Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
Xueya Zhou(Columbia University Irving Medical Center), Pamela Feliciano(Simons Foundation), Chang Shu(Columbia University Irving Medical Center), Tianyun Wang(University of Washington), Irina Astrovskaya(Simons Foundation), Jacob B. Hall(Simons Foundation), Joseph Obiajulu(Columbia University Irving Medical Center), Jessica Wright(Simons Foundation), Shwetha C. Murali(Howard Hughes Medical Institute), Simon Xu(Simons Foundation), Leo Brueggeman(University of Iowa), Taylor Thomas(University of Iowa), Olena Marchenko(Simons Foundation), Christopher Fleisch(Simons Foundation), Sarah D. Barns(Simons Foundation), LeeAnne Green Snyder(Simons Foundation), Bing Han(Simons Foundation), Timothy S. Chang(University of California, Los Angeles), Tychele N. Turner(Washington University in St. Louis), William T. Harvey(University of Washington), Andrew Nishida(Oregon Health & Science University), Brian J. O’Roak(Oregon Health & Science University), Daniel H. Geschwind(University of California, Los Angeles), Adrienne Adams(Rush University Medical Center), Alpha Amatya(Simons Foundation), Alicia Andrus(University of Utah), Asif Bashar(Simons Foundation), Anna Berman(Vanderbilt University Medical Center), Alison Brown(Kennedy Krieger Institute), Alexies Camba(University of California, Los Angeles), Amanda C. Gulsrud(University of California, Los Angeles), Anthony D. Krentz, Amanda D. Shocklee(University of Missouri), Amy Esler(University of Minnesota), Alex Lash(Simons Foundation), Anne Fanta(Yale University), Ali Fatemi(Kennedy Krieger Institute), Angela Fish(University of Michigan), Alexandra Goler(Simons Foundation), Antonio González(University of Miami), Anibal Gutierrez(University of Miami), Antonio Y. Hardan(Stanford University), Amy Hess(Nationwide Children's Hospital), Anna Hirshman(Rush University Medical Center), Alison Holbrook(Simons Foundation), Andrea J. Ace(Simons Foundation), Anthony J. Griswold(University of Miami), Angela Gruber, A Jarratt(University of Minnesota), Anna Jelinek(Cincinnati Children's Hospital Medical Center), Alissa Jorgenson(University of Minnesota), Aline Juárez(Vanderbilt University Medical Center), Annes Kim(University of Michigan), Alex Kitaygorodsky(Columbia University Irving Medical Center), Addie Luo(Oregon Health & Science University), Angela L. Rachubinski(University of Colorado Denver), Allison Wainer(Rush University Medical Center), Amy M. Daniels(Simons Foundation), Anup Mankar(Simons Foundation), Andrew L. Mason(University of California San Diego), Alexandra Miceli(Vanderbilt University Medical Center), Anna Milliken(Boston Children's Hospital), Amy Morales-Lara(Albert Einstein College of Medicine), Alexandra N. Stephens(Simons Foundation), Ai Nhu Nguyen(Simons Foundation), Amy Nicholson(Vanderbilt University Medical Center), Anna Marie Paolicelli(Cornell University), Alexander P. McKenzie(Kennedy Krieger Institute), Abha R. Gupta(Yale University), A Raven(University of Michigan), Anna Rhea(Medical University of South Carolina), Andrea Simon(Baylor College of Medicine), Aubrie Soucy(Boston Children's Hospital), Amy Swanson(Vanderbilt University Medical Center), Anthony Sziklay(University of California San Diego), Amber Tallbull(University of Colorado Denver), Angela Tesng(University of Minnesota), Audrey W. M. Ward(Medical University of South Carolina), Allyson Zick(University of Michigan), Brittani A. Hilscher(University of California, Davis), Brandi Bell(Medical University of South Carolina), Barbara Enright(Children's Specialized Hospital), B. E. Robertson(Simons Foundation), Brenda Hauf(University of North Carolina Health Care), Bill Jensen(Simons Foundation), Brandon Lobisi(University of Miami), Brianna M. Vernoia(Simons Foundation), Brady Schwind(Simons Foundation), Bonnie VanMetre(Kennedy Krieger Institute), Craig A. Erickson(Cincinnati Children's Hospital Medical Center), Catherine Sullivan(Yale University), Charles F. Albright(Nationwide Children's Hospital), Claudine Anglo(University of California, Davis), Cate Buescher(University of Iowa), Catherine C. Bradley(Medical University of South Carolina), Claudia Campo-Soria(University of Minnesota), Cheryl Cohen(Simons Foundation), Costanza Colombi(University of Michigan), Chris Diggins(Simons Foundation), Catherine Edmonson(Kennedy Krieger Institute), Catherine E. Rice(Emory University), Carrie Fassler(Cincinnati Children's Hospital Medical Center), Catherine Gray(University of North Carolina Health Care), Chris Gunter(Emory University), Corrie H. Walston(University of North Carolina Health Care), Cheryl Klaiman(Emory University), Caroline Leonczyk(Rush University Medical Center), Christa Lese Martin(Autism & Developmental Medicine Institute), Catherine Lord(University of California, Los Angeles), Cora Taylor(Autism & Developmental Medicine Institute), Caitlin McCarthy(Medical University of South Carolina), Cesar Ochoa-Lubinoff(Rush University Medical Center), Crissy Ortiz(Medical University of South Carolina), Cynthia L. Pierre(Rush University Medical Center), Cordelia Robinson Rosenberg(University of Colorado Denver), Chris Rigby(Simons Foundation), Casey Roche(Medical University of South Carolina), Clara Shrier(Medical University of South Carolina), Christopher R. Smith(University of California San Diego), Candace Van Wade(Medical University of South Carolina), Casey White‐Lehman(Simons Foundation), Christopher Zaro(Boston Children's Hospital), Cindy Zha(University of Miami), Dawn Bentley(University of Utah), Dahriana Correa(University of Miami), Dustin E. Sarver(Jackson Memorial Hospital), David Giancarla(University of Miami), David G. Amaral(University of California, Davis), D.R. Howes(University of Minnesota), Dalia Istephanous(University of Minnesota), Daniel L. Coury(Nationwide Children's Hospital), Deana Li(University of California, Davis), Danica L. Limon(Baylor College of Medicine), Desi Limpoco(Oregon Health & Science University), Diamond Phillips(Rush University Medical Center), Desiree Rambeck(University of Minnesota), Daniela Rojas(Stanford University), Diksha Srishyla(University of Minnesota), Danielle Stamps(Jackson Memorial Hospital), Dennis Vasquez Montes(Simons Foundation), Daniel Cho(University of Washington), Dave Cho(University of Washington), Emily Fox(University of Washington), Ethan Bahl(University of Iowa), Elizabeth Berry‐Kravis(Rush University Medical Center), Elizabeth Blank(Cincinnati Children's Hospital Medical Center), Erin Bower(University of California San Diego), Elizabeth Brooks(Simons Foundation), Eric Courchesne(University of California San Diego), Emily Dillon(Kennedy Krieger Institute), Erin Doyle(Medical University of South Carolina), Erin Given(Nationwide Children's Hospital), Ellen Grimes(Vanderbilt University Medical Center), Erica Jones(Simons Foundation), Éric Fombonne(Oregon Health & Science University), Elizabeth Kryszak(Nationwide Children's Hospital), Ericka L. Wodka(Kennedy Krieger Institute), Elena Lamarche(University of North Carolina Health Care), Erica Lampert(Cincinnati Children's Hospital Medical Center), Eric Butter(Nationwide Children's Hospital), Eirene O’Connor(Simons Foundation), Edith V. Ocampo(Rush University Medical Center), Elizabeth Orrick(Stanford University), Esmeralda Perez(Simons Foundation), Elizabeth K. Ruzzo(University of California, Los Angeles), Emily Singer(Simons Foundation), Emily T. Matthews(Boston Children's Hospital), Ernest V. Pedapati(Cincinnati Children's Hospital Medical Center), Faris Z. Fazal(Oregon Health & Science University), Fiona K. Miller(University of Michigan), Gabriella Aberbach(Boston Children's Hospital), Gabriele K. Baraghoshi(University of Utah), Gabrielle F. Duhon(Baylor College of Medicine), Gregory Hooks(University of Minnesota), Gregory J. Fischer, Gabriela Marzano(Baylor College of Medicine), Gregory Schoonover(University of Utah), Gabriel S. Dichter(University of North Carolina Health Care), Gabrielle Tiede(Nationwide Children's Hospital), Hannah Cottrell(University of Missouri), Hannah E. Kaplan(University of California San Diego), Haidar Ghina(University of Washington), Hanna Hutter(Kennedy Krieger Institute), Hope Koene(Yale University), Hoa Lam Schneider(University of Miami), Holly Lechniak(Rush University Medical Center), Hai Li(Rush University Medical Center), Hadley Morotti(Oregon Health & Science University), Hongjian Qi(University of California San Diego), Harper Richardson(Medical University of South Carolina), Hana Zaydens(Simons Foundation), Haicang Zhang(University of California San Diego), Haoquan Zhao(University of California San Diego), Ivette Arriaga(University of California, Los Angeles), Ivy F. Tso(University of Michigan), John Acampado(Simons Foundation), Jennifer Gerdts(University of Washington), Josh Beeson(Rush University Medical Center), Jennylyn Brown(Simons Foundation), Joaquin Comitre(University of Miami), Jeanette M Cordova(University of Colorado Denver), Jennifer Delaporte(University of Missouri), Joseph F. Cubells(Emory University), Jill Harris(Children's Specialized Hospital), Xinyi Gong(Stanford University), Jaclyn Gunderson(University of Minnesota), Jessica Hernández(Simons Foundation), Jessyca Judge(University of Michigan), Jane Jurayj(Yale University), Kiely Law(Simons Foundation), Julie Manoharan(Simons Foundation), Jessie Montezuma(Medical University of South Carolina), Jason Neely(Kennedy Krieger Institute), Jéssica Orobio(Baylor College of Medicine), Juhi Pandey(Children's Hospital of Philadelphia), Joseph Piven(University of North Carolina Health Care), José Polanco(Cincinnati Children's Hospital Medical Center), Jibrielle Polite(Simons Foundation), Jacob Rosewater(University of Miami), Jessica Scherr(Nationwide Children's Hospital), James S. Sutcliffe(Vanderbilt University), James T. McCracken(University of California, Los Angeles), Jennifer Tjernagel(Simons Foundation), Jaimie Toroney(Simons Foundation), Jeremy Veenstra‐VanderWeele(Columbia University Irving Medical Center), Jiayao Wang(University of California San Diego), Katie Ahlers(University of Washington), Kathryn A. Schweers(Rush University Medical Center), Kelli Baalman(Baylor College of Medicine), Katie Beard(University of Minnesota), Kristen Callahan(Jackson Memorial Hospital), Kendra Coleman(University of California San Diego), Kate D. Fitzgerald(University of Michigan), Kate Dent(Autism & Developmental Medicine Institute), Katharine Diehl(Simons Foundation), Kelsey Gonring(Rush University Medical Center), Katherine G. Pawlowski(Boston Children's Hospital), Kathy Hirst(University of Missouri), Karen Pierce(University of California San Diego), Karla Murillo(University of California, Los Angeles), K. Daniel Murray(University of North Carolina Health Care), Kerri P. Nowell(University of Missouri), Kaela O’Brien(Cincinnati Children's Hospital Medical Center), Katrina Pama(Kennedy Krieger Institute), Kelli Real(University of North Carolina Health Care), Kaitlyn Singer(Autism & Developmental Medicine Institute), Kaitlin N. Smith(University of California, Davis), Kevin G. Stephenson(Nationwide Children's Hospital), Katherine Tsai(University of California, Los Angeles), Leonard Abbeduto(University of California, Davis), Lindsey A. Cartner(Simons Foundation), Landon Beeson(Oregon Health & Science University), Laura A. Carpenter(Medical University of South Carolina), Lucas G. Casten(University of Iowa), Leigh A. Coppola(Oregon Health & Science University), Lisa Cordiero(University of Colorado Denver), Lindsey DeMarco(Children's Hospital of Philadelphia), Lillian D. Pacheco(Oregon Health & Science University), Lorena Ferreira Corzo(Rush University Medical Center), Lisa H. Shulman(Albert Einstein College of Medicine), Lauren Kasperson Walsh(Autism & Developmental Medicine Institute), Laurie Lesher(University of Utah), Lynette M. Herbert(University of Miami), Lisa M. Prock(Boston Children's Hospital), Lacy Malloch(Jackson Memorial Hospital), Lori Mann(Simons Foundation), Luke P. Grosvenor(Simons Foundation), Laura Simon(University of Minnesota), Latha Soorya(Rush University Medical Center), Lucy Wasserburg(University of Minnesota), Lisa C. Yeh(Rush University Medical Center), Lark Y. Huang-Storms(Oregon Health & Science University), Michael Alessandri(University of Miami), Marc A. Popp, Melissa Baer(Rush University Medical Center), Malia Beckwith(Children's Specialized Hospital), Myriam Casseus(Children's Specialized Hospital), Michelle Coughlin(Boston Children's Hospital), Mary Hannah Currin(University of North Carolina Health Care), Michele Cutri(University of Miami), Malcolm D. Mallardi(Simons Foundation), Megan DuBois(University of Minnesota), Megan Dunlevy(Emory University), Martin E. Butler(Simons Foundation), Margot Frayne(Stanford University), McLeod F. Gwynette(Medical University of South Carolina), Mohammad Ghaziuddin(University of Michigan), Monica Haley(University of California, Los Angeles), Michelle Heyman(Cornell University), Margaret A. Hojlo(Boston Children's Hospital), Michelle Jordy(University of North Carolina Health Care), Michael J. Morrier(Emory University), Misia Kowanda(Simons Foundation), Melinda Koza(Kennedy Krieger Institute), Marilyn Lopez(Children's Specialized Hospital), Megan McTaggart(Kennedy Krieger Institute), Megan Norris(Nationwide Children's Hospital), Melissa N. Hale(University of Miami), Molly O’Neil(Albert Einstein College of Medicine), Madison Printen(Rush University Medical Center), Madelyn Rayos(University of Miami), Mahfuza Sabiha(Simons Foundation), Mustafa Şahin(Boston Children's Hospital), Marina Sarris(Simons Foundation), Mojeeb Shir(University of California San Diego), Matthew Siegel(Maine Medical Center), Morgan Steele(Stanford University), Megan Sweeney(University of Missouri), Maira Tafolla(University of California, Los Angeles), Maria Valicenti-McDermott(Albert Einstein College of Medicine), Mary Verdi(Maine Medical Center), Megan Y. Dennis(University of California, Davis), Nicolas Alvarez(Kennedy Krieger Institute), Nicole Bardett(Vanderbilt University Medical Center), Natalie Berger(Rush University Medical Center), Norma Eugenia García Calderón(Rush University Medical Center), Nickelle Decius(University of Miami), Natalia González(Children's Specialized Hospital), Nina Harris(Vanderbilt University Medical Center), Noah Lawson(Simons Foundation), Natasha Lillie(University of Minnesota), Nathan Lo(Simons Foundation), Nancy Long(Nationwide Children's Hospital), Nicole M. Russo‐Ponsaran(Rush University Medical Center), Natalie Madi(Cincinnati Children's Hospital Medical Center), Nicole Amber McCoy(Cincinnati Children's Hospital Medical Center), Natalie Nagpal(Simons Foundation), Nicki Rodriguez(University of California, Davis), Nicholas Russell(Nationwide Children's Hospital), Neelay Shah(Simons Foundation), Nicole Takahashi(University of Missouri), Nicole Targalia(University of Colorado Denver), O Newman(University of Minnesota), Opal Ousley(Emory University), Peter Heydemann(Rush University Medical Center), Patricia Manning(Cincinnati Children's Hospital Medical Center), Paul S. Carbone(University of Utah), Raphael Bernier(University of Washington), Rachel Gordon(Rush University Medical Center), Rebecca C. Shaffer(Cincinnati Children's Hospital Medical Center), Robert D. Annett(Jackson Memorial Hospital), Renee D. Clark(University of North Carolina Health Care), Roger J. Jou(Yale University), Rebecca Landa(Kennedy Krieger Institute), Rachel K. Earl(University of Washington), Robin A. Libove(Stanford University), Richard P. Marini(Simons Foundation), Ryan N. Doan(Boston Children's Hospital), Robin P. Goin‐Kochel(Baylor College of Medicine), Rishiraj Rana(Simons Foundation), Richard Remington(Simons Foundation), Roman Shikov(Kennedy Krieger Institute), Robert T. Schultz(Children's Hospital of Philadelphia), S. B. D. Aberle(Oregon Health & Science University), Shelby Birdwell(University of Missouri), Sarah Boland(Yale University), Stephanie Booker(Cincinnati Children's Hospital Medical Center), Simon Carpenter(Vanderbilt University Medical Center), Sharmista Chintalapalli(University of Michigan), Sarah Conyers(Medical University of South Carolina), Sophia D’Ambrosi(Medical University of South Carolina), Sara Eldred(Nationwide Children's Hospital), Sunday M. Francis(University of Minnesota), Swami Ganesan(Simons Foundation), Susan Hepburn(University of Colorado Denver), Susannah Horner(Children's Hospital of Philadelphia), Samantha Hunter(University of Missouri), Stephanie Brewster(Boston Children's Hospital), Soo J. Lee(Rush University Medical Center), Suma Jacob(University of Minnesota), Stanley Jean(Simons Foundation), So Hyun(Cornell University), Sydney Kramer(University of Iowa), Sandra Friedman(University of Colorado Denver), Sarely Licona(Rush University Medical Center), Sandy Littlefield(Stanford University), Stephen M. Kanne(University of Missouri Health System), Sarah Mastel(Oregon Health & Science University), Sheena Mathai(Emory University), Sophia Melnyk(Cincinnati Children's Hospital Medical Center), Sarah Michaels(Kennedy Krieger Institute), Sarah Mohiuddin(University of Michigan), Samiza Palmer(Children's Hospital of Philadelphia), Samantha Plate(Children's Hospital of Philadelphia), Shanping Qiu(Cornell University), Shelley Randall(Cincinnati Children's Hospital Medical Center), Sophia Sandhu(University of California, Los Angeles), Susan L. Santangelo(Maine Medical Center), Swapnil Shah(Simons Foundation), Steve A. Skinner(Greenwood Genetic Center), Samantha Thompson(University of California, Davis), Sabrina White(Emory University), Stormi P. White(Emory University), Sabrina Xiao(Simons Foundation), Sidi Xu(University of California San Diego), Simon Xu(Simons Foundation), Tia Chen(University of California San Diego), Tunisia Greene(Simons Foundation), Theodore Ho(University of Washington), Teresa Ibáñez(Nationwide Children's Hospital), Tanner Koomar(University of Iowa), Tiziano Pramparo(University of California San Diego), Tara M. Rutter(University of Washington), Tamim H. Shaikh(University of Colorado Denver), Thao Tran(Rush University Medical Center), Timothy W. Yu(Boston Children's Hospital), V. H. Galbraith(Medical University of South Carolina), Vahid Gazestani(University of California San Diego), Vincent J. Myers(Simons Foundation), Vaikunt Ranganathan(Children's Hospital of Philadelphia), Vini Singh(Kennedy Krieger Institute), W Curtis Weaver(Autism & Developmental Medicine Institute), Wenteng CaI(University of Minnesota), Wubin Chin(Simons Foundation), Wha S. Yang(University of California, Los Angeles), Y. B. Choi(Cornell University), Zachary Warren(Vanderbilt University Medical Center), Jacob J. Michaelson(University of Iowa), Natalia Volfovsky(Simons Foundation), Evan E. Eichler(Howard Hughes Medical Institute), Yufeng Shen(Columbia University Irving Medical Center), Wendy K. Chung(Columbia University Irving Medical Center)
Cited by 454Open Access
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.
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