![]() In stage 1, we analyzed DNVs in 16,877 ASD trios and assessed transmission of rare LoF variants from 20,491 parents without ASD diagnoses or intellectual disability to offspring with ASD (including 9,504 trios and 2,966 single-parent-proband duos). We aggregated exome or whole genome sequencing (WGS) data of 35,130 new cases from SPARK and 7,665 cases from published ASD studies (ASC 3, 8, MSSNG 6 and SSC 2, 30) (Supplementary Table 1) and performed a two-stage analysis (Fig. Finally, we estimated the effect sizes of known and newly identified genes and conducted power calculations to inform the design of future studies. By combining evidence from DNVs, transmission disequilibrium tests (TDTs) and case-control comparisons, we identified 60 ASD risk genes with exome-wide significance, including five new genes not previously implicated in NDDs. Results from the first stage informed the second stage meta-analysis of 404 genes. In our two-stage design, we first characterized the contribution of DNVs and rare inherited LoF variants to ASD risk. Here, we present an integrated analysis of de novo and inherited coding variants in over 42,607 ASD cases, including cases from previously published ASD cohorts and 35,130 new cases from SPARK. ![]() Methods to distinguish between high-confidence and low-confidence LoF variants 18, 26, 27 have been used to quantify gene-level LoF intolerance 18, 26, 28, 29 and to refine the role of LoF DNVs in NDDs 20. Rare LoF variants are enriched in developmental disorders including ASD 22, 24, but may also result from sequencing and annotation artifacts 25 and present technical challenges in large sequencing studies. We have established the largest ASD cohort, Simons Foundation Powering Autism Research for Knowledge (SPARK) 23, which currently includes over 100,000 people with ASD, to advance research on the genetic, behavioral and clinical features associated with ASD. ![]() However, identification of the individual risk genes enriched by such inherited variants has remained elusive. Rare LoF variants in genes intolerant of variation 9, 18 are overtransmitted to probands compared with siblings without ASD 7, 8, 19, 20, 21, 22. ASD is highly heritable 14, 15, 16, and previous studies estimated that common variants explain up to half of the heritability 14, although only five genome-wide significant loci have been identified 17. However, despite the large effect size of individual pathogenic DNVs, all DNVs combined explain only ~2% of variance in liability for ASD 8, 14. Statistical modeling suggests that there are ~1,000 genes with DNVs in ASD 12, 13. Over 100 high-confidence ASD genes enriched with likely deleterious DNVs have been identified 8, most of which are also enriched for DNVs in other neurodevelopmental disorders (NDDs) 9, 10, 11. Many previous genetic studies in autism spectrum disorder (ASD), a neurodevelopmental condition characterized by social communication difficulties and repetitive behaviors 1, focused on de novo variants (DNVs) identified from parent–offspring trios 2, 3, 4, 5, 6, 7, 8. Nature Genetics volume 54, pages 1305–1319 ( 2022) Cite this article
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