GRIK5 Genetically Regulated Expression Associated with Eye and Vascular Phenomes: Discovery through Iteration among Biobanks, Electronic Health Records, and Zebrafish

• Published in: American journal of human genetics Vol. 104; no. 3; pp. 503 - 519
• Main Authors: Unlu, Gokhan, Gamazon, Eric R., Qi, Xinzi, Levic, Daniel S., Bastarache, Lisa, Denny, Joshua C., Roden, Dan M., Mayzus, Ilya, Breyer, Max, Zhong, Xue, Konkashbaev, Anuar I., Rzhetsky, Andrey, Knapik, Ela W., Cox, Nancy J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2019; Elsevier
• Subjects: Animals; Biological Specimen Banks; disease mechanisms; EHR; Electronic Health Records; Embryo, Nonmammalian - metabolism; Embryo, Nonmammalian - pathology; eye disease; Eye Diseases - genetics; Eye Diseases - metabolism; Eye Diseases - pathology; Gene Expression Regulation; genetics; Genotype; Humans; Phenomics; Phenotype; Receptors, Kainic Acid - genetics; Receptors, Kainic Acid - metabolism; transcriptome; vascular biology; Vascular Diseases - genetics; Vascular Diseases - metabolism; Vascular Diseases - pathology; Zebrafish; genetics; transcriptome; disease mechanisms; vascular biology; zebrafish; eye disease; EHR
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2019.01.017

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.