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Joint mouse-human phenome-wide association to test gene function and disease risk.

ABSTRACT: Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for ?5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of ?4,500 metabolic, physiological, pharmacological and behavioural traits, and more than 90 independent expression quantitative trait locus (QTL), transcriptome, proteome, metagenome and metabolome data sets--by far the largest coherent phenome for any experimental cohort (www.genenetwork.org). We tested downstream effects of subsets of variants and discovered several novel associations, including a missense mutation in fumarate hydratase that controls variation in the mitochondrial unfolded protein response in both mouse and Caenorhabditis elegans, and missense mutations in Col6a5 that underlies variation in bone mineral density in both mouse and human.

SUBMITTER: Wang X

PROVIDER: S-EPMC4740880 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Joint mouse-human phenome-wide association to test gene function and disease risk.

Wang Xusheng X Pandey Ashutosh K AK Mulligan Megan K MK Williams Evan G EG Mozhui Khyobeni K Li Zhengsheng Z Jovaisaite Virginija V Quarles L Darryl LD Xiao Zhousheng Z Huang Jinsong J Capra John A JA Chen Zugen Z Taylor William L WL Bastarache Lisa L Niu Xinnan X Pollard Katherine S KS Ciobanu Daniel C DC Reznik Alexander O AO Tishkov Artem V AV Zhulin Igor B IB Peng Junmin J Nelson Stanley F SF Denny Joshua C JC Auwerx Johan J Lu Lu L Williams Robert W RW

Nature communications 20160202

Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for ∼5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of ∼4,500 metabolic, physiological, pharmacological and behavioural traits, ...[more]

PMID: 26833085

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Project description:BackgroundEndometriosis affects 1 in 9 women, yet it is poorly understood with long diagnostic delays, invasive diagnoses, and poor treatment outcomes. Characterised by the presence of endometrial-like tissue outside of the uterus, its main symptoms are pain and infertility. Endometriosis often co-occurs with other conditions, which may provide insights into the origins of endometriosis.MethodsHere a polygenic risk score phenome-wide association study of endometriosis was conducted in the UK Biobank to investigate the pleiotropic effects of a genetic liability to endometriosis. The relationship between the polygenic risk score for endometriosis and health conditions, blood and urine biomarkers and reproductive factors were investigated separately in females, males and females without an endometriosis diagnosis. The relationship between endometriosis and the blood and urine biomarkers was further investigated using genetic correlation and Mendelian randomisation approaches to identify causal relationships.ResultsMultiple health conditions, blood and urine biomarkers and reproductive factors were associated with genetic liability to endometriosis in each group, indicating many endometriosis comorbidities are not dependent on the physical manifestation of endometriosis. Differences in the associated traits between males and females highlighted the importance of sex-specific pathways in the overlap of endometriosis with many other traits. Notably, an association of genetic liability to endometriosis with lower testosterone levels was identified. Follow-up analysis utilising Mendelian randomisation approaches suggested lower testosterone may be causal for both endometriosis and clear cell ovarian cancer.ConclusionsThis study highlights the diversity of the pleiotropic effects of genetic risk to endometriosis irrespective of a diagnosis of endometriosis. A key finding was the identification of a causal effect of the genetic liability to lower testosterone on endometriosis using Mendelian randomisation.

Dataset Information

Joint mouse-human phenome-wide association to test gene function and disease risk.

Publications

Joint mouse-human phenome-wide association to test gene function and disease risk.

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