Identification of common genetic risk variants for autism spectrum disorder

作者：Jakob Grove, BUPGEN, Stephan Ripke, Thomas D. Als, Manuel Mattheisen, Raymond K. Walters, Hyejung Won, Jonatan Pallesen, Esben Agerbo, Ole A. Andreassen, Richard Anney, Swapnil Awashti, Rich Belliveau, Francesco Bettella, Joseph D. Buxbaum, Jonas Bybjerg‐Grauholm, Marie Bækvad‐Hansen, Felecia Cerrato, Kimberly Chambert, Jane Christensen, Claire Churchhouse, Karin Dellenvall, Ditte Demontis, Silvia De Rubeis, Bernie Devlin, Srdjan Djurovic, Ashley Dumont, Jacqueline I. Goldstein, Christine Søholm Hansen, Mads E. Hauberg, Mads V. Hollegaard, Sigrun Hope, Daniel P. Howrigan, Hailiang Huang, Christina M. Hultman, Lambertus Klei, Julian Maller, Joanna Martin, Alicia R. Martin, Jennifer L. Moran, Mette Nyegaard, Terje Nærland, Duncan S. Palmer, Aarno Palotie, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy dPoterba, Jesper Buchhave Poulsen, Beaté St Pourcain, Per Qvist, Karola Rehnström, Abraham Reichenberg, Jennifer Reichert, Elise Robinson, Kathryn Roeder, Panos Roussos, Evald Sæmundsen, Sven Sandin, F. Kyle Satterstrom, George Davey Smith, Hreinn Stefánsson, Stacy Steinberg, Christine Stevens, Patrick F. Sullivan, Patrick Turley, G. Bragi Walters, Xinyi Xu, Kāri Stefánsson, Daniel H. Geschwind, Merete Nordentoft, David M. Hougaard, Thomas Werge, Ole Mors, Preben Bo Mortensen, Benjamin M. Neale, Mark J. Daly, Anders D. Børglum · 发表于：Nature Genetics · 年份：2019 · DOI：10.1038/s41588-019-0344-8 · 被引用次数：2709 · 研究领域：Genetic Associations and Epidemiology、Autism Spectrum Disorder Research、Genomic variations and chromosomal abnormalities

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD. A genome-wide-association meta-analysis of 18,381 austim spectrum disorder (ASD) cases and 27,969 controls identifies five risk loci. The authors find quantitative and qualitative polygenic heterogeneity across ASD subtypes.