title: Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders.
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.
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.|Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Ileena
authors.identifier: http://orcid.org/0000-0002-9882-3165
authors.initials: I
authors.lastname: Mitra
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.|Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.|Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, Paris, France.
authors.forename: Alinoë
authors.identifier: http://orcid.org/0000-0002-3727-9530
authors.initials: A
authors.lastname: Lavillaureix
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.|Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Erika
authors.identifier: http://orcid.org/0000-0002-2374-1528
authors.initials: E
authors.lastname: Yeh
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.|Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Michela
authors.initials: M
authors.lastname: Traglia
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.|Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Tsang
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, United States of America.|Department of Psychology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Bearden
authors.affiliation: Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.|Department of Pediatrics, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.|Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Lauren A
authors.identifier: http://orcid.org/0000-0002-5700-135X
authors.initials: LA
authors.lastname: Weiss
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002460:Cell Line; D004843:Epistasis, Genetic; D005260:Female; D060045:Genes, Modifier; D055106:Genome-Wide Association Study; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D058953:Neural Stem Cells / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: D043562:Receptors, G-Protein-Coupled; D018631:ras Proteins