A probable contributor to the small genetic effect sizes observed so far is that current investigations have incompletely surveyed the potential causal variants within each gene. Relative risks observed for marker SNPs may underestimate the actual risks associated with the true causal variants. Notably, 11 out of 30 genes implicated as carrying common variants associated with lipid levels also carry known rare alleles of large effect identified in Mendelian dyslipidemias, including ABCA1, PCSK9 and LDLR22,32, suggesting that genes containing common variants with modest effects on complex traits may also contain rare variants with larger effects.
