title: Identifying genetic loci associated with antidepressant drug response with drug-gene interaction models in a population-based study.
abstract: It has been difficult to identify genes affecting drug response to Selective Serotonin Reuptake Inhibitors (SSRIs). We used multiple cross-sectional assessments of depressive symptoms in a population-based study to identify potential genetic interactions with SSRIs as a model to study genetic variants associated with SSRI response. This study, embedded in the prospective Rotterdam Study, included all successfully genotyped participants with data on depressive symptoms (CES-D scores). We used repeated measurement models to test multiplicative interaction between genetic variants and use of SSRIs on repeated CESD scores. Besides a genome-wide analysis, we also performed an analysis which was restricted to genes related to the serotonergic signaling pathway. A total of 273 out of 14,937 assessments of depressive symptoms in 6443 participants, use of an SSRI was recorded. After correction for multiple testing, no plausible loci were identified in the genome-wide analysis. However, among the top 10 independent loci with the lowest p-values, findings within two genes (FSHR and HMGB4) might be of interest. Among 26 genes related to the serotonergic signaling pathway, the rs6108160 polymorphism in the PLCB1 gene reached statistical significance after Bonferroni correction (p-value = 8.1e-5). Also, the widely replicated 102C > T polymorphism in the HTR2A gene showed a statistically significant drug-gene interaction with SSRI use. Therefore, the present study suggests that drug-gene interaction models on (repeated) cross-sectional assessments of depressive symptoms in a population-based study can identify potential loci that may influence SSRI response.
authors: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: r.noordam@erasmusmc.nl.
authors: Raymond
authors: R
authors: Noordam
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: n.direk@erasmusmc.nl.
authors: Nese
authors: N
authors: Direk
authors: Department of Medicine, University of Washington, Seattle, WA, USA. Electronic address: csitlani@uw.edu.
authors: Colleen M
authors: CM
authors: Sitlani
authors: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: n.aarts@erasmusmc.nl.
authors: Nikkie
authors: N
authors: Aarts
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: h.tiemeier@erasmusmc.nl.
authors: Henning
authors: H
authors: Tiemeier
authors: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands. Electronic address: a.hofman@erasmusmc.nl.
authors: Albert
authors: A
authors: Hofman
authors: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands. Electronic address: a.g.uitterlinden@erasmusmc.nl.
authors: André G
authors: AG
authors: Uitterlinden
authors: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA. Electronic address: pasty@u.washington.edu.
authors: Bruce M
authors: BM
authors: Psaty
authors: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Inspectorate of Health Care, The Hague, The Netherlands; The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands. Electronic address: b.stricker@erasmusmc.nl.
authors: Bruno H
authors: BH
authors: Stricker
authors: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Apotheek Haagse Ziekenhuizen, HAGA, The Hague, The Netherlands. Electronic address: l.e.visser@erasmusmc.nl.
authors: Loes E
authors: LE
authors: Visser
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000928:Antidepressive Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D018672:Community Health Planning; D003430:Cross-Sectional Studies; D003863:Depression / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales
chemical_list: D000928:Antidepressive Agents
keywords: Drug response biomarkers; Gene–environment interaction; Genome-wide association study; Pharmacogenetics; Serotonin uptake inhibitors