Sex-dependent association of common variants of microcephaly genes with brain structure

Abstract

Loss-of-function mutations in the genes associated with primary microcephaly (MCPH) reduce human brain size by about two-thirds, without producing gross abnormalities in brain organization or physiology and leaving other organs largely unaffected [Woods CG, et al. (2005) Am J Hum Genet 76:717-728]. There is also evidence suggesting that MCPH genes have evolved rapidly in primates and humans and have been subjected to selection in recent human evolution [Vallender EJ, et al. (2008) Trends Neurosci 31:637-644]. Here, we show that common variants of MCPH genes account for some of the common variation in brain structure in humans, independently of disease status. We investigated the correlations of SNPs from four MCPH genes with brain morphometry phenotypes obtained with MRI. We found significant, sex-specific associations between common, nonexonic, SNPs of the genes CDK5RAP2, MCPH1, and ASPM, with brain volume or cortical surface area in an ethnically homogenous Norwegian discovery sample (n = 287), including patients with mental illness. The most strongly associated SNP findings were replicated in an independent North American sample (n = 656), which included patients with dementia. These results are consistent with the view that common variation in brain structure is associated with genetic variants located in nonexonic, presumably regulatory, regions.

Fig. 1.

Negative log P-values corrected for multiple comparisons, for all SNPs in CDK5RAP2 for cortical area. The horizontal, dotted line marks the significance threshold (0.05). The bar below the figure marks the exon-intron structure of the gene. The LD map at the bottom was generated from the control group.

Fig. 2.

Association of CDK5RAP2 SNP rs2282168 with cortical area in (A) males and (B) females. The map shows the distribution of −log P-values (sign indicating direction of effect per copy of minor allele) across the reconstructed cortical surface. The corresponding maps for rs4836817, rs4836817, rs10818453, rs4836819, rs4836820, rs7859743, rs2297453, rs914592, rs1888893, and rs914593 were similar to that shown in this figure, which is probably because of the fact that all these polymorphisms are in strong LD. Fig. S1 shows the corresponding effect of MCPH1 SNP rs11779303 on cortical area in females.