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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 <jats:italic>q<\/jats:italic>&lt;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, <jats:italic>P<\/jats:italic>=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\u20131.2), <jats:italic>P<\/jats:italic>=9.8 \u00d7 10<jats:sup>\u221211<\/jats:sup>) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3\u20131.6), <jats:italic>P<\/jats:italic>=1.3 \u00d7 10<jats:sup>\u221210<\/jats:sup>). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations.<\/jats:p>","DOI":"10.1038\/ncomms11433","type":"journal-article","created":{"date-parts":[[2016,4,25]],"date-time":"2016-04-25T11:01:32Z","timestamp":1461582092000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Identifying genetically driven clinical phenotypes using linear mixed models"],"prefix":"10.1038","volume":"7","author":[{"given":"Jonathan D.","family":"Mosley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Witte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma K.","family":"Larkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Bastarache","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M.","family":"Shaffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason H.","family":"Karnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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