Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
Xueya Zhou, Pamela Feliciano, Chang Shu, Tianyun Wang, Irina Astrovskaya, Jacob B. Hall, Joseph Obiajulu, Jessica Wright, Shwetha C. Murali, Simon Xu, Leo Brueggeman, Taylor Thomas, Olena Marchenko, Christopher Fleisch, Sarah D. Barns, LeeAnne Green Snyder, Bing Han, Timothy S. Chang, Tychele N. Turner, William T. Harvey, Andrew Nishida, Brian J. O’Roak, Daniel H. Geschwind, Adrienne Adams, Alpha Amatya, Alicia Andrus, Asif Bashar, Anna Berman, Alison Brown, Alexies Camba, Amanda C. Gulsrud, Anthony D. Krentz, Amanda D. Shocklee, Amy Esler, Alex Lash, Anne Fanta, Ali Fatemi, Angela Fish, Alexandra Goler, Antonio González, Anibal Gutierrez, Antonio Y. Hardan, Amy Hess, Anna Hirshman, Alison Holbrook, Andrea J. Ace, Anthony J. Griswold, Angela Gruber, A Jarratt, Anna Jelinek, Alissa Jorgenson, Aline Juárez, Annes Kim, Alex Kitaygorodsky, Addie Luo, Angela L. Rachubinski, Allison Wainer, Amy M. Daniels, Anup Mankar, Andrew L. Mason, Alexandra Miceli, Anna Milliken, Amy Morales-Lara, Alexandra N. Stephens, Ai Nhu Nguyen, Amy Nicholson, Anna Marie Paolicelli, Alexander P. McKenzie, Abha R. Gupta, A Raven, Anna Rhea, Andrea Simon, Aubrie Soucy, Amy Swanson, Anthony Sziklay, Amber Tallbull, Angela Tesng, Audrey W. M. Ward, Allyson Zick, Brittani A. Hilscher, Brandi Bell, Barbara Enright, B. E. Robertson, Brenda Hauf, Bill Jensen, Brandon Lobisi, Brianna M. Vernoia, Brady Schwind, Bonnie VanMetre, Craig A. Erickson, Catherine Sullivan, Charles F. Albright, Claudine Anglo, Cate Buescher, Catherine C. Bradley, Claudia Campo-Soria, Cheryl Cohen, Costanza Colombi, Chris Diggins, Catherine Edmonson
Abstract
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.