1. Joint mouse–human phenome-wide association to test gene function and disease risk
- Author
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Jinsong Huang, Artem Tishkov, Virginija Jovaisaite, Katherine S. Pollard, Robert W. Williams, Ashutosh K. Pandey, John A. Capra, Lu Lu, Megan K. Mulligan, Johan Auwerx, Zugen Chen, William L. Taylor, Junmin Peng, Khyobeni Mozhui, Lisa Bastarache, L. Darryl Quarles, Daniel C. Ciobanu, Z. Li, Evan G. Williams, Alexander O. Reznik, Joshua C. Denny, Xinnan Niu, Zhousheng Xiao, Stanley F. Nelson, Xusheng Wang, and Igor B. Zhulin
- Subjects
0301 basic medicine ,Science ,Quantitative Trait Loci ,General Physics and Astronomy ,Genomics ,Genome-wide association study ,Phenome ,Quantitative trait locus ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Fumarate Hydratase ,Mice ,03 medical and health sciences ,Bone Density/genetics ,Bone Density ,Genetic variation ,Animals ,Humans ,Genetic Predisposition to Disease ,Caenorhabditis elegans ,Gene ,Gene Library ,Regulation of gene expression ,Genetics ,Multidisciplinary ,Gene Expression Regulation/physiology ,Genetic Variation ,General Chemistry ,Phenotype ,Fumarate Hydratase/genetics/metabolism ,030104 developmental biology ,Gene Expression Regulation ,Mice, Inbred DBA ,Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] ,Genome-Wide Association Study - 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., Phenome-wide association is a novel method that links sequence variants to a spectrum of phenotypes and diseases. Here the authors generate detailed mouse genetic and phenome data which links their phenome-wide association study (PheWAS) of mouse to corresponding PheWAS in human.
- Published
- 2016