Genomic regulation of natural variation in cortical and noncortical brain volume

An ANOVA revealed that more than half of the variance of these regressed phenotypes is genetically determined. We then identified the regions of the genome regulating this heritability. We located genomic regions in which a linkage disequilibrium was present using WebQTL as both a mapping engine and genomic database. For neocortex, we found a genome-wide significant quantitative trait locus (QTL) on chromosome 11 (marker D11Mit19), as well as a suggestive QTL on chromosome 16 (marker D16Mit100). In contrast, for noncortex the effect of chromosome 11 was markedly reduced, and a significant QTL appeared on chromosome 19 (D19Mit22).This classic pattern of double dissociation argues strongly for different genetic factors regulating relative cortical size, as opposed to brain volume more generally. It is likely, however, that the effects of proximal chromosome 11 extend beyond the neocortex strictly defined. An analysis of single nucleotide polymorphisms in these regions indicated that ciliary neurotrophic factor (Cntf) is quite possibly the gene underlying the noncortical QTL. Evidence for a candidate gene modulating neocortical volume was much weaker, but Otx1 deserves further consideration.The absolute and relative volumes of anatomically defined brain regions-such as the mammalian cerebral cortex-are of functional importance both within and across species [1-4]. In humans, the volume of the cerebral hemispheres ranges between 850 and 1380 cm3 in young adults [5]. Further, neocortical size is hereditarily specified, with over eighty percent of the variance of human neocortical gray matter volume being genetically determined [6]. At present, little is known about the genomic determinants of such natural variation.Further, cognitive ability is related to neocortical size. For example, Reiss et al. showed that IQ is positively correlated with cerebral volume in children [7]. Thompson et al. provided evidence based on quantitative MRI volumetric measurements that not only