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Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders
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نویسنده
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mitra i. ,lavillaureix a. ,yeh e. ,traglia m. ,tsang k. ,bearden c.e. ,rauen k.a. ,weiss l.a.
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منبع
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plos genetics - 2017 - دوره : 13 - شماره : 1
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چکیده
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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. © 2017 mitra et al.
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آدرس
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department of psychiatry,university of california san francisco,san francisco,ca,united states,institute for human genetics,university of california san francisco,san francisco,ca, United States, department of psychiatry,university of california san francisco,san francisco,ca,united states,institute for human genetics,university of california san francisco,san francisco,ca,united states,université paris descartes,sorbonne paris cité,faculty of medicine,paris, France, department of psychiatry,university of california san francisco,san francisco,ca,united states,institute for human genetics,university of california san francisco,san francisco,ca, United States, department of psychiatry,university of california san francisco,san francisco,ca,united states,institute for human genetics,university of california san francisco,san francisco,ca, United States, department of psychiatry,university of california san francisco,san francisco,ca,united states,institute for human genetics,university of california san francisco,san francisco,ca, United States, department of psychiatry and biobehavioral sciences,semel institute for neuroscience and human behavior,university of california los angeles,los angeles,ca,united states,department of psychology,university of california los angeles,los angeles,ca, United States, institute for human genetics,university of california san francisco,san francisco,ca,united states,department of pediatrics,school of medicine,university of california san francisco,san francisco,ca,united states,division of genomic medicine,department of pediatrics,uc davis mind institute,university of california at davis,sacramento,ca, United States, department of psychiatry,university of california san francisco,san francisco,ca,united states,institute for human genetics,university of california san francisco,san francisco,ca, United States
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Authors
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