1. Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
- Author
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Pamela Feliciano, Xueya Zhou, Irina Astrovskaya, Tychele N. Turner, Tianyun Wang, Leo Brueggeman, Rebecca Barnard, Alexander Hsieh, LeeAnne Green Snyder, Donna M. Muzny, Aniko Sabo, The SPARK Consortium, Richard A. Gibbs, Evan E. Eichler, Brian J. O’Roak, Jacob J. Michaelson, Natalia Volfovsky, Yufeng Shen, and Wendy K. Chung
- Subjects
0301 basic medicine ,medicine.medical_specialty ,lcsh:QH426-470 ,Intellectual and Developmental Disabilities (IDD) ,Autism ,lcsh:Medicine ,Biology ,behavioral disciplines and activities ,Article ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,mental disorders ,Genetics ,medicine ,SPARK Consortium ,2.1 Biological and endogenous factors ,Spectrum disorder ,Genetic Testing ,Copy-number variation ,Aetiology ,Molecular Biology ,Genotyping ,Genetics (clinical) ,Exome sequencing ,Pediatric ,Genetic heterogeneity ,Prevention ,Human Genome ,lcsh:R ,Autism spectrum disorders ,medicine.disease ,Brain Disorders ,3. Good health ,lcsh:Genetics ,Mental Health ,030104 developmental biology ,Autism spectrum disorder ,030220 oncology & carcinogenesis ,Behavioural genetics ,Medical genetics ,Medical genomics ,Biotechnology - Abstract
Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. In addition, we identified variants that are possibly associated with ASD in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.1 provides statistical support for 26 ASD risk genes. While most of these genes are already known ASD risk genes, BRSK2 has the strongest statistical support and reaches genome-wide significance as a risk gene for ASD (p-value = 2.3e−06). Future studies leveraging the thousands of individuals with ASD who have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate ASD research that incorporates genetic etiology.
- Published
- 2019