Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

Ileena Mitra, Alinoë Lavillaureix, Erika Yeh, Michela Traglia, Kathryn Tsang, Carrie E. Bearden, Katherine A Rauen, Lauren A. Weiss

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.

Original languageEnglish (US)
Article numbere1006516
JournalPLoS Genetics
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Mitra, I., Lavillaureix, A., Yeh, E., Traglia, M., Tsang, K., Bearden, C. E., Rauen, K. A., & Weiss, L. A. (2017). Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders. PLoS Genetics, 13(1), [e1006516]. https://doi.org/10.1371/journal.pgen.1006516