Genome-wide scan of healthy human connectome discoversSPON1gene variant influencing dementia severity
Authors: Jahanshad Neda , Rajagopalan Priya , Hua Xue , Hibar Derrek P. , Nir Talia M. , Toga Arthur W. , Jack Clifford R. , Saykin Andrew J. , Green Robert C. , Weiner Michael W. , Medland Sarah E. , Montgomery Grant W. , Hansell Narelle K. , McMahon Katie L. , de Zubicaray Greig I. , Martin Nicholas G. , Wright Margaret J. , Thompson Paul M. ,   the Alzheimer’s Disease Neuroimaging Initiative, Weiner Michael , Aisen Paul , Weiner Michael , Aisen Paul , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowski John Q. , Toga Arthur W. , Beckett Laurel , Green Robert C. , Saykin Andrew J. , Morris John , Liu Enchi , Green Robert C. , Montine Tom , Petersen Ronald , Aisen Paul , Gamst Anthony , Thomas Ronald G. , Donohue Michael , Walter Sarah , Gessert Devon , Sather Tamie , Beckett Laurel , Harvey Danielle , Gamst Anthony , Donohue Michael , Kornak John , Jack Clifford R. , Dale Anders , Bernstein Matthew , Felmlee Joel , Fox Nick , Thompson Paul , Schuff Norbert , Alexander Gene , DeCarli Charles , Jagust William , Bandy Dan , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Mathis Chet , Morris John , Cairns Nigel J. , Taylor-Reinwald Lisa , Trojanowki J.Q. , Shaw Les , Lee Virginia M.Y. , Korecka Magdalena , Toga Arthur W. , Crawford Karen , Neu Scott , Saykin Andrew J. , Foroud Tatiana M. , Potkin Steven , Shen Li , Khachaturian Zaven , Frank Richard , Snyder Peter J. , Molchan Susan , Kaye Jeffrey , Quinn Joseph , Lind Betty , Dolen Sara , Schneider Lon S. , Pawluczyk Sonia , Spann Bryan M. , Brewer James , Vanderswag Helen , Heidebrink Judith L. , Lord Joanne L. , Petersen Ronald , Johnson Kris , Doody Rachelle S. , Villanueva-Meyer Javier , Chowdhury Munir , Stern Yaakov , Honig Lawrence S. , Bell Karen L. , Morris John C. , Ances Beau , Carroll Maria , Leon Sue , Mintun Mark A. , Schneider Stacy , Marson Daniel , Griffith Randall , Clark David , Grossman Hillel , Mitsis Effie , Romirowsky Aliza , deToledo-Morrell Leyla , Shah Raj C. , Duara Ranjan , Varon Daniel , Roberts Peggy , Albert Marilyn , Onyike Chiadi , Kielb Stephanie , Rusinek Henry , de Leon Mony J. , Glodzik Lidia , De Santi Susan , Doraiswamy P. Murali , Petrella Jeffrey R. , Coleman R. Edward , Arnold Steven E. , Karlawish Jason H. , Wolk David , Smith Charles D. , Jicha Greg , Hardy Peter , Lopez Oscar L. , Oakley MaryAnn , Simpson Donna M. , Porsteinsson Anton P. , Goldstein Bonnie S. , Martin Kim , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Mulnard Ruth A. , Thai Gaby , Mc-Adams-Ortiz Catherine , Womack Kyle , Mathews Dana , Quiceno Mary , Diaz-Arrastia Ramon , King Richard , Weiner Myron , Martin-Cook Kristen , DeVous Michael , Levey Allan I. , Lah James J. , Cellar Janet S. , Burns Jeffrey M. , Anderson Heather S. , Swerdlow Russell H. , Apostolova Liana , Lu Po H. , Bartzokis George , Silverman Daniel H.S. , Graff-Radford Neill R. , Parfitt Francine , Johnson Heather , Farlow Martin R. , Hake Ann Marie , Matthews Brandy R. , Herring Scott , van Dyck Christopher H. , Carson Richard E. , MacAvoy Martha G. , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Stefanovic Bojana , Caldwell Curtis , Hsiung Ging-Yuek Robin , Feldman Howard , Mudge Benita , Assaly Michele , Kertesz Andrew , Rogers John , Trost Dick , Bernick Charles , Munic Donna , Kerwin Diana , Mesulam Marek-Marsel , Lipowski Kristina , Wu Chuang-Kuo , Johnson Nancy , Sadowsky Carl , Martinez Walter , Villena Teresa , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , Sperling Reisa A. , Johnson Keith A. , Marshall Gad , Frey Meghan , Yesavage Jerome , Taylor Joy L. , Lane Barton , Rosen Allyson , Tinklenberg Jared , Sabbagh Marwan , Belden Christine , Jacobson Sandra , Kowall Neil , Killiany Ronald , Budson Andrew E. , Norbash Alexander , Johnson Patricia Lynn , Obisesan Thomas O. , Wolday Saba , Bwayo Salome K. , Lerner Alan , Hudson Leon , Ogrocki Paula , Fletcher Evan , Carmichael Owen , Olichney John , DeCarli Charles , Kittur Smita , Borrie Michael , Lee T.-Y. , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Potkin Steven G. , Preda Adrian , Nguyen Dana , Tariot Pierre , Fleisher Adam , Reeder Stephanie , Bates Vernice , Capote Horacio , Rainka Michelle , Scharre Douglas W. , Kataki Maria , Zimmerman Earl A. , Celmins Dzintra , Brown Alice D. , Pearlson Godfrey D. , Blank Karen , Anderson Karen , Saykin Andrew J. , Santulli Robert B. , Schwartz Eben S. , Sink Kaycee M. , Williamson Jeff D. , Garg Pradeep , Watkins Franklin , Ott Brian R. , Querfurth Henry , Tremont Geoffrey , Salloway Stephen , Malloy Paul , Correia Stephen , Rosen Howard J. , Miller Bruce L. , Mintzer Jacobo , Longmire Crystal Flynn , Spicer Kenneth , Finger Elizabeth , Rachinsky Irina , Rogers John , Kertesz Andrew , Drost Dick 
Published: March 2013

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with theSPON1variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.