Kumar Veerapen
Research Fellow, Massachusetts General Hospital, the Broad Institute of MIT and Harvard, and Harvard Medical School
Assessing the Genetic Contribution of Drug Response Variability in Selective Serotonin Reuptake Inhibitors from 1,711,695 purchases in the Finnish National Drug Registry
Drug use and response is highly variable between individuals e.g. up to 65% of major depressive disorder (MDD) do not respond to selective serotonin reuptake inhibitors (SSRI, ATC code: N06AB). Moreover, molecular mechanisms of interindividual differences that cause SSRI response variability is poorly understood but is largely genetic. We hypothesize that large scale biobanks can be used to understand the genetic basis of SSRI response variability. We utilized the FinnGen integrated biobank data to interrogate SSRI use and response variability. The FinnGen biobank aims to recruit a total of 500,000 Finnish individuals who will be genotyped and linked with lifetime health and drug data from the national Finnish registries. Currently, 218,792 individuals have complete genetic and phenotypic data: 51,519 are individuals who have longitudinal SSRI purchase history. We aim to understand genetic differences contributing to the variability in SSRI usage and response in FinnGen. Each genetic association was assessed using mixed-models and significant loci were determined using a p<5×10-8 threshold. The use of SSRI and MDD is highly correlated in FinnGen (Rg = 0.73): pointing towards a genetic basis in response variability of SSRI. From a total of 1,711,695 antidepressant purchases, 853,286 (49.9%) were SSRI comprising 51,519 individuals. We first investigated the SSRI users (N=51,519) relative to non-users (N=159,788) and identified 3 significant loci where a signal in HLA-A (chr6:29978172:G:A) is located near to a previously reported locus in a recent MDD GWAS (r2 = 0.39). An additional signal in the PHF21A (chr11:46035522:T:C) locus could point towards functional relevance: PHF21A has been shown to impair serotonin metabolism in mouse models. After confirming that drug usage data identifies known MDD loci, we analyzed the genetic differences in adherence of SSRI: 18,691 individuals consumed only SSRI and 13,325 individuals switched from an SSRI to any other antidepressant. We identified 1 significant locus in HLA-DQB1-AS1 (chr6:32658495:C:A) which has been associated with immune and neurological phenotypes (FinnGen phewas). Finally, we attempted to understand genetic differences contributing to longitudinal SSRI use over time between individuals who had no change vs an increase in dosage over time. We identified a significant polygenic risk load in patients with increased dosage (p<0.05); and 1 significant locus in PTDSS2 (chr11:476394:G:A) (p<5×10-8). The protein PTDSS2 has been shown to have a high affinity to docosahexaenoic acid (DHA) where DHA has been clinically used to augment SSRI efficacy.
