By 2009, a number of GWAS studies had been performed on neuroimaging data. Among the first studies to report a positive finding—a so-called “genome-wide hit”—was the report by (Potkin et al. 2009a) that identified a key genetic variant in TOMM40, in linkage disequilibrium with APOE, the known risk gene for AD. Using hippocampal atrophy as a quantitative phenotype in a genome-wide scan, they assessed 381 participants in the ADNI (Alzheimer’s Disease Neuroimaging Initiative) study, to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait. Variants in TOMM40 appeared to affect hippocampal volume differently in AD patients versus controls. Working with genetic-founder populations, some GWAS-based studies revealed genome-wide hits in relatively small samples; in the Saguenay Youth Study, genetic variations in the KCTD8 region were associated with brain size in a community-based sample of adolescent girls (rs716890, P = 5.40 × 10−9); (Paus et al. 2012). Furthermore, genotype in the top hit (rs716890) interacted with prenatal exposure to maternal cigarette smoking vis-à-vis cortical area and cortical folding; in exposed girls only, this genotype explained ~21 % of variance in the cortical area (Paus et al. 2012).
