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 - Shulman, Lisa H.
AU - Valicenti-McDermott, Maria
N1 - 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.
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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 -