Kohannim et al. Discovering genes that affect brain images FIGURE 2 | Post hoc gene effects on temporal lobe structure. We conducted voxelwise associations for the 22 signiﬁcant genes we identiﬁed (gene names are shown at the bottom left of the images). A representative, axial slice is shown for all gene effects. Warmer colors represent more signiﬁcant effects (i.e., higher effect sizes in the analysis of overall temporal lobe volume). p-values are corrected for multiple comparisons within the 3D image search region, using a regional false discovery rate method. also discussed in Hibar et al. (2011a), there are cases where a uni- variate test for the top SNP in a gene offers more power to detect an effect than a multivariate F -test for the whole gene. ADAMTS2, for instance, is a gene that contains a SNP with the lowest uni- variate p-value (rs12513486, p D 2.23 10 5) in our dataset just below the signiﬁcance threshold considered in Stein et al. (2010a). With our F -test approach following LASSO regression, the gene actually obtained a weaker association (p D 4.83 10 5). Thus, our approach complements univariate GWAS, but does not always boost detection power by including multiple loci. Several of the genes we identiﬁed have been well studied in the context of psychiatric and neurological disorders, including Alzheimer’s disease. Our most signiﬁcant gene, MACROD2, which we also replicated in a new cohort, was recently discovered in the context of autism spectrum disorder (ASD), as the gene containing the top SNP (p < 5 10 8) in a GWAS of 1,558 families of whom some members had been diagnosed with ASD (Anney et al., 2010). The investigators of that study reported that although the precise function of this gene is mostly unknown, it is involved in several biological functions and the region comprising their top SNP may www.frontiersin.org August 2012 | Volume 6 | Article 115 | 7