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Here we perform genome-wide association studies (GWAS) and accompanying phenome-wide association studies (PheWAS) to validate phenotype-genotype associations of BMI, and to a greater extent, severe Class 2 obesity, using comprehensive diagnostic and clinical data from the EHR database of our cohort. Three GWASs of 500,000 variants on the Illumina platform of 6,645 Healthy Nevada participants identified several published and novel variants that affect BMI and obesity. Each GWAS was followed with two independent PheWASs to examine associations between extensive phenotypes (incidence of diagnoses, condition, or disease), significant SNPs, BMI, and incidence of extreme obesity. The first GWAS examines associations with BMI in a cohort with no type 2 diabetics, focusing exclusively on BMI. The second GWAS examines associations with BMI in a cohort that includes type 2 diabetics. In the second GWAS, type 2 diabetes is a comorbidity, and thus becomes a covariate in the statistical model. The intersection of significant variants of these two studies is surprising. The third GWAS is a case vs. control study, with cases defined as extremely obese (Class 2 or 3 obesity), and controls defined as participants with BMI between 18.5 and 25. This last GWAS identifies strong associations with extreme obesity, including established variants in the FTO and NEGR1 genes, as well as loci not yet linked to obesity. The PheWASs validate published associations between BMI and extreme obesity and incidence of specific diagnoses and conditions, yet also highlight novel links. This study emphasizes the importance of our extensive longitudinal EHR database to validate known associations and identify putative novel links with BMI and obesity.<\/jats:p>","DOI":"10.1534\/g3.119.400910","type":"journal-article","created":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T21:55:12Z","timestamp":1577742912000},"page":"645-664","source":"Crossref","is-referenced-by-count":34,"title":["A Comprehensive Genome-Wide and Phenome-Wide Examination of BMI and Obesity in a Northern Nevadan Cohort"],"prefix":"10.1093","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6916-8571","authenticated-orcid":false,"given":"Karen A","family":"Schlauch","sequence":"first","affiliation":[{"name":"Institute for Health Innovation, Renown Health, Reno, NV"},{"name":"Desert Research Institute, Reno, NV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6967-5634","authenticated-orcid":false,"given":"Robert W","family":"Read","sequence":"additional","affiliation":[{"name":"Institute for Health Innovation, Renown Health, Reno, NV"},{"name":"Desert Research Institute, Reno, NV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4474-8662","authenticated-orcid":false,"given":"Vincent C","family":"Lombardi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Nevada, School of Medicine, Reno, NV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gai","family":"Elhanan","sequence":"additional","affiliation":[{"name":"Institute for Health Innovation, Renown Health, Reno, NV"},{"name":"Desert Research Institute, Reno, NV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J","family":"Metcalf","sequence":"additional","affiliation":[{"name":"Institute for Health Innovation, Renown Health, Reno, NV"},{"name":"Desert Research Institute, Reno, NV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony D","family":"Slonim","sequence":"additional","affiliation":[{"name":"Institute for Health Innovation, Renown Health, Reno, NV"},{"name":"Renown Health, Reno, NV, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the 23andMe Research Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J","family":"Grzymski","sequence":"additional","affiliation":[{"name":"Institute for Health Innovation, Renown Health, Reno, NV"},{"name":"Desert Research Institute, Reno, NV"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,2,1]]},"reference":[{"key":"2021042011140974200_bib1","doi-asserted-by":"publisher","first-page":"1640","DOI":"10.1161\/CIRCULATIONAHA.109.192644","article-title":"Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.","volume-title":"Circulation","author":"Alberti","year":"2009"},{"key":"2021042011140974200_bib2","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/0002-9343(62)90052-9","article-title":"Observations on some clinical features of extreme obesity, with particular reference to cardiorespiratory effects.","volume":"32","author":"Alexander","year":"1962","journal-title":"Am. 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