Neuropsychiatric disorders, such as depression, have not shown conclusive linkage or association study results. Today, an enormous portion of heritability for depression remains unexplained. Rather than reiterating studies attempting to identify genetic variants underlying depression pathophysiology, I propose a different approach of evaluating genetic variation in the safety and efficacy of the major class of antidepressants. I will identify patients with the quantitative and discrete phenotypes of serotonin-specific reuptake inhibitor (SSRI) response (as measured through the Patient's Health Questionnaire-9 pre- and post-SSRI treatment), and SSRI-associated serious side effects, such as abnormal bleeding and serotonin syndrome. After identification of these phenotypes from the electronic Medical Records and Genetic Epidemiology (eMERGE) consortium, I will perform a genome-wide association study (GWAS) on 50,109 subjects to identify candidate genes involved in SSRI pharmacology and then leverage overlapping exome sequence data to identify rare, potentially causative mutations. As many GWAS and rare variant studies suffer from a lack of functional validation (i.e., that the identified variant truly causes the phenotype), I will functionally valiate these identified rare mutations in the model organism Saccharomyces cerevisiae using a yeast growth-based assay as a direct measure of protein function. The P450 enzyme CYP3A4, which has been implicated in SSRI metabolism, will be used as a proof of concept for the yeast assay. Finally, I will then use this yeast growth assay to perform deep mutational scanning to create a pharmacogenomic map of all possible mutations and their effect on enzyme hydrolysis, thereby linking DNA sequence to protein function. This work will provide a unique resource for understanding SSRI pharmacology. Through completion of a GWAS on the pharmacogenomic phenotypes of SSRI response and separately, risk of SSRI-associated bleeding and serotonin syndrome, I will likely identify numerous candidate genes that may further inform on the metabolism, transport, and mechanism of action of SSRIs, thereby furthering basic science. Moreover, through functional validation and creation of a pharmacogenomic map with deep mutational scanning, I will create an invaluable resource for clinicians to interpret the likely efect of their patient's rare mutation. Through this project, I hope to further the effort to bring personalized, genomic medicine into clinical practice, to decrease the morbidity and mortality of depression, which is estimated by the Center for Disease Control to affect 1 in 10 adults in the U.S.

Public Health Relevance

Depression is affects 1 in 10 adults in the United States and is one of the leading causes of disability. Depression is primarily treated with serotonin-specific reuptake inhibitors (SSRIs). Understanding how mutations in genes affect SSRI response and risk of side effects forwards the implementation of personalized, genomic medicine into evidence-based clinical practice. This integration of genomic information will likely greatly decrease the morbidity of depression in the United States and globally.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Rosemond, Erica K
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Kim, Daniel Seung; Li, Yatong K; Kim, Jerry H et al. (2018) Autosomal dominant mannose-binding lectin deficiency is associated with worse neurodevelopmental outcomes after cardiac surgery in infants. J Thorac Cardiovasc Surg 155:1139-1147.e2
Kim, Daniel Seung; Burt, Amber A; Ranchalis, Jane E et al. (2017) Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet 174:381-389
Kim, Daniel Seung; Kim, Jerry H; Burt, Amber A et al. (2016) Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival. J Thorac Cardiovasc Surg 151:1147-51.e4
Kim, Daniel Seung; Burt, Amber A; Ranchalis, Jane E et al. (2015) PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity. J Lipid Res 56:1351-62
Schick, Ursula M; Auer, Paul L; Bis, Joshua C et al. (2015) Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Hum Mol Genet 24:559-71
Gaynor, J William; Kim, Daniel Seung; Arrington, Cammon B et al. (2014) Validation of association of the apolipoprotein E ?2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. J Thorac Cardiovasc Surg 148:2560-6
Kim, Daniel S; Smith, Jennifer A; Bielak, Lawrence F et al. (2014) The relationship between diastolic blood pressure and coronary artery calcification is dependent on single nucleotide polymorphisms on chromosome 9p21.3. BMC Med Genet 15:89
Hutchins, Patrick M; Ronsein, Graziella E; Monette, Jeffrey S et al. (2014) Quantification of HDL particle concentration by calibrated ion mobility analysis. Clin Chem 60:1393-401
Kim, Daniel Seung; Kim, Jerry H; Burt, Amber A et al. (2014) Patient genotypes impact survival after surgery for isolated congenital heart disease. Ann Thorac Surg 98:104-10; discussion 110-1
Kim, Daniel Seung; Burt, Amber A; Ranchalis, Jane E et al. (2014) Effects of dietary components on high-density lipoprotein measures in a cohort of 1,566 participants. Nutr Metab (Lond) 11:44

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