Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort
Li Shen, Sungeun Kim, Shannon L Risacher, Kwangsik Nho, Shanker Swaminathan, John D West, Tatiana Foroud, Nathan Pankratz, Jason H Moore, Chantel D Sloan, Matthew J Huentelman, David W Craig, Bryan M Dechairo, Steven G Potkin, Clifford R Jack Jr, Michael W Weiner, Andrew J Saykin, Alzheimer's Disease Neuroimaging Initiative, Michael Weiner, Paul Aisen, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack Jr, William Jagust, John Trojanowki, Arthur W Toga, Laurel Beckett, Robert C Green, Anthony Gamst, Andrew J Saykin, John Morris, William Z Potter, Robert C Green, Tom Montine, Ronald Petersen, Paul Aisen, Anthony Gamst, Ronald G Thomas, Michael Donohue, Sarah Walter, Clifford R Jack Jr, Anders Dale, Matthew Bernstein, Joel Felmlee, Nick Fox, Paul Thompson, Norbert Schuf, Gene Alexander, Charles DeCarli, William Jagust, Dan Bandy, Robert A Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, Chet Mathis, John Morris, Nigel J Cairns, Lisa Taylor-Reinwald, John Trojanowki, Les Shaw, Virginia M Y Lee, Magdalena Korecka, Arthur W Toga, Karen Crawford, Scott Neu, Laurel Beckett, Danielle Harvey, Anthony Gamst, John Kornak, Andrew J Saykin, Tatiana M Foroud, Steven Potkin, Li Shen, Zaven Kachaturian, Richard Frank, Peter J Snyder, Susan Molchan, Jeffrey Kaye, Sara Dolen, Joseph Quinn, Lon Schneider, Sonia Pawluczyk, Bryan M Spann, James Brewer, Helen Vanderswag, Judith L Heidebrink, Joanne L Lord, Ronald Petersen, 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, David Clark, Hillel Grossman, Cheuk Tang, George Marzloff, Leyla deToledo-Morrell, Raj C Shah, Ranjan Duara, Daniel Varon, Peggy Roberts, Marilyn S Albert, Nicholas Kozauer, Maria Zerrate, Henry Rusinek, Mony J de Leon, Susan M De Santi, P Murali Doraiswamy, Jeffrey R Petrella, Marilyn Aiello, Steve Arnold, Jason H Karlawish, David Wolk, Charles D Smith, Curtis A Given 2nd, Peter Hardy, Oscar L Lopez, MaryAnn Oakley, Donna M Simpson, M Saleem Ismail, Connie Brand, Jennifer Richard, Ruth A Mulnard, Gaby Thai, Catherine Mc-Adams-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, Liana Apostolova, Daniel H S Silverman, Po H Lu, Neill R Graff-Radford, Francine Parfitt, Heather Johnson, Martin Farlow, Scott Herring, Ann M Hake, Christopher H van Dyck, Martha G MacAvoy, Amanda L Benincasa, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Howard Feldman, Michele Assaly, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Donna Munic, Chuang-Kuo Wu, Nancy Johnson, Marsel Mesulam, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A Sperling, Dorene M Rentz, Keith A Johnson, Allyson Rosen, Jared Tinklenberg, Wes Ashford, Marwan Sabbagh, Donald Connor, Sandra Jacobson, Ronald Killiany, Alexander Norbash, Anil Nair, Thomas O Obisesan, Annapurni Jayam-Trouth, Paul Wang, Alan Lerner, Leon Hudson, Paula Ogrocki, Charles DeCarli, Evan Fletcher, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M Carlsson, Steven G Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Barry A Hendin, Douglas W Scharre, Maria Kataki, Earl A Zimmerman, Dzintra Celmins, Alice D Brown, Godfrey Pearlson, Karen Blank, Karen Anderson, Andrew J Saykin, Robert B Santulli, Jessica Englert, Jeff D Williamson, Kaycee M Sink, Franklin Watkins, Brian R Ott, Edward Stopa, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J Rosen, Bruce L Miller, Jacobo Mintzer, Crystal Flynn Longmire, Kenneth Spicer, Li Shen, Sungeun Kim, Shannon L Risacher, Kwangsik Nho, Shanker Swaminathan, John D West, Tatiana Foroud, Nathan Pankratz, Jason H Moore, Chantel D Sloan, Matthew J Huentelman, David W Craig, Bryan M Dechairo, Steven G Potkin, Clifford R Jack Jr, Michael W Weiner, Andrew J Saykin, Alzheimer's Disease Neuroimaging Initiative, Michael Weiner, Paul Aisen, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack Jr, William Jagust, John Trojanowki, Arthur W Toga, Laurel Beckett, Robert C Green, Anthony Gamst, Andrew J Saykin, John Morris, William Z Potter, Robert C Green, Tom Montine, Ronald Petersen, Paul Aisen, Anthony Gamst, Ronald G Thomas, Michael Donohue, Sarah Walter, Clifford R Jack Jr, Anders Dale, Matthew Bernstein, Joel Felmlee, Nick Fox, Paul Thompson, Norbert Schuf, Gene Alexander, Charles DeCarli, William Jagust, Dan Bandy, Robert A Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, Chet Mathis, John Morris, Nigel J Cairns, Lisa Taylor-Reinwald, John Trojanowki, Les Shaw, Virginia M Y Lee, Magdalena Korecka, Arthur W Toga, Karen Crawford, Scott Neu, Laurel Beckett, Danielle Harvey, Anthony Gamst, John Kornak, Andrew J Saykin, Tatiana M Foroud, Steven Potkin, Li Shen, Zaven Kachaturian, Richard Frank, Peter J Snyder, Susan Molchan, Jeffrey Kaye, Sara Dolen, Joseph Quinn, Lon Schneider, Sonia Pawluczyk, Bryan M Spann, James Brewer, Helen Vanderswag, Judith L Heidebrink, Joanne L Lord, Ronald Petersen, 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, David Clark, Hillel Grossman, Cheuk Tang, George Marzloff, Leyla deToledo-Morrell, Raj C Shah, Ranjan Duara, Daniel Varon, Peggy Roberts, Marilyn S Albert, Nicholas Kozauer, Maria Zerrate, Henry Rusinek, Mony J de Leon, Susan M De Santi, P Murali Doraiswamy, Jeffrey R Petrella, Marilyn Aiello, Steve Arnold, Jason H Karlawish, David Wolk, Charles D Smith, Curtis A Given 2nd, Peter Hardy, Oscar L Lopez, MaryAnn Oakley, Donna M Simpson, M Saleem Ismail, Connie Brand, Jennifer Richard, Ruth A Mulnard, Gaby Thai, Catherine Mc-Adams-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, Liana Apostolova, Daniel H S Silverman, Po H Lu, Neill R Graff-Radford, Francine Parfitt, Heather Johnson, Martin Farlow, Scott Herring, Ann M Hake, Christopher H van Dyck, Martha G MacAvoy, Amanda L Benincasa, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Howard Feldman, Michele Assaly, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Donna Munic, Chuang-Kuo Wu, Nancy Johnson, Marsel Mesulam, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A Sperling, Dorene M Rentz, Keith A Johnson, Allyson Rosen, Jared Tinklenberg, Wes Ashford, Marwan Sabbagh, Donald Connor, Sandra Jacobson, Ronald Killiany, Alexander Norbash, Anil Nair, Thomas O Obisesan, Annapurni Jayam-Trouth, Paul Wang, Alan Lerner, Leon Hudson, Paula Ogrocki, Charles DeCarli, Evan Fletcher, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M Carlsson, Steven G Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Barry A Hendin, Douglas W Scharre, Maria Kataki, Earl A Zimmerman, Dzintra Celmins, Alice D Brown, Godfrey Pearlson, Karen Blank, Karen Anderson, Andrew J Saykin, Robert B Santulli, Jessica Englert, Jeff D Williamson, Kaycee M Sink, Franklin Watkins, Brian R Ott, Edward Stopa, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J Rosen, Bruce L Miller, Jacobo Mintzer, Crystal Flynn Longmire, Kenneth Spicer
Abstract
A genome-wide, whole brain approach to investigate genetic effects on neuroimaging phenotypes for identifying quantitative trait loci is described. The Alzheimer's Disease Neuroimaging Initiative 1.5 T MRI and genetic dataset was investigated using voxel-based morphometry (VBM) and FreeSurfer parcellation followed by genome-wide association studies (GWAS). One hundred forty-two measures of grey matter (GM) density, volume, and cortical thickness were extracted from baseline scans. GWAS, using PLINK, were performed on each phenotype using quality-controlled genotype and scan data including 530,992 of 620,903 single nucleotide polymorphisms (SNPs) and 733 of 818 participants (175 AD, 354 amnestic mild cognitive impairment, MCI, and 204 healthy controls, HC). Hierarchical clustering and heat maps were used to analyze the GWAS results and associations are reported at two significance thresholds (p<10(-7) and p<10(-6)). As expected, SNPs in the APOE and TOMM40 genes were confirmed as markers strongly associated with multiple brain regions. Other top SNPs were proximal to the EPHA4, TP63 and NXPH1 genes. Detailed image analyses of rs6463843 (flanking NXPH1) revealed reduced global and regional GM density across diagnostic groups in TT relative to GG homozygotes. Interaction analysis indicated that AD patients homozygous for the T allele showed differential vulnerability to right hippocampal GM density loss. NXPH1 codes for a protein implicated in promotion of adhesion between dendrites and axons, a key factor in synaptic integrity, the loss of which is a hallmark of AD. A genome-wide, whole brain search strategy has the potential to reveal novel candidate genes and loci warranting further investigation and replication.
Copyright 2010 Elsevier Inc. All rights reserved.
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Source: PubMed