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Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):384-8. doi: 10.1073/pnas.0908454107. Epub 2009 Dec 22.

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

Collaborators (194)

Weiner MW, Thal L, Petersen R, Jack CR, Jagust W, Trojanowki J, Toga AW, Beckett L, Green RC, Gamst A, Potter WZ, Montine T, Anders D, Bernstein M, Felmlee J, Fox N, Thompson P, Schuff N, Alexander G, Bandy D, Koeppe RA, Foster N, Reiman EM, Chen K, Trojanowki J, Shaw L, Lee VM, Korecka M, Toga A, Crawford K, Neu S, Harvey D, Gamst A, Kornak J, Kachaturian Z, Frank R, Snyder PJ, Molchan S, Kaye J, Vorobik R, Quinn J, Schneider L, Pawluczyk S, Spann B, Fleisher AS, Vanderswag H, Heidebrink JL, Lord JL, Johnson K, Doody RS, Villanueva J, Chowdhury M, Stern Y, Honig L, Bell K, Morris JC, Mintun M, Schneider S, Marson D, Griffith R, Badger B, Grossman H, Tang C, Stern J, de Toledo-Morrell L, Shah RC, Bach J, Duara R, Isaacson R, Strauman S, Albert MS, Pedroso J, Toroney J, Rusinek H, de Leon MJ, De Santi SM, Doraiswamy PM, Petrella JR, Aiello M, Clark CM, Pham C, Nunez J, Smith CD, Given CA 2nd, Hardy P, DeKosky ST, Oakley MA, Simpson DM, Ismail MS, Portsteinsson A, McCallum C, Cramer SC, Mulnard RA, McAdams-Ortiz C, Diaz-Arrastia R, Martin-Cook K, DeVous M, Levey AI, Lah JJ, Cellar JS, Burns JM, Anderson HS, Laubinger MM, Bartzokis G, Silverman DH, Lu PH, Fletcher R, Parfitt F, Johnson H, Farlow M, Herring S, Hake AM, Van Dyck CH, MacAvoy MG, Bifano LA, Chertkow H, Bergman H, Hosein C, Black S, Graham S, Caldwell C, Feldman H, Assaly M, Hsiung GY, Kertesz A, Rodgers J, Trost D, Bernick C, Gitelman D, Johnson N, Mesulam M, Sadowsky C, Villena T, Mesner S, Aisen PS, Johnson KB, Behan KE, Sperling RA, Rentz DM, Johnson KA, Rosen A, Tinklenberg J, Ashford W, Sabbagh M, Connor D, Obradov S, Killiany R, Norbash A, Obisesan TO, Jayam-Trouth A, Wang P, Auchus A, Huang J, Friedland RP, DeCarli C, Fletcher E, Carmichael O, Kittur S, Mirje S, Johnson SC, Borrie M, Lee T-, Asthana S, Carlsson CM, Potkin SG, Highum D, Preda A, Nguyen D, Tariot PN, Hendin BA, Scharre DW, Kataki M, Beversdorf DQ, Zimmerman EA, Celmins D, Brown AD, Gandy S, Marenberg ME, Rovner BW, Pearlson G, Blank K, Anderson K, Saykin AJ, Santulli RB, Pare N, Williamson JD, Sink KM, Potter H, Ashok Raj B, Giordano A, Ott BR, Wu CK, Cohen R, Wilks KL.

Author information

Division of Psychiatry, Oslo University Hospital-Ulleval, 0407 Oslo, Norway.


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.

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