Identifying genetically driven clinical phenotypes using linear mixed models.
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.
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Jonathan D
JD
Mosley
Department of Epidemiology and Biostatistics, University of California, San Francisco, California 94158, USA.
John S
JS
Witte
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Emma K
EK
Larkin
Biomedical Informatics, Vanderbilt University, Nashville, Tennessee 37203, USA.
Lisa
L
Bastarache
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Christian M
CM
Shaffer
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Jason H
JH
Karnes
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
C Michael
CM
Stein
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Elizabeth
E
Phillips
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, USA.
Scott J
SJ
Hebbring
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, USA.
Murray H
MH
Brilliant
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, USA.
John
J
Mayer
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, USA.
Zhan
0000-0002-0426-0382
Z
Ye
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Dan M
DM
Roden
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.|Biomedical Informatics, Vanderbilt University, Nashville, Tennessee 37203, USA.
Joshua C
JC
Denny
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004194:Disease / Q000235:genetics*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D006680:HLA Antigens