Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes

The SPARK Consortium, Sunday Francis

Research output: Contribution to journalArticlepeer-review

101 Scopus citations


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.

Original languageEnglish (US)
Article number19
Journalnpj Genomic Medicine
Issue number1
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
We are extremely grateful to the thousands of individuals and families who are participating in this study. We are grateful to the many ASD advocacy and service organizations that have helped us inform the community about SPARK, including the Autism Society of America and its affiliates, Autism Speaks, Autism Science Foundation, Easter Seals, Arkansas Autism Resource and Outreach Center, Global and Regional Asperger’s Syndrome Partnership, Kentucky Autism Training Center, and Autistic Self Advocacy Network. We thank the members of SPARK’s Community Advisory Council for providing feedback and advice. We thank members of our Scientific and Community Advisory Board and SFARI scientists for advice on our protocol and participant outreach and retention strategies. We thank PreventionGenetics for managing and processing biospecimens, DNA Genotek for handling saliva kit logistics, and Baylor College of Medicine Human Genome Sequencing Center for exome sequencing. The SPARK initiative is funded by the Simons Foundation as part of SFARI. This research was supported, in part, by a grant from the National Institute of Mental Health (NIMH R01MH101221) and a grant from the Simons Foundation (SFARI #608045) to E.E.E., a grant from the National Institute of Mental Health to T.N.T. (1K99MH117165) and grants MH105527 and DC014489 from the National Institute of Health to L.B. and J.J.M. E.E.E. is an investigator of the Howard Hughes Medical Institute. B.J.O. is a Klingenstein-Simons Fellow (Esther A. & Joseph Klingenstein Fund, Simons Foundation).

Publisher Copyright:
© 2019, The Author(s).


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