title: 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.
authors.affiliation: Division of Psychiatry, Oslo University Hospital-Ulleval, 0407 Oslo, Norway.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Rimol
authors.forename: Ingrid
authors.initials: I
authors.lastname: Agartz
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Brown
authors.forename: J Cooper
authors.initials: JC
authors.lastname: Roddey
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kähler
authors.forename: Morten
authors.initials: M
authors.lastname: Mattingsdal
authors.forename: Lavinia
authors.initials: L
authors.lastname: Athanasiu
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Joyner
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Eric
authors.initials: E
authors.lastname: Halgren
authors.forename: Kjetil
authors.initials: K
authors.lastname: Sundet
authors.forename: Ingrid
authors.initials: I
authors.lastname: Melle
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000473:pathology; D001931:Brain Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors