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Nat Genet DOI:10.1038/s41588-022-01104-0

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

Publication TypeJournal Article
Year of Publication2022
AuthorsFu, JM, F Satterstrom, K, 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, H Y Chung, B, Cook, EH, Cuccaro, ML, Domenici, E, Ferrero, GBattista, J Gargus, J, Herman, GE, Hertz-Picciotto, I, Maciel, P, Manoach, DS, Passos-Bueno, MRita, Persico, AM, Renieri, A, Sutcliffe, JS, Tassone, F, Trabetti, E, Campos, G, Cardaropoli, S, Carli, D, C Y Chan, M, Fallerini, C, Giorgio, E, Girardi, ACristina, Hansen-Kiss, E, Lee, SLun, 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, Cutler, DJ, De Rubeis, S, Buxbaum, JD, Daly, MJ, Devlin, B, Roeder, K, Sanders, SJ, Talkowski, ME
Corporate AuthorsAutism Sequencing Consortium (ASC), Broad Institute Center for Common Disease Genomics (Broad-CCDG), iPSYCH-Broad Consortium
JournalNat Genet
Date Published2022 Aug 18
ISSN1546-1718
Abstract

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.

DOI10.1038/s41588-022-01104-0
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35982160?dopt=Abstract

Alternate JournalNat Genet
PubMed ID35982160
Grant List573206 / / Simons Foundation /
606362 / / Simons Foundation /
608540 / / Simons Foundation /
606362 / / Simons Foundation /
608540 / / Simons Foundation /
573206 / / Simons Foundation /
608540 / / Simons Foundation /
606362 / / Simons Foundation /
608540 / / Simons Foundation /
575097 / / Simons Foundation /
575097 / / Simons Foundation /
606362 / / Simons Foundation /
608540 / / Simons Foundation /
574598 / / Simons Foundation /
606362 / / Simons Foundation /
608540 / / Simons Foundation /
647371 / / Simons Foundation /
MH115957 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
MH111661 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
MH100233 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
MH111660 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
MH057881 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
MH109900 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
MH100027 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
HG008895 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /
HG008895 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /
HG008895 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /
HD081256 / / U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) /
11852 / / Autism Speaks (Autism Speaks Inc.) /
2017240332 / / National Science Foundation (NSF) /