The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression

Azmeraw T. Amare, Klaus Oliver Schubert, Fasil Tekola-Ayele, Yi Hsiang Hsu, Katrin Sangkuhl, Gregory Jenkins, Ryan M. Whaley, Poulami Barman, Anthony Batzler, Russ B. Altman, Volker Arolt, Jürgen Brockmöller, Chia Hui Chen, Katharina Domschke, Daniel K. Hall-Flavin, Chen Jee Hong, Ari Illi, Yuan Ji, Olli Kampman, Toshihiko KinoshitaEsa Leinonen, Ying Jay Liou, Taisei Mushiroda, Shinpei Nonen, Michelle K. Skime, Liewei Wang, Masaki Kato, Yu Li Liu, Verayuth Praphanphoj, Julia C. Stingl, William V. Bobo, Shih Jen Tsai, Michiaki Kubo, Teri E. Klein, Richard M. Weinshilboum, Joanna M. Biernacka, Bernhard T. Baune

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.

Original languageEnglish (US)
Pages (from-to)35-45
Number of pages11
JournalJournal of Neural Transmission
Issue number1
StatePublished - Jan 21 2019


  • Antidepressants
  • Body mass index
  • Coronary artery disease
  • Major depression
  • Obesity
  • Pharmacogenomics
  • Pleiotropy
  • Polygenic score
  • SSRIs

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry


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