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

• Published in: Nature genetics Vol. 54; no. 9; pp. 1305 - 1319
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2022; Nature Publishing Group
• Subjects: 631/208/366/1373; 631/208/514; 631/378; ADNP protein; Agriculture; Animal Genetics and Genomics; Autism; Autism Spectrum Disorder - genetics; Autistic Disorder - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cognitive ability; Exome - genetics; Exome Sequencing; Forkhead Transcription Factors - genetics; Foxp1 protein; Gene Function; Genes; Genetic Predisposition to Disease; Genomes; Human Genetics; Humans; Intellectual disabilities; Mutation; Protein-serine/threonine kinase; Repressor Proteins - genetics; Risk
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-022-01148-2

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.
An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.