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

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.