Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

J. M., Fu; Satterstrom, F. K.; Peng, M.; Brand, H.; Collins, R. L.; Dong, S.; Wamsley, B.; Klei, L.; Wang, L.; Hao, S. P.; Stevens, C. R.; Cusick, C.; Babadi, M.; Banks, E.; Collins, B.; Dodge, S.; Gabriel, S. B.; Gauthier, L.; Lee, S. K.; Liang, L.; Ljungdahl, A.; Mahjani, B.; Sloofman, L.; Smirnov, A. N.; Barbosa, M.; Betancur, C.; Brusco, A.; Chung, B. H. Y.; Cook, E. H.; Cuccaro, M. L.; Domenici, E.; Ferrero, G. B.; Gargus, J. J.; Herman, G. E.; Hertz-Picciotto, I.; Maciel, P.; Manoach, D. S.; Passos-Bueno, M. R.; Persico, A. M.; Renieri, A.; Sutcliffe, J. S.; Tassone, F.; Trabetti, E.; Campos, G.; Cardaropoli, S.; Carli, D.; Chan, M. C. Y.; Fallerini, C.; Giorgio, E.; Girardi, A. C.; Hansen-Kiss, E.; Lee, S. L.; Lintas, C.; Ludena, Y.; Nguyen, R.; Pavinato, L.; Pericak-Vance, M.; Pessah, I. N.; Schmidt, R. J.; Smith, M.; Costa, C. I. S.; Trajkova, S.; Wang, J. Y. T.; M. H. C., Yu; Aleksic, B.; Artomov, M.; Benetti, E.; Biscaldi-Schafer, M.; Borglum, A. D.; Carracedo, A.; Chiocchetti, A. G.; Coon, H.; Doan, R. N.; Fernandez-Prieto, M.; Freitag, C. M.; Gerges, S.; Guter, S.; Hougaard, D. M.; Hultman, C. M.; Jacob, S.; Kaartinen, M.; Kolevzon, A.; Kushima, I.; Lehtimaki, T.; Rizzo, C. L.; Maltman, N.; Manara, M.; Meiri, G.; Menashe, I.; Miller, J.; Minshew, N.; Mosconi, M.; Ozaki, N.; Palotie, A.; Parellada, M.; Puura, K.; Reichenberg, A.; Sandin, S.; Scherer, S. W.; Schlitt, S.; Schmitt, L.; Schneider-Momm, K.; Siper, P. M.; Suren, P.; Sweeney, J. A.; Teufel, K.; del Pilar Trelles, M.; Weiss, L. A.; Yuen, R.; Cutler, D. J.; De Rubeis, S.; Buxbaum, J. D.; Daly, M. J.; Devlin, B.; Roeder, K.; Sanders, S. J.; Talkowski, M. E.

doi:10.1038/s41588-022-01104-0

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) <= 0.001 (185 at FDR <= 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR <= 0.001 (664 at FDR <= 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.