Identifying genetically driven clinical phenotypes using linear mixed models

J.D. Mosley; J.S. Witte; E.K. Larkin; L. Bastarache; C.M. Shaffer; J.H. Karnes; C.M. Stein; E. Phillips; S.J. Hebbring; M.H. Brilliant; J. Mayer; Z. Ye; D.M. Roden; J.C. Denny

doi:10.1038/ncomms11433

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Identifying genetically driven clinical phenotypes using linear mixed models

Journal article

Open access

Peer reviewed

Identifying genetically driven clinical phenotypes using linear mixed models

J.D. Mosley, J.S. Witte, E.K. Larkin, L. Bastarache, C.M. Shaffer, J.H. Karnes, C.M. Stein, E. Phillips, S.J. Hebbring, M.H. Brilliant, …

Nature Communications, Vol.7

2016

DOI: https://doi.org/10.1038/ncomms11433

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Abstract

We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q<0.05) phenotypes associated with HLA SNP variation and show that hypothyroidism is genetically correlated with Type I diabetes (rG=0.31, s.e. 0.12, P=0.003). We also report novel SNP associations for hypothyroidism near HLA-DQA1/HLA-DQB1 at rs6906021 (combined odds ratio (OR)=1.2 (95% confidence interval (CI): 1.1–1.2), P=9.8 × 10−11) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3–1.6), P=1.3 × 10−10). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations.

Details

Title: Identifying genetically driven clinical phenotypes using linear mixed models
Authors/Creators: J.D. Mosley (Author/Creator) - Vanderbilt University
J.S. Witte (Author/Creator) - University of California, San Francisco
E.K. Larkin (Author/Creator) - Vanderbilt University
L. Bastarache (Author/Creator) - Vanderbilt University
C.M. Shaffer (Author/Creator) - Vanderbilt University
J.H. Karnes (Author/Creator) - Vanderbilt University
C.M. Stein (Author/Creator) - Vanderbilt University
E. Phillips (Author/Creator) - Vanderbilt University
S.J. Hebbring (Author/Creator) - Marshfield Clinic
M.H. Brilliant (Author/Creator) - Marshfield Clinic
J. Mayer (Author/Creator) - Marshfield Clinic
Z. Ye (Author/Creator) - Marshfield Clinic
D.M. Roden (Author/Creator) - Vanderbilt University
J.C. Denny (Author/Creator) - Vanderbilt University
Publication Details: Nature Communications, Vol.7
Publisher: Nature Publishing Group
Identifiers: 991005541974807891
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.189 Genome Studies; 1.189.455 Genome-Wide Association Studies
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics