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

14 Citations (Scopus)

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

Fingerprint

epistasis
Reverse Genetics
gene
genome
Genome
Genes
Genome-Wide Association Study
genes
signs and symptoms (animals and humans)
Single Nucleotide Polymorphism
modifiers (genes)
gene interaction
Autism Spectrum Disorder
autism
neurons
cell lines
Observation
Cell Line
organisms

ASJC Scopus subject areas

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

Cite this

Mitra, I., Lavillaureix, A., Yeh, E., Traglia, M., Tsang, K., Bearden, C. E., ... 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

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders. / Mitra, Ileena; Lavillaureix, Alinoë; Yeh, Erika; Traglia, Michela; Tsang, Kathryn; Bearden, Carrie E.; Rauen, Katherine A; Weiss, Lauren A.

In: PLoS Genetics, Vol. 13, No. 1, e1006516, 01.01.2017.

Research output: Contribution to journalArticle

Mitra, I, Lavillaureix, A, Yeh, E, Traglia, M, Tsang, K, Bearden, CE, Rauen, KA & Weiss, LA 2017, 'Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders', PLoS Genetics, vol. 13, no. 1, e1006516. https://doi.org/10.1371/journal.pgen.1006516
Mitra I, Lavillaureix A, Yeh E, Traglia M, Tsang K, Bearden CE et al. Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders. PLoS Genetics. 2017 Jan 1;13(1). e1006516. https://doi.org/10.1371/journal.pgen.1006516
Mitra, Ileena ; Lavillaureix, Alinoë ; Yeh, Erika ; Traglia, Michela ; Tsang, Kathryn ; Bearden, Carrie E. ; Rauen, Katherine A ; Weiss, Lauren A. / Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders. In: PLoS Genetics. 2017 ; Vol. 13, No. 1.
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