do not appear biased upwards. Consistent with many other complex traits, a majority of the genetic variance can be explained by common SNPs with very modest effects.
Author Disclosures: E.L. Salfati: None. J. Li: None. L. Del Gobbo: None. T.L. Assimes: Research Grant; Significant; Telomere Diagnostics, Regeneron Genetics Center.
- © 2016 by American Heart Association, Inc.