%0 Journal Article %J Genet Med %D 2020 %T Electronic health record phenotypes associated with genetically regulated expression of CFTR and application to cystic fibrosis. %A Zhong, Xue %A Yin, Zhijun %A Jia, Gengjie %A Zhou, Dan %A Wei, Qiang %A Faucon, Annika %A Evans, Patrick %A Gamazon, Eric R %A Li, Bingshan %A Tao, Ran %A Rzhetsky, Andrey %A Bastarache, Lisa %A Cox, Nancy J %K Adult %K Cystic Fibrosis %K Cystic Fibrosis Transmembrane Conductance Regulator %K Electronic Health Records %K Humans %K Mutation %K Phenotype %X

PURPOSE: The increasing use of electronic health records (EHRs) and biobanks offers unique opportunities to study Mendelian diseases. We described a novel approach to summarize clinical manifestations from patient EHRs into phenotypic evidence for cystic fibrosis (CF) with potential to alert unrecognized patients of the disease.

METHODS: We estimated genetically predicted expression (GReX) of cystic fibrosis transmembrane conductance regulator (CFTR) and tested for association with clinical diagnoses in the Vanderbilt University biobank (Nā€‰=ā€‰9142 persons of European descent with 71 cases of CF). The top associated EHR phenotypes were assessed in combination as a phenotype risk score (PheRS) for discriminating CF case status in an additional 2.8 million patients from Vanderbilt University Medical Center (VUMC) and 125,305 adult patients including 25,314 CF cases from MarketScan, an independent external cohort.

RESULTS: GReX of CFTR was associated with EHR phenotypes consistent with CF. PheRS constructed using the EHR phenotypes and weights discovered by the genetic associations improved discriminative power for CF over the initially proposed PheRS in both VUMC and MarketScan.

CONCLUSION: Our study demonstrates the power of EHRs for clinical description of CF and the benefits of using a genetics-informed weighing scheme in construction of a phenotype risk score. This research may find broad applications for phenomic studies of Mendelian disease genes.

%B Genet Med %V 22 %P 1191-1200 %8 2020 07 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/32296164?dopt=Abstract %R 10.1038/s41436-020-0786-5 %0 Journal Article %J Am J Hum Genet %D 2019 %T GRIK5 Genetically Regulated Expression Associated with Eye and Vascular Phenomes: Discovery through Iteration among Biobanks, Electronic Health Records, and Zebrafish. %A Unlu, Gokhan %A Gamazon, Eric R %A Qi, Xinzi %A Levic, Daniel S %A Bastarache, Lisa %A Denny, Joshua C %A Roden, Dan M %A Mayzus, Ilya %A Breyer, Max %A Zhong, Xue %A Konkashbaev, Anuar I %A Rzhetsky, Andrey %A Knapik, Ela W %A Cox, Nancy J %X

Although the use of model systems for studying the mechanism of mutations that have a large effect is common, we highlight here the ways that zebrafish-model-system studies of a gene, GRIK5, that contributes to the polygenic liability to develop eye diseases have helped to illuminate a mechanism that implicates vascular biology in eye disease. A gene-expression prediction derived from a reference transcriptome panel applied to BioVU, a large electronic health record (EHR)-linked biobank at Vanderbilt University Medical Center, implicated reduced GRIK5 expression in diverse eye diseases. We tested the function of GRIK5 by depletion of its ortholog in zebrafish, and we observed reduced blood vessel numbers and integrity in the eye and increased vascular permeability. Analyses of EHRs in >2.6 million Vanderbilt subjects revealed significant comorbidity of eye and vascular diseases (relative risks 2-15); this comorbidity was confirmed in 150 million individuals from a large insurance claims dataset. Subsequent studies in >60,000 genotyped BioVU participants confirmed the association of reduced genetically predicted expression of GRIK5 with comorbid vascular and eye diseases. Our studies pioneer an approach that allows a rapid iteration of the discovery of gene-phenotype relationships to the primary genetic mechanism contributing to the pathophysiology of human disease. Our findings also add dimension to the understanding of the biology driven by glutamate receptors such as GRIK5 (also referred to as GLUK5 in protein form) and to mechanisms contributing to human eye diseases.

%B Am J Hum Genet %V 104 %P 503-519 %8 2019 Mar 07 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30827500?dopt=Abstract %R 10.1016/j.ajhg.2019.01.017