Genomic architecture of Autism Spectrum Disorder from comprehensive whole-genome sequence annotation
Authors: Trost Brett , Thiruvahindrapuram Bhooma , Chan Ada J.S. , Engchuan Worrawat , Higginbotham Edward J. , Howe Jennifer L. , Loureiro Livia O. , Reuter Miriam S. , Roshandel Delnaz , Whitney Joe , Zarrei Mehdi , Bookman Matthew , Somerville Cherith , Shaath Rulan , Abdi Mona , Aliyev Elbay , Patel Rohan V. , Nalpathamkalam Thomas , Pellecchia Giovanna , Hamdan Omar , Kaur Gaganjot , Wang Zhuozhi , MacDonald Jeffrey R. , Wei John , Sung Wilson W.L. , Lamoureux Sylvia , Hoang Ny , Selvanayagam Thanuja , Deflaux Nicole , Geng Melissa , Ghaffari Siavash , Bates John , Young Edwin J. , Ding Qiliang , Shum Carole , D’abate Lia , Bradley Clarissa A. , Rutherford Annabel , Aguda Vernie , Apresto Beverly , Chen Nan , Desai Sachin , Du Xiaoyan , Fong Matthew L.Y. , Pullenayegum Sanjeev , Samler Kozue , Wang Ting , Ho Karen , Paton Tara , Pereira Sergio L. , Herbrick Jo-Anne , Wintle Richard F. , Fuerth Jonathan , Noppornpitak Juti , Ward Heather , Magee Patrick , Baz Ayman Al , Kajendirarajah Usanthan , Kapadia Sharvari , Vlasblom Jim , Valluri Monica , Green Joseph , Seifer Vicki , Quirbach Morgan , Rennie Olivia , Kelley Elizabeth , Masjedi Nina , Lord Catherine , Szego Michael J. , Zawati Ma’n H. , Lang Michael , Strug Lisa J. , Marshall Christian R. , Costain Gregory , Calli Kristina , Iaboni Alana , Yusuf Afiqah , Ambrozewicz Patricia , Gallagher Louise , Amaral David G. , Brian Jessica , Elsabbagh Mayada , Georgiades Stelios , Messinger Daniel S. , Ozonoff Sally , Sebat Jonathan , Sjaarda Calvin , Smith Isabel M. , Szatmari Peter , Zwaigenbaum Lonnie , Kushki Azadeh , Frazier Thomas W. , Vorstman Jacob A.S. , Fakhro Khalid A. , Fernandez Bridget A. , Lewis M.E. Suzanne , Weksberg Rosanna , Fiume Marc , Yuen Ryan K.C. , Anagnostou Evdokia , Sondheimer Neal , Glazer David , Hartley Dean M. , Scherer Stephen W. 
Published: May 2022

Fully understanding the genetic factors involved in Autism Spectrum Disorder (ASD) requires whole-genome sequencing (WGS), which theoretically allows the detection of all types of genetic variants. With the aim of generating an unprecedented resource for resolving the genomic architecture underlying ASD, we analyzed genome sequences and phenotypic data from 5,100 individuals with ASD and 6,212 additional parents and siblings (total n=11,312) in the Autism Speaks MSSNG Project, as well as additional individuals from other WGS cohorts. WGS data and autism phenotyping were based on high-quality short-read sequencing (>30x coverage) and clinically accepted diagnostic measures for ASD, respectively. For initial discovery of ASD-associated genes, we used exonic sequence-level variants from MSSNG as well as whole-exome sequencing-based ASD data from SPARK and the Autism Sequencing Consortium (>18,000 trios plus additional cases and controls), identifying 135 ASD-associated protein-coding genes with false discovery rate <10%. Combined with ASD-associated genes curated from the literature, this list was used to guide the interpretation of all other variant types in WGS data from MSSNG and the Simons Simplex Collection (SSC; n=9,205). We identified ASD-associated rare variants in 789/5,100 individuals with ASD from MSSNG (15%) and 421/2,419 from SSC (17%). Considering the genomic architecture, 57% of ASD-associated rare variants were nuclear sequence-level variants, 41% were nuclear structural variants (SVs) (mainly copy number variants, but also including inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Several of the ASD-associated SVs would have been difficult to detect without WGS, including an inversion disrupting SCN2A and a nuclear mitochondrial insertion impacting SYNGAP1. Polygenic risk scores did not differ between children with ASD in multiplex families versus simplex, and rare, damaging recessive events were significantly depleted in multiplex families, collectively suggesting that rare, dominant variation plays a predominant role in multiplex ASD. Our study provides a guidebook for exploring genotype-phenotype correlations in the 15-20% of ASD families who carry ASD-associated rare variants, as well as an entry point to the larger and more diverse studies that will be required to dissect the etiology in the >80% of the ASD population that remains idiopathic. All data resulting from this study are available to the medical genomics research community in an open but protected manner.