For a more accurate estimate of the proportion of AD variation captured by GWAS markers, we conducted variance component analysis via mixed linear modeling, with allelic effects treated as statistically random. Using this approach (Yang et al. 2010), we determined that around one-third of the phenotypic variation is collectively accounted for by common SNPs in our EA and AA samples. Thus, if recent estimates of AD heritability are reliable, this result still leaves much of the additive genetic variation to be explained, with a potentially important role for rare causal variants. One example that is particularly instructive is rs1229984, a functional variant in ADH1B known to modify the conversion of alcohol to acetaldehyde, with a low frequency in non-Asian populations (∼1–3%) and, as a result, is poorly tagged by genotyped markers in current GWAS arrays. However, when this coding variant was directly genotyped in the COGA sample, a genome-wide significant association with AD was revealed, with a strong protective effect (Bierut et al. 2012).
