Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
Fu JM., Satterstrom FK., Peng M., Brand H., Collins RL., Dong S., Wamsley B., Klei L., Wang L., Hao SP., Stevens CR., Cusick C., Babadi M., Banks E., Collins B., Dodge S., Gabriel SB., Gauthier L., Lee SK., Liang L., Ljungdahl A., Mahjani B., Sloofman L., Smirnov AN., Barbosa M., Betancur C., Brusco A., Chung BHY., Cook EH., Cuccaro ML., Domenici E., Ferrero GB., Gargus JJ., Herman GE., Hertz-Picciotto I., Maciel P., Manoach DS., Passos-Bueno MR., Persico AM., Renieri A., Sutcliffe JS., Tassone F., Trabetti E., Campos G., Cardaropoli S., Carli D., Chan MCY., Fallerini C., Giorgio E., Girardi AC., Hansen-Kiss E., Lee SL., Lintas C., Ludena Y., Nguyen R., Pavinato L., Pericak-Vance M., Pessah IN., Schmidt RJ., Smith M., Costa CIS., Trajkova S., Wang JYT., Yu MHC., Aleksic B., Artomov M., Benetti E., Biscaldi-Schafer M., Børglum AD., Carracedo A., Chiocchetti AG., Coon H., Doan RN., Fernández-Prieto M., Freitag CM., Gerges S., Guter S., Hougaard DM., Hultman CM., Jacob S., Kaartinen M., Kolevzon A., Kushima I., Lehtimäki T., Rizzo CL., 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 SW., Schlitt S.
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.