Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

the SPARK Consortium

doi:10.1038/s41588-022-01148-2

Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

the SPARK Consortium

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158 Scopus citations

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.

Original language	English
Pages (from-to)	1305-1319
Number of pages	15
Journal	Nature Genetics
Volume	54
Issue number	9
DOIs	https://doi.org/10.1038/s41588-022-01148-2
State	Published - Sep 2022

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10.1038/s41588-022-01148-2

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@article{31ceb29de4444086aa1a29fef62e348a,

title = "Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes",

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.",

author = "{the SPARK Consortium} and Xueya Zhou and Pamela Feliciano and Chang Shu and Tianyun Wang and Irina Astrovskaya and Hall, {Jacob B.} and Obiajulu, {Joseph U.} and Wright, {Jessica R.} and Murali, {Shwetha C.} and Xu, {Simon Xuming} and Leo Brueggeman and Thomas, {Taylor R.} and Olena Marchenko and Christopher Fleisch and Barns, {Sarah D.} and Snyder, {Lee Anne Green} and Bing Han and Chang, {Timothy S.} and Turner, {Tychele N.} and Harvey, {William T.} and Andrew Nishida and O{\textquoteright}Roak, {Brian J.} and Geschwind, {Daniel H.} and Adrienne Adams and Alpha Amatya and Alicia Andrus and Asif Bashar and Anna Berman and Alison Brown and Alexies Camba and Gulsrud, {Amanda C.} and Krentz, {Anthony D.} and Shocklee, {Amanda D.} and Amy Esler and Lash, {Alex E.} and Anne Fanta and Ali Fatemi and Angela Fish and Alexandra Goler and Antonio Gonzalez and Anibal Gutierrez and Antonio Hardan and Amy Hess and Anna Hirshman and Alison Holbrook and Ace, {Andrea J.} and Griswold, {Anthony J.} and Gruber, {Angela J.} and Andrea Jarratt and Anna Jelinek and Alissa Jorgenson and Juarez, {A. Pablo} and Annes Kim and Alex Kitaygorodsky and Addie Luo and Rachubinski, {Angela L.} and Wainer, {Allison L.} and Daniels, {Amy M.} and Anup Mankar and Andrew Mason and Alexandra Miceli and Anna Milliken and Amy Morales-Lara and Stephens, {Alexandra N.} and Nguyen, {Ai Nhu} and Amy Nicholson and Paolicelli, {Anna Marie} and McKenzie, {Alexander P.} and Gupta, {Abha R.} and Ashley Raven and Anna Rhea and Andrea Simon and Aubrie Soucy and Amy Swanson and Anthony Sziklay and Amber Tallbull and Angela Tesng and Audrey Ward and Allyson Zick and Hilscher, {Brittani A.} and Brandi Bell and Barbara Enright and Robertson, {Beverly E.} and Brenda Hauf and Bill Jensen and Brandon Lobisi and Vernoia, {Brianna M.} and Brady Schwind and Bonnie VanMetre and Erickson, {Craig A.} and Sullivan, {Catherine A.W.} and Charles Albright and Claudine Anglo and Cate Buescher and Bradley, {Catherine C.} and Claudia Campo-Soria and Cheryl Cohen and Costanza Colombi and Chris Diggins and Catherine Edmonson and Rice, {Catherine E.} and Carrie Fassler and Catherine Gray and Chris Gunter and Walston, {Corrie H.} and Cheryl Klaiman and Caroline Leonczyk and Martin, {Christa Lese} and Catherine Lord and Taylor, {Cora M.} and Caitlin McCarthy and Cesar Ochoa-Lubinoff and Crissy Ortiz and Cynthia Pierre and Rosenberg, {Cordelia R.} and Chris Rigby and Casey Roche and Clara Shrier and Chris Smith and {Van Wade}, Candace and Casey White-Lehman and Christopher Zaro and Cindy Zha and Dawn Bentley and Dahriana Correa and Sarver, {Dustin E.} and David Giancarla and Amaral, {David G.} and Dain Howes and Dalia Istephanous and Coury, {Daniel Lee} and Deana Li and Danica Limon and Desi Limpoco and Diamond Phillips and Desiree Rambeck and Daniela Rojas and Diksha Srishyla and Danielle Stamps and Montes, {Dennis Vasquez} and Daniel Cho and Dave Cho and Fox, {Emily A.} and Ethan Bahl and Elizabeth Berry-Kravis and Elizabeth Blank and Erin Bower and Elizabeth Brooks and Eric Courchesne and Emily Dillon and Erin Doyle and Erin Given and Ellen Grimes and Erica Jones and Fombonne, {Eric J.} and Elizabeth Kryszak and Wodka, {Ericka L.} and Elena Lamarche and Erica Lampert and Butter, {Eric M.} and Eirene O{\textquoteright}Connor and Edith Ocampo and Elizabeth Orrick and Esmeralda Perez and Elizabeth Ruzzo and Emily Singer and Matthews, {Emily T.} and Pedapati, {Ernest V.} and Faris Fazal and Miller, {Fiona K.} and Gabriella Aberbach and Gabriele Baraghoshi and Gabrielle Duhon and Gregory Hooks and Fischer, {Gregory J.} and Gabriela Marzano and Gregory Schoonover and Dichter, {Gabriel S.} and Gabrielle Tiede and Hannah Cottrell and Kaplan, {Hannah E.} and Haidar Ghina and Hanna Hutter and Hope Koene and Schneider, {Hoa Lam} and Holly Lechniak and Hai Li and Hadley Morotti and Hongjian Qi and Harper Richardson and Hana Zaydens and Haicang Zhang and Haoquan Zhao and Ivette Arriaga and Tso, {Ivy F.} and John Acampado and Gerdts, {Jennifer A.} and Josh Beeson and Jennylyn Brown and Joaquin Comitre",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

doi = "10.1038/s41588-022-01148-2",

language = "English",

volume = "54",

pages = "1305--1319",

journal = "Nature Genetics",

issn = "1061-4036",

number = "9",

}

TY - JOUR

T1 - Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

AU - the SPARK Consortium

AU - Zhou, Xueya

AU - Feliciano, Pamela

AU - Shu, Chang

AU - Wang, Tianyun

AU - Astrovskaya, Irina

AU - Hall, Jacob B.

AU - Obiajulu, Joseph U.

AU - Wright, Jessica R.

AU - Murali, Shwetha C.

AU - Xu, Simon Xuming

AU - Brueggeman, Leo

AU - Thomas, Taylor R.

AU - Marchenko, Olena

AU - Fleisch, Christopher

AU - Barns, Sarah D.

AU - Snyder, Lee Anne Green

AU - Han, Bing

AU - Chang, Timothy S.

AU - Turner, Tychele N.

AU - Harvey, William T.

AU - Nishida, Andrew

AU - O’Roak, Brian J.

AU - Geschwind, Daniel H.

AU - Adams, Adrienne

AU - Amatya, Alpha

AU - Andrus, Alicia

AU - Bashar, Asif

AU - Berman, Anna

AU - Brown, Alison

AU - Camba, Alexies

AU - Gulsrud, Amanda C.

AU - Krentz, Anthony D.

AU - Shocklee, Amanda D.

AU - Esler, Amy

AU - Lash, Alex E.

AU - Fanta, Anne

AU - Fatemi, Ali

AU - Fish, Angela

AU - Goler, Alexandra

AU - Gonzalez, Antonio

AU - Gutierrez, Anibal

AU - Hardan, Antonio

AU - Hess, Amy

AU - Hirshman, Anna

AU - Holbrook, Alison

AU - Ace, Andrea J.

AU - Griswold, Anthony J.

AU - Gruber, Angela J.

AU - Jarratt, Andrea

AU - Jelinek, Anna

AU - Jorgenson, Alissa

AU - Juarez, A. Pablo

AU - Kim, Annes

AU - Kitaygorodsky, Alex

AU - Luo, Addie

AU - Rachubinski, Angela L.

AU - Wainer, Allison L.

AU - Daniels, Amy M.

AU - Mankar, Anup

AU - Mason, Andrew

AU - Miceli, Alexandra

AU - Milliken, Anna

AU - Morales-Lara, Amy

AU - Stephens, Alexandra N.

AU - Nguyen, Ai Nhu

AU - Nicholson, Amy

AU - Paolicelli, Anna Marie

AU - McKenzie, Alexander P.

AU - Gupta, Abha R.

AU - Raven, Ashley

AU - Rhea, Anna

AU - Simon, Andrea

AU - Soucy, Aubrie

AU - Swanson, Amy

AU - Sziklay, Anthony

AU - Tallbull, Amber

AU - Tesng, Angela

AU - Ward, Audrey

AU - Zick, Allyson

AU - Hilscher, Brittani A.

AU - Bell, Brandi

AU - Enright, Barbara

AU - Robertson, Beverly E.

AU - Hauf, Brenda

AU - Jensen, Bill

AU - Lobisi, Brandon

AU - Vernoia, Brianna M.

AU - Schwind, Brady

AU - VanMetre, Bonnie

AU - Erickson, Craig A.

AU - Sullivan, Catherine A.W.

AU - Albright, Charles

AU - Anglo, Claudine

AU - Buescher, Cate

AU - Bradley, Catherine C.

AU - Campo-Soria, Claudia

AU - Cohen, Cheryl

AU - Colombi, Costanza

AU - Diggins, Chris

AU - Edmonson, Catherine

AU - Rice, Catherine E.

AU - Fassler, Carrie

AU - Gray, Catherine

AU - Gunter, Chris

AU - Walston, Corrie H.

AU - Klaiman, Cheryl

AU - Leonczyk, Caroline

AU - Martin, Christa Lese

AU - Lord, Catherine

AU - Taylor, Cora M.

AU - McCarthy, Caitlin

AU - Ochoa-Lubinoff, Cesar

AU - Ortiz, Crissy

AU - Pierre, Cynthia

AU - Rosenberg, Cordelia R.

AU - Rigby, Chris

AU - Roche, Casey

AU - Shrier, Clara

AU - Smith, Chris

AU - Van Wade, Candace

AU - White-Lehman, Casey

AU - Zaro, Christopher

AU - Zha, Cindy

AU - Bentley, Dawn

AU - Correa, Dahriana

AU - Sarver, Dustin E.

AU - Giancarla, David

AU - Amaral, David G.

AU - Howes, Dain

AU - Istephanous, Dalia

AU - Coury, Daniel Lee

AU - Li, Deana

AU - Limon, Danica

AU - Limpoco, Desi

AU - Phillips, Diamond

AU - Rambeck, Desiree

AU - Rojas, Daniela

AU - Srishyla, Diksha

AU - Stamps, Danielle

AU - Montes, Dennis Vasquez

AU - Cho, Daniel

AU - Cho, Dave

AU - Fox, Emily A.

AU - Bahl, Ethan

AU - Berry-Kravis, Elizabeth

AU - Blank, Elizabeth

AU - Bower, Erin

AU - Brooks, Elizabeth

AU - Courchesne, Eric

AU - Dillon, Emily

AU - Doyle, Erin

AU - Given, Erin

AU - Grimes, Ellen

AU - Jones, Erica

AU - Fombonne, Eric J.

AU - Kryszak, Elizabeth

AU - Wodka, Ericka L.

AU - Lamarche, Elena

AU - Lampert, Erica

AU - Butter, Eric M.

AU - O’Connor, Eirene

AU - Ocampo, Edith

AU - Orrick, Elizabeth

AU - Perez, Esmeralda

AU - Ruzzo, Elizabeth

AU - Singer, Emily

AU - Matthews, Emily T.

AU - Pedapati, Ernest V.

AU - Fazal, Faris

AU - Miller, Fiona K.

AU - Aberbach, Gabriella

AU - Baraghoshi, Gabriele

AU - Duhon, Gabrielle

AU - Hooks, Gregory

AU - Fischer, Gregory J.

AU - Marzano, Gabriela

AU - Schoonover, Gregory

AU - Dichter, Gabriel S.

AU - Tiede, Gabrielle

AU - Cottrell, Hannah

AU - Kaplan, Hannah E.

AU - Ghina, Haidar

AU - Hutter, Hanna

AU - Koene, Hope

AU - Schneider, Hoa Lam

AU - Lechniak, Holly

AU - Li, Hai

AU - Morotti, Hadley

AU - Qi, Hongjian

AU - Richardson, Harper

AU - Zaydens, Hana

AU - Zhang, Haicang

AU - Zhao, Haoquan

AU - Arriaga, Ivette

AU - Tso, Ivy F.

AU - Acampado, John

AU - Gerdts, Jennifer A.

AU - Beeson, Josh

AU - Brown, Jennylyn

AU - Comitre, Joaquin

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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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U2 - 10.1038/s41588-022-01148-2

DO - 10.1038/s41588-022-01148-2

M3 - Article

C2 - 35982159

AN - SCOPUS:85136297829

SN - 1061-4036

VL - 54

SP - 1305

EP - 1319

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

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