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Sex-Dependent Association of Common Variants of Microcephaly Genes with Brain Structure

Lars M. Rimol, Ingrid Agartz, Srdjan Djurovic, Andrew A. Brown, J. Cooper Roddey, Anna K. Kähler, Morten Mattingsdal, Lavinia Athanasiu, Alexander H. Joyner, Nicholas J. Schork, Eric Halgren, Kjetil Sundet, Ingrid Melle, Anders M. Dale, Ole A. Andreassen and Charles F. Stevens
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 1 (Jan. 5, 2010), pp. 384-388
Stable URL: http://www.jstor.org/stable/40536283
Page Count: 5
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Sex-Dependent Association of Common Variants of Microcephaly Genes with Brain Structure
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Abstract

Loss-of-function mutations in the genes associated with primary microcephaly (MCPH) reduce human brain size by about twothirds, 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 Neurosa 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.

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