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

2009; National Academy of Sciences; Volume: 107; Issue: 1 Linguagem: Inglês

10.1073/pnas.0908454107

1091-6490

Lars M. Rimol, Ingrid Agartz, Srdjan Djurovic, Andrew 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 W. Weiner, Leon J. Thal, Ronald Petersen, Clifford R. Jack, William J. Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Anthony Gamst, William Z. Potter, Tom Montine, Dale Anders, Matt A. Bernstein, Joel P. Felmlee, Nick C. Fox, Paul M. Thompson, Norbert Schuff, Gene E. Alexander, Dan Bandy, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, John Q. 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 S. Schneider, Sonia Pawluczyk, Bryan Spann, Adam Fleisher, Helen Vanderswag, Judith L. Heidebrink, Joanne 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 Y. 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 Nuñez, Charles D. Smith, Curtis A. Given, Peter Hardy, Steven T. DeKosky, MaryAnn Oakley, Donna M. Simpson, M. Saleem Ismail, Anton P. Porsteinsson, Colleen McCallum, Steven C. Cramer, Ruth A. Mulnard, Catherine Mc-Adams-Ortiz, Ramon Diaz‐Arrastia, Kristen Martin-Cook, Michael D. Devous, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Heather S. Anderson, Mary M. Laubinger, George Bartzokis, Daniel Silverman, Po H. Lu, Rita Fletcher, Francine Parfitt, Heather Johnson, Martin R. Farlow, Scott Herring, Ann Marie Hake, Christopher H. van Dyck, Martha G. MacAvoy, Laurel A. Bifano, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Simon J. Graham, Curtis Caldwell, Howard Feldman, Michele Assaly, Ging‐Yuek Robin Hsiung, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Darren R. Gitelman, Nancy E. Johnson, Marsel Mesulam, Carl Sadowsky, Teresa Villena, Scott Mesner, Paul Aisen, Kathleen Johnson, Kelly E. Behan, Reisa A. Sperling, Dorene M. Rentz, Keith A. Johnson, Allyson Rosen, Jared Tinklenberg, Wes Ashford, Marwan Sabbagh, Donald J. Connor, Sanja Obradov, Ronald Killiany, Alexander 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 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 D. Pearlson, Karen Blank, Karen Anderson, Andrew J. Saykin, Robert B. Santulli, Nadia Paré, Jeff D. Williamson, Kaycee M. Sink, Huntington Potter, Balebail Ashok Raj, Amy T. Giordano, Brian R. Ott, Chuang‐Kuo Wu, Ronald A. Cohen, Kerri Wilks,

Machine Learning in Bioinformatics

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.