The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression
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.
KeywordsPharmacogenomics Polygenic score Major depression Antidepressants SSRIs Obesity Body mass index Coronary artery disease Pleiotropy
Azmeraw T. Amare received a Postgraduate Research Scholarship support from the University of Adelaide through the Adelaide Scholarship International (ASI) program. The authors are grateful to all patients who participated in the two studies and we appreciate the contributions of clinicians, scientists, research assistants and study staff who helped in the patient recruitment, data collection and sample preparation of the studies. The authors also would like to thank the National Institutes of Health (NIH), USA for making the STAR*D accessible to us. The complete clinical data for the ISPC is available to registered PharmGKB users at http://www.pharmgkb.org/downloads/. The STAR*D data were obtained through controlled access distributed from the NIH in the dbGaP http://www.ncbi.nlm.nih.gov/projects/gap/.
The ISPC study was supported by the NIH/NIGMS grant R24 GM61374, NIH/NCRR/NCATS CTSA grant number UL1 RR024150, Thailand Research Fund (TRF), Thailand Center of Excellence for Life Sciences (TCELS), National Center for Genetic Engineering and Biotechnology (BIOTEC), Tampere University Hospital Research Fund, the German Ministry of research and education in the German lead project on pharmacogenetic diagnostics grants in 2000–2004, grants from SENSHIN Medical Research Foundation and Grant-in-Aid for Scientific Research (KAKENHI), grants from the National Research Program for Genomic Medicine (NSC 98-3112-B-400-011, NSC 99-3112-B-400-003 and NSC 100-3112-B-400-015), the National Science Council (NSC 97-2314-B-400-001-MY3 and NSC 100-2314-B-400-002-MY3), the National Health Research Institutes, Taiwan (MD-095-PP-01, MD-095-PP-02, MD-097-PP-14, PH-098-PP-41, PH-098-PP-46, PH-098-PP-38, PH-098, 99-PP-42, PH-100-PP-37) and the Taiwan Psychiatric Research Network (PH-98, 99, 100-SP-11). The “Sequenced Treatment Alternatives to Relieve Depression” (STAR*D) study was supported by NIMH Contract # N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528.
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Conflict of interest
VA is a member of the advisory boards (past 5 years) for Astra-Zeneca, Eli Lilly, Lundbeck, Otsuka, Servier, Trommsdorff. BTB is a member of advisory board (past 5 years) of Lundbeck. RW and LW own stock in OneOme LLC. RBA is a stockholder in Personalis Inc. and a paid advisor for Pfizer and Karius. TEK is a paid scientific advisor to the Rxight Pharmacogenetics Program. Other authors declare they have no competing interests.
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