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

Jack Fu (1, 2) , F. Kyle Satterstrom (2, 1) , Minshi Peng (3) , Harrison Brand (2, 1) , Ryan Collins (4, 2, 1) , Shan Dong (5) , Brie Wamsley (6) , Lambertus Klei (7) , Lily Wang (2, 4) , Stephanie Hao (2, 1) , Christine Stevens (2, 1) , Caroline Cusick (2) , Mehrtash Babadi (2) , Eric Banks (2) , Brett Collins (8) , Sheila Dodge (2) , Stacey Gabriel (2) , Laura Gauthier (2) , Samuel Lee (2) , Lindsay Liang (5) , Alicia Ljungdahl (5) , Behrang Mahjani (8) , Laura Sloofman (8) , Andrey Smirnov (2) , Mafalda Barbosa (8) , Catalina Betancur (9) , Alfredo Brusco (10, 11) , Brian Chung (12) , Edwin Cook (13) , Michael Cuccaro (14) , Enrico Domenici (15) , Giovanni Battista Ferrero (10) , J. Jay Gargus (16) , Gail Herman (17) , Irva Hertz-Picciotto (18) , Patricia Maciel (19) , Dara Manoach (20) , Maria Rita Passos-Bueno (21) , Antonio Persico (22) , Alessandra Renieri (23, 24) , James Sutcliffe (25, 26) , Flora Tassone (18) , Elisabetta Trabetti (27) , Gabriele Campos (21) , Simona Cardaropoli (10) , Diana Carli (10) , Marcus Chan (12) , Chiara Fallerini (23) , Elisa Giorgio (10) , Ana Cristina Girardi (21) , Emily Hansen-Kiss (28) , So Lun Lee (12) , Carla Lintas (29) , Yunin Ludena (18) , Rachel Nguyen (16) , Lisa Pavinato (10) , Margaret Pericak-Vance (14) , Isaac Pessah (18) , Rebecca Schmidt (18) , Moyra Smith (16) , Claudia Costa (21) , Slavica Trajkova (10) , Jaqueline Wang (21) , Mullin Yu (12) , David Cutler (30) , Silvia de Rubeis (8) , Joseph Buxbaum (8) , Mark Daly (1, 2, 4, 31) , Bernie Devlin (7) , Kathryn Roeder (3) , Stephan Sanders (5) , Michael Talkowski (1)

1 Massachusetts General Hospital [Boston]
2 BROAD INSTITUTE - Broad Institute of MIT and Harvard
3 CMU - Carnegie Mellon University [Pittsburgh]
4 HMS - Harvard Medical School [Boston]
5 UC San Francisco - University of California [San Francisco]
6 UCLA - University of California [Los Angeles]
7 University of Pittsburgh School of Medicine
8 MSSM - Icahn School of Medicine at Mount Sinai [New York]
9 NPS - Neuroscience Paris Seine
10 UNITO - Università degli studi di Torino = University of Turin
11 Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino
12 HKU - The University of Hong Kong
13 UIC - University of Illinois [Chicago]
14 UMMSM - University of Miami Leonard M. Miller School of Medicine
15 UNITN - Università degli Studi di Trento = University of Trento
16 UC Irvine - University of California [Irvine]
17 Nationwide Children's Hospital
18 UC Davis - University of California [Davis]
19 Universidade do Minho = University of Minho [Braga]
20 Massachusetts General Hospital [Boston, MA, USA]
21 Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
22 UniMe - Università degli Studi di Messina = University of Messina
23 UNISI - Università degli Studi di Siena = University of Siena
24 Azienda Ospedaliera Universitaria Senese
25 Vanderbilt University [Nashville]
26 Vanderbilt University School of Medicine [Nashville]
27 UNIVR - Università degli studi di Verona = University of Verona
28 University of Texas Health Science Center
29 UCBM - Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome
30 Emory University School of Medicine
31 Helsingin yliopisto = Helsingfors universitet = University of Helsinki

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.

Domaines: Génétique humaine; Neurobiologie

Jack Fu, F. Kyle Satterstrom, Minshi Peng, Harrison Brand, Ryan Collins, et al.. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nature Genetics, 2022, 54 (9), pp.1320-1331. ⟨10.1038/s41588-022-01104-0⟩. ⟨inserm-03949950⟩