Sex-dependent association of common variants of microcephaly genes with brain structure
Authors: Rimol Lars M. , Agartz Ingrid , Djurovic Srdjan , Brown Andrew A. , Roddey J. Cooper , Kähler Anna K. , Mattingsdal Morten , Athanasiu Lavinia , Joyner Alexander H. , Schork Nicholas J. , Halgren Eric , Sundet Kjetil , Melle Ingrid , Dale Anders M. , Andreassen Ole A. , Weiner Michael , Thal Leon , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowki John , Toga Arthur W. , Beckett Laurel , Green Robert C. , Gamst Anthony , Potter William Z. , Montine Tom , Anders Dale , Bernstein Matthew , Felmlee Joel , Fox Nick , Thompson Paul , Schuff Norbert , Alexander Gene , Bandy Dan , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Trojanowki John , Shaw Les , Lee Virginia M.-Y. , Korecka Magdalena , Toga Arthur W. , Crawford Karen , Neu Scott , Harvey Danielle , Gamst Anthony , Kornak John , Kachaturian Zaven , Frank Richard , Snyder Peter J. , Molchan Susan , Kaye Jeffrey , Vorobik Remi , Quinn Joseph , Schneider Lon , Pawluczyk Sonia , Spann Bryan , Fleisher Adam S. , Vanderswag Helen , Heidebrink Judith L. , Lord Joanne L. , Johnson Kris , Doody Rachelle S. , Villanueva-Meyer Javier , Chowdhury Munir , Stern Yaakov , Honig Lawrence S. , Bell Karen L. , Morris John C. , Mintun Mark A. , Schneider Stacy , Marson Daniel , Griffith Randall , Badger Beverly , Grossman Hillel , Tang Cheuk , Stern Jessica , deToledo-Morrell Leyla , Shah Raj C. , Bach Julie , Duara Ranjan , Isaacson Richard , Strauman Silvia , Albert Marilyn S. , Pedroso Julia , Toroney Jaimie , Rusinek Henry , de Leon Mony J , De Santi Susan M , Doraiswamy P. Murali , Petrella Jeffrey R. , Aiello Marilyn , Clark Christopher M. , Pham Cassie , Nunez Jessica , Smith Charles D. , Given II Curtis A. , Hardy Peter , DeKosky Steven T. , Oakley MaryAnn , Simpson Donna M. , Ismail M. Saleem , Porsteinsson Anton , McCallum Colleen , Cramer Steven C. , Mulnard Ruth A. , McAdams-Ortiz Catherine , Diaz-Arrastia Ramon , Martin-Cook Kristen , DeVous Michael , Levey Allan I. , Lah James J. , Cellar Janet S. , Burns Jeffrey M. , Anderson Heather S. , Laubinger Mary M. , Bartzokis George , Silverman Daniel H.S. , Lu Po H. , Fletcher Rita , Parfitt Francine , Johnson Heather , Farlow Martin , Herring Scott , Hake Ann M. , van Dyck Christopher H. , MacAvoy Martha G. , Bifano Laurel A. , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Graham Simon , Caldwell Curtis , Feldman Howard , Assaly Michele , Hsiung Ging-Yuek R. , Kertesz Andrew , Rogers John , Trost Dick , Bernick Charles , Gitelman Darren , Johnson Nancy , Mesulam Marsel , Sadowsky Carl , Villena Teresa , Mesner Scott , Aisen Paul S. , Johnson Kathleen B. , Behan Kelly E. , Sperling Reisa A. , Rentz Dorene M. , Johnson Keith A. , Rosen Allyson , Tinklenberg Jared , Ashford Wes , Sabbagh Marwan , Connor Donald , Obradov Sanja , Killiany Ron , Norbash Alex , Obisesan Thomas O. , Jayam-Trouth Annapurni , Wang Paul , Auchus Alexander P. , Huang Juebin , Friedland Robert P. , DeCarli Charles , Fletcher Evan , Carmichael Owen , Kittur Smita , Mirje Seema , Johnson Sterling C. , Borrie Michael , Lee T-Y , Asthana Sanjay , Carlsson Cynthia M. , Potkin Steven G. , Highum Diane , Preda Adrian , Nguyen Dana , Tariot Pierre N. , Hendin Barry A. , Scharre Douglas W. , Kataki Maria , Beversdorf David Q. , Zimmerman Earl A. , Celmins Dzintra , Brown Alice D. , Gandy Sam , Marenberg Marjorie E. , Rovner Barry W. , Pearlson Godfrey , Blank Karen , Anderson Karen , Saykin Andrew J. , Santulli Robert B. , Pare Nadia , Williamson Jeff D. , Sink Kaycee M. , Potter Huntington , Ashok Raj B. , Giordano Amy , Ott Brian R. , Wu Chuang-Kuo , Cohen Ronald , Wilks Kerri L. 
Published: December 2009

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.