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Abstract
To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10-6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.
Details
Title
Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
Author
Zhou, Xueya 1 ; Feliciano, Pamela 2 ; Shu, Chang 1 ; Wang, Tianyun 3 ; Astrovskaya, Irina 2 ; Hall, Jacob B; Obiajulu, Joseph U; Wright, Jessica R; Murali, Shwetha C; Xu, Simon Xuming; Brueggeman, Leo; Thomas, Taylor R; Marchenko, Olena; Fleisch, Christopher; Barns, Sarah D; Snyder, LeeAnne Green; Han, Bing; Chang, Timothy S; Turner, Tychele N; Harvey, William T; Nishida, Andrew; O'Roak, Brian J; Geschwind, Daniel H; Michaelson, Jacob J; Volfovsky, Natalia; Eichler, Evan E; Shen, Yufeng; Chung, Wendy K; Adams, Adrienne; Amatya, Alpha; Andrus, Alicia; Bashar, Asif; Berman, Anna; Brown, Alison; Camba, Alexies; Gulsrud, Amanda C; Krentz, Anthony D; Shocklee, Amanda D; Esler, Amy; Lash, Alex E; Fanta, Anne; Fatemi, Ali; Fish, Angela; Goler, Alexandra; Gonzalez, Antonio; Gutierrez, Anibal, Jr; Hardan, Antonio; Hess, Amy; Hirshman, Anna; Holbrook, Alison; Ace, Andrea J; Griswold, Anthony J; Gruber, Angela J; Jarratt, Andrea; Jelinek, Anna; Jorgenson, Alissa; Juarez, A Pablo; Kim, Annes; Kitaygorodsky, Alex; Luo, Addie; Rachubinski, Angela L; Wainer, Allison L; Daniels, Amy M; Mankar, Anup; Mason, Andrew; Miceli, Alexandra; Milliken, Anna; Morales-Lara, Amy; Stephens, Alexandra N; Nguyen, Ai Nhu; Nicholson, Amy; Paolicelli, Anna Marie; McKenzie, Alexander P; Gupta, Abha R; Raven, Ashley; Rhea, Anna; Simon, Andrea; Soucy, Aubrie; Swanson, Amy; Sziklay, Anthony; Tallbull, Amber; Tesng, Angela; Ward, Audrey; Zick, Allyson; Hilscher, Brittani A; Bell, Brandi; Enright, Barbara; Robertson, Beverly E; Hauf, Brenda; Jensen, Bill; Lobisi, Brandon; Vernoia, Brianna M; Schwind, Brady; VanMetre, Bonnie; Erickson, Craig A; Sullivan, Catherine A W; Albright, Charles; Anglo, Claudine; Buescher, Cate; Bradley, Catherine C; Campo-Soria, Claudia; Cohen, Cheryl; Colombi, Costanza; Diggins, Chris; Edmonson, Catherine; Rice, Catherine E; Fassler, Carrie; Gray, Catherine; Gunter, Chris; Walston, Corrie H; Klaiman, Cheryl; Leonczyk, Caroline; Martin, Christa Lese; Lord, Catherine; Taylor, Cora M; McCarthy, Caitlin; Ocho-Lubinoff, Cesar; Ortiz, Crissy; Pierre, Cynthia; Rosenberg, Cordelia R; Rigby, Chris; Roche, Casey; Shrier, Clara; Smith, Chris; Van Wade, Candace; White-Lehman, Casey; Zaro, Christopher; Zha, Cindy; Bentley, Dawn; Correa, Dahriana; Sarver, Dustin E; Giancarla, David; Amaral, David G; Howes, Dain; Istephanous, Dalia; Coury, Daniel Lee; Li, Deana; Limon, Danica; Limpoco, Desi; Phillips, Diamond; Rambeck, Desiree; Rojas, Daniela; Srishyla, Diksha; Stamps, Danielle; Montes, Dennis Vasquez; Cho, Daniel; Cho, Dave; Fox, Emily A; Bahl, Ethan; Berry-Kravis, Elizabeth; Blank, Elizabeth; Bower, Erin; Brooks, Elizabeth; Courchesne, Eric; Dillon, Emily; Doyle, Erin; Given, Erin; Grimes, Ellen; Jones, Erica; Fombonne, Eric J; Kryszak, Elizabeth; Wodka, Ericka L; Lamarche, Elena; Lampert, Erica; Butter, Eric M; O'Connor, Eirene; Ocampo, Edith; Orrick, Elizabeth; Perez, Esmeralda; Ruzzo, Elizabeth; Singer, Emily; Matthews, Emily T; Pedapati, Ernest V; Fazal, Faris; Miller, Fiona K; Aberbach, Gabriella; Baraghoshi, Gabriele; Duhon, Gabrielle; Hooks, Gregory; Fischer, Gregory J; Marzano, Gabriela; Schoonover, Gregory; Dichter, Gabriel S; Tiede, Gabrielle; Cottrell, Hannah; Kaplan, Hannah E; Ghina, Haidar; Hutter, Hanna; Koene, Hope; Schneider, Hoa Lam; Lechniak, Holly; Li, Hai; Morotti, Hadley; Qi, Hongjian; Richardson, Harper; Zaydens, Hana; Zhang, Haicang; Zhao, Haoquan; Arriaga, Ivette; Tso, Ivy F; Acampado, John; Gerdts, Jennifer A; Beeson, Josh; Brown, Jennylyn; Comitre, Joaquin; Cordova, Jeanette; Delaporte, Jennifer; Cubells, Joseph F; Harris, Jill F; Gong, Jared; Gunderson, Jaclyn; Hernandez, Jessica; Judge, Jessyca; Jurayj, Jane; Law, J Kiely; Manoharan, Julie; Montezuma, Jessie; Neely, Jason; Orobio, Jessica; Pandey, Juhi; Piven, Joseph; Polanco, Jose; Polite, Jibrielle; Rosewater, Jacob; Scherr, Jessica; Sutcliffe, James S; McCracken, James T; Tjernagel, Jennifer; Toroney, Jaimie; Veenstra-Vanderweele, Jeremy; Wang, Jiayao; Ahlers, Katie; Schweers, Kathryn A; Baalman, Kelli; Beard, Katie; Callahan, Kristen; Coleman, Kendra; Fitzgerald, Kate D; Dent, Kate; Diehl, Katharine; Gonring, Kelsey; Pawlowski, Katherine G; Hirst, Kathy; Pierce, Karen L; Murillo, Karla; Murray, Kailey; Nowell, Kerri; O'Brien, Kaela; Pama, Katrina; Real, Kelli; Singer, Kaitlyn; Smith, Kaitlin; Stephenson, Kevin; Tsai, Katherine; Abbeduto, Leonard; Cartner, Lindsey A; Beeson, Landon; Carpenter, Laura; Casten, Lucas; Coppola, Leigh; Cordiero, Lisa; DeMarco, Lindsey; Pacheco, Lillian D; Corzo, Lorena Ferreira; Shulman, Lisa H; Walsh, Lauren Kasperson; Lesher, Laurie; Herbert, Lynette M; Prock, Lisa M; Malloch, Lacy; Mann, Lori; Grosvenor, Luke P; Simon, Laura; Soorya, Latha V; Wasserburg, Lucy; Yeh, Lisa; Huang-Storms, Lark Y; Alessandri, Michael; Popp, Marc A; Baer, Melissa; Beckwith, Malia; Casseus, Myriam; Coughlin, Michelle; Currin, Mary; Cutri, Michele; Mallardi, Malcolm D; DuBois, Megan; Dunlevy, Megan; Butler, Martin E; Frayne, Margot; Gwynette, McLeod F; Ghaziuddin, Mohammad; Haley, Monica; Heyman, Michelle; Hojlo, Margaret; Jordy, Michelle; Morrier, Michael J; Kowanda, Misia; Koza, Melinda; Lopez, Marilyn; McTaggart, Megan; Norris, Megan; Hale, Melissa N; O'Neil, Molly; Printen, Madison; Rayos, Madelyn; Sabiha, Mahfuza; Sahin, Mustafa; Sarris, Marina; Shir, Mojeeb; Siegel, Matthew; Steele, Morgan; Sweeney, Megan; Tafolla, Maira; Valicenti-McDermott, Maria; Verdi, Mary; Dennis, Megan Y; Alvarez, Nicolas; Bardett, Nicole; Berger, Natalie; Calderon, Norma; Decius, Nickelle; Gonzalez, Natalia; Harris, Nina; Lawson, Noah; Lillie, Natasha; Lo, Nathan; Long, Nancy; Russo-Ponsaran, Nicole M; Madi, Natalie; Mccoy, Nicole; Nagpal, Natalie; Rodriguez, Nicki; Russell, Nicholas; Shah, Neelay; Takahashi, Nicole; Targalia, Nicole; Newman, Olivia; Ousley, Opal Y; Heydemann, Peter; Manning, Patricia; Carbone, Paul S; Bernier, Raphael A; Gordon, Rachel A; Shaffer, Rebecca C; Annett, Robert D; Clark, Renee D; Jou, Roger; Landa, Rebecca J; Earl, Rachel K; Libove, Robin; Marini, Richard; Doan, Ryan N; Goin-Kochel, Robin P; Rana, Rishiraj; Remington, Richard; Shikov, Roman; Schultz, Robert T; Aberle, Shelley; Birdwell, Shelby; Boland, Sarah; Booker, Stephanie; Carpenter, S; Chintalapalli, Sharmista; Conyers, Sarah; D'Ambrosi, Sophia; Eldred, Sara; Francis, Sunday; Ganesa, Swami; Hepburn, Susan; Horner, Susannah; Hunter, Samantha; Brewster, Stephanie J; Lee, Soo J; Jacob, Suma; Jean, Stanley; Hyun, So; Kramer, Sydney; Friedman, Sandra L; Licona, Sarely; Littlefield, Sandy; Kanne, Stephen M; Mastel, Sarah; Mathai, Sheena; Melnyk, Sophia; Michaels, Sarah; Mohiuddin, Sarah; Palmer, Samiza; Plate, Samantha; Qiu, Shanping; Randall, Shelley; Sandhu, Sophia; Santangelo, Susan; Shah, Swapnil; Skinner, Steve; Thompson, Samantha; White, Sabrina; White, Stormi; Xiao, Sabrina; Xu, Sidi; Xu, Simon; Chen, Tia; Greene, Tunisia; Ho, Theodore; Ibanez, Teresa; Koomar, Tanner; Pramparo, Tiziano; Rutter, Tara; Shaikh, Tamim; Tran, Thao; Yu, Timothy W; Galbraith, Virginia; Gazestani, Vahid; Myers, Vincent J; Ranganathan, Vaikunt; Singh, Vini; Weaver, William Curtis; Cal, Wenteng; Chin, Wubin; Yang, Wha S; Choi, Y B; Warren, Zachary E
1 Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
2 Simons Foundation, New York, NY, USA
3 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
1 Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
2 Simons Foundation, New York, NY, USA
3 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Pages
1305-3,1319A-1319M
Section
ARTICLES
Publication year
2022
Publication date
Sep 2022
ISSN
10614036
e-ISSN
15461718
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2714944805
Copyright
Copyright Nature Publishing Group Sep 2022