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PgmNr 142: Insights into the genetic architecture of autism from exome and genome sequencing of over 60,000 individuals.

Authors:
F.K. Satterstrom 1,2,3,4,22; J. Fu 3,4,5,22; H. Brand 3,4,5,22; J.A. Kosmicki 1,2,3,4,6,22; H. Wang 3,4; X. Zhao 3,4,5; R.L. Collins 3,4,6; M.S. Breen 7,8,9; S. De Rubeis 7,8,9; C.E. Carey 1,2,3,4; C. Stevens 1,3; C. Cusick 1,3; E.B. Robinson 1,2,3,4,10; A.D. Børglum 11,12,13; D.J. Cutler 14; J.D. Buxbaum 7,8,9,15,16,17; K. Roeder 18; B. Devlin 19,23; S.J. Sanders 20,23; M.J. Daly 1,2,3,4,6,21,23; M.E. Talkowski 1,3,4,5,6,23; Autism Sequencing Consortium

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Affiliations:
1) Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; 2) Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; 3) Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; 4) Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; 5) Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; 6) Division of Medical Sciences, Harvard Medical School, Boston, MA, USA; 7) Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 8) Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 9) Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 10) Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 11) The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; 12) iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark; 13) Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark; 14) Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA; 15) Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 16) Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 17) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 18) Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA; 19) Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 20) Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; 21) Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; 22) These authors contributed equally; 23) These authors also contributed equally


The genetic architecture of autism spectrum disorder (ASD) includes a well-established etiological role for rare and de novo protein-truncating variants (PTVs) in genes highly intolerant of such variation, as well as an increased burden of large copy number variants (CNVs). Here, we present the largest-ever analysis of rare and de novo variation in ASD by combining whole-exome sequencing (WES) from over 60,000 individuals (19,028 ASD cases, 14,031 unaffected siblings and controls, and parents) and whole-genome sequencing (WGS) of 10,049 genomes from 2,669 ASD families, including samples from the Autism Sequencing Consortium, the Simons Simplex Collection, SPARK, and the Danish iPSYCH study. Analyses restricted to de novo coding single nucleotide variants (SNVs) and indels conservatively identified 31 genes associated with ASD at a Bonferroni-corrected threshold, while a Bayesian framework that combines de novo and rare case-control SNVs and indels discovered 125 genes associated with ASD at a false discovery rate less than 0.1.

We further processed these WES data for rare and de novo CNVs using our recently developed GATK-gCNV algorithm, which is well-calibrated to detect CNVs of ≥5 exons when compared against microarray and WGS (sensitivity >99.7%; positive predictive value >90%). As expected, these analyses identified a higher proportion of large de novo coding CNVs in probands (5.6%) than in unaffected siblings (2.3%; p<2.2e-16), and more exons were affected by de novo CNVs in probands than in siblings (p=1.1e-3). When we considered the 125 genes identified in the Bayesian framework above, 13 were localized to recurrent genomic disorder (GD) segments (e.g. 16p11.2). De novo deletions within established GD regions were enriched for paternal origin across all loci but one: 16p11.2, in which de novo CNVs displayed a 95% bias for maternal origin (p=4.1e-10). Within the 112 genes not localized to GD regions, we observed strong enrichment of de novo CNVs in probands (86 in 11,598 individuals) compared to siblings (1 in 4,547 individuals), supporting the predicted role of these loci in ASD. Finally, WGS analyses of the initial 7,608 genomes revealed an association of ASD with de novo variants in conserved promoter regions, with analyses of the full cohort ongoing. These studies suggest that integrated analyses of all classes of genomic variation can provide novel insights into ASD.