Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders.

Title	Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders.
Publication Type	Journal Article
Year of Publication	2017
Authors	Mitra I, Lavillaureix A, Yeh E, Traglia M, Tsang K, Bearden CE, Rauen KA, Weiss LA
Journal	PLoS genetics
Volume	13
Pagination	e1006516
Date Published	1
ISSN	1553-7404
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.
DOI	10.1371/journal.pgen.1006516