- Main
Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
- Zhou, Xueya;
- Feliciano, Pamela;
- Shu, Chang;
- Wang, Tianyun;
- Astrovskaya, Irina;
- Hall, Jacob B;
- Obiajulu, Joseph U;
- Wright, Jessica R;
- Murali, Shwetha C;
- Xu, Simon Xuming;
- Brueggeman, Leo;
- Thomas, Taylor R;
- Marchenko, Olena;
- Fleisch, Christopher;
- Barns, Sarah D;
- Snyder, LeeAnne Green;
- Han, Bing;
- Chang, Timothy S;
- Turner, Tychele N;
- Harvey, William T;
- Nishida, Andrew;
- O’Roak, Brian J;
- Geschwind, Daniel H;
- Michaelson, Jacob J;
- Volfovsky, Natalia;
- Eichler, Evan E;
- Shen, Yufeng;
- Chung, Wendy K
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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