TY - JOUR
T1 - Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
AU - The Autism Sequencing Consortium (ASC)
AU - Broad Institute Center for Common Disease Genomics (Broad-CCDG)
AU - iPSYCH-Broad Consortium
AU - Fu, Jack M.
AU - Satterstrom, F. Kyle
AU - Peng, Minshi
AU - Brand, Harrison
AU - Collins, Ryan L.
AU - Dong, Shan
AU - Wamsley, Brie
AU - Klei, Lambertus
AU - Wang, Lily
AU - Hao, Stephanie P.
AU - Stevens, Christine R.
AU - Cusick, Caroline
AU - Babadi, Mehrtash
AU - Banks, Eric
AU - Collins, Brett
AU - Dodge, Sheila
AU - Gabriel, Stacey B.
AU - Gauthier, Laura
AU - Lee, Samuel K.
AU - Liang, Lindsay
AU - Ljungdahl, Alicia
AU - Mahjani, Behrang
AU - Sloofman, Laura
AU - Smirnov, Andrey N.
AU - Barbosa, Mafalda
AU - Betancur, Catalina
AU - Brusco, Alfredo
AU - Chung, Brian H.Y.
AU - Cook, Edwin H.
AU - Cuccaro, Michael L.
AU - Domenici, Enrico
AU - Ferrero, Giovanni Battista
AU - Gargus, J. Jay
AU - Herman, Gail E.
AU - Hertz-Picciotto, Irva
AU - Maciel, Patricia
AU - Manoach, Dara S.
AU - Passos-Bueno, Maria Rita
AU - Persico, Antonio M.
AU - Renieri, Alessandra
AU - Sutcliffe, James S.
AU - Tassone, Flora
AU - Trabetti, Elisabetta
AU - Campos, Gabriele
AU - Cardaropoli, Simona
AU - Kolevzon, Alexander
AU - Reichenberg, Abraham
AU - Sandin, Sven
AU - De Rubeis, Silvia
AU - Buxbaum, Joseph D.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85136292014&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01104-0
DO - 10.1038/s41588-022-01104-0
M3 - Article
C2 - 35982160
AN - SCOPUS:85136292014
SN - 1061-4036
VL - 54
SP - 1320
EP - 1331
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -