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 | |
| State | Published - Sep 2022 |
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Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. / the SPARK Consortium.
In: Nature Genetics, Vol. 54, No. 9, 09.2022, p. 1305-1319.Research output: Contribution to journal › Article › peer-review
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
N1 - Funding Information: We are extremely grateful to the thousands of individuals and families who are participating in this study. We thank the sites, staff and volunteers of the SPARK Clinical Site Network and SFARI for their invaluable contributions. We are grateful to the many ASD advocacy and service organizations that have helped us inform the community about SPARK, including the Autism Society of America and its affiliates, the Global and Regional Autism Spectrum Partnership (GRASP), Autism Speaks, and the Autism Science Foundation. We thank the members of SPARK’s Community Advisory Council for providing feedback and advice. We thank members of our Scientific Advisory Board and SFARI scientists for advice on our protocol and participant outreach and retention strategies. Our de novo analyses involved primary data from SSC and results from published ASD studies, including ASC and MSSNG, and our case-control analysis used published population controls from gnomAD (exome v2.1.1, non-neuro subset) and TOPMed (WGS, freeze 8). Approved researchers can obtain the SPARK population dataset described in this study by applying at https://base.sfari.org . The SPARK initiative is funded by the Simons Foundation as part of SFARI. This research was supported, in part, by a grant from the National Institute of Mental Health (NIMH R01MH101221) and grants from the Simons Foundation (SFARI nos. 608045 and 810018EE) to E.E.E., a grant from the National Institutes of Health (NIH R01GM120609) and from the Simons Foundation (SFARI no. 606450) to Y.S., a grant from the Simons Foundation (SFARI no. 644038) to B.J.O. and J.J.M., a grant from the National Institute of Mental Health to T.N.T. (NIMH 1K99MH117165), and grants MH105527 and DC014489 from the National Institute of Health to J.J.M. E.E.E. is an investigator of the Howard Hughes Medical Institute. Funding Information: We are extremely grateful to the thousands of individuals and families who are participating in this study. We thank the sites, staff and volunteers of the SPARK Clinical Site Network and SFARI for their invaluable contributions. We are grateful to the many ASD advocacy and service organizations that have helped us inform the community about SPARK, including the Autism Society of America and its affiliates, the Global and Regional Autism Spectrum Partnership (GRASP), Autism Speaks, and the Autism Science Foundation. We thank the members of SPARK’s Community Advisory Council for providing feedback and advice. We thank members of our Scientific Advisory Board and SFARI scientists for advice on our protocol and participant outreach and retention strategies. Our de novo analyses involved primary data from SSC and results from published ASD studies, including ASC and MSSNG, and our case-control analysis used published population controls from gnomAD (exome v2.1.1, non-neuro subset) and TOPMed (WGS, freeze 8). Approved researchers can obtain the SPARK population dataset described in this study by applying at https://base.sfari.org. The SPARK initiative is funded by the Simons Foundation as part of SFARI. This research was supported, in part, by a grant from the National Institute of Mental Health (NIMH R01MH101221) and grants from the Simons Foundation (SFARI nos. 608045 and 810018EE) to E.E.E., a grant from the National Institutes of Health (NIH R01GM120609) and from the Simons Foundation (SFARI no. 606450) to Y.S., a grant from the Simons Foundation (SFARI no. 644038) to B.J.O. and J.J.M., a grant from the National Institute of Mental Health to T.N.T. (NIMH 1K99MH117165), and grants MH105527 and DC014489 from the National Institute of Health to J.J.M. E.E.E. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: © 2022, The Author(s).
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.
UR - http://www.scopus.com/inward/record.url?scp=85136297829&partnerID=8YFLogxK
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 -