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 Kinoshita & 17 others Esa 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 journalArticle

2 Citations (Scopus)

Abstract

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
Pages (from-to)35-45
Number of pages11
JournalJournal of Neural Transmission
Volume126
Issue number1
DOIs
Publication statusPublished - 21-01-2019

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Serotonin Uptake Inhibitors
Coronary Artery Disease
Obesity
Depression
Genes
Major Depressive Disorder
Therapeutics
Meta-Analysis
Genetic Loci
Genome-Wide Association Study
Antidepressive Agents
Body Mass Index
Logistic Models

All Science Journal Classification (ASJC) codes

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

Cite this

Amare, A. T., Schubert, K. O., Tekola-Ayele, F., Hsu, Y. H., Sangkuhl, K., Jenkins, G., ... Baune, B. T. (2019). The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression. Journal of Neural Transmission, 126(1), 35-45. https://doi.org/10.1007/s00702-018-01966-x
Amare, Azmeraw T. ; Schubert, Klaus Oliver ; Tekola-Ayele, Fasil ; Hsu, Yi Hsiang ; Sangkuhl, Katrin ; Jenkins, Gregory ; Whaley, Ryan M. ; Barman, Poulami ; Batzler, Anthony ; Altman, Russ B. ; Arolt, Volker ; Brockmöller, Jürgen ; Chen, Chia Hui ; Domschke, Katharina ; Hall-Flavin, Daniel K. ; Hong, Chen Jee ; Illi, Ari ; Ji, Yuan ; Kampman, Olli ; Kinoshita, Toshihiko ; Leinonen, Esa ; Liou, Ying Jay ; Mushiroda, Taisei ; Nonen, Shinpei ; Skime, Michelle K. ; Wang, Liewei ; Kato, Masaki ; Liu, Yu Li ; Praphanphoj, Verayuth ; Stingl, Julia C. ; Bobo, William V. ; Tsai, Shih Jen ; Kubo, Michiaki ; Klein, Teri E. ; Weinshilboum, Richard M. ; Biernacka, Joanna M. ; Baune, Bernhard T. / The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression. In: Journal of Neural Transmission. 2019 ; Vol. 126, No. 1. pp. 35-45.
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abstract = "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.",
author = "Amare, {Azmeraw T.} and Schubert, {Klaus Oliver} and Fasil Tekola-Ayele and Hsu, {Yi Hsiang} and Katrin Sangkuhl and Gregory Jenkins and Whaley, {Ryan M.} and Poulami Barman and Anthony Batzler and Altman, {Russ B.} and Volker Arolt and J{\"u}rgen Brockm{\"o}ller and Chen, {Chia Hui} and Katharina Domschke and Hall-Flavin, {Daniel K.} and Hong, {Chen Jee} and Ari Illi and Yuan Ji and Olli Kampman and Toshihiko Kinoshita and Esa Leinonen and Liou, {Ying Jay} and Taisei Mushiroda and Shinpei Nonen and Skime, {Michelle K.} and Liewei Wang and Masaki Kato and Liu, {Yu Li} and Verayuth Praphanphoj and Stingl, {Julia C.} and Bobo, {William V.} and Tsai, {Shih Jen} and Michiaki Kubo and Klein, {Teri E.} and Weinshilboum, {Richard M.} and Biernacka, {Joanna M.} and Baune, {Bernhard T.}",
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Amare, AT, Schubert, KO, Tekola-Ayele, F, Hsu, YH, Sangkuhl, K, Jenkins, G, Whaley, RM, Barman, P, Batzler, A, Altman, RB, Arolt, V, Brockmöller, J, Chen, CH, Domschke, K, Hall-Flavin, DK, Hong, CJ, Illi, A, Ji, Y, Kampman, O, Kinoshita, T, Leinonen, E, Liou, YJ, Mushiroda, T, Nonen, S, Skime, MK, Wang, L, Kato, M, Liu, YL, Praphanphoj, V, Stingl, JC, Bobo, WV, Tsai, SJ, Kubo, M, Klein, TE, Weinshilboum, RM, Biernacka, JM & Baune, BT 2019, 'The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression', Journal of Neural Transmission, vol. 126, no. 1, pp. 35-45. https://doi.org/10.1007/s00702-018-01966-x

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

In: Journal of Neural Transmission, Vol. 126, No. 1, 21.01.2019, p. 35-45.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression

AU - Amare, Azmeraw T.

AU - Schubert, Klaus Oliver

AU - Tekola-Ayele, Fasil

AU - Hsu, Yi Hsiang

AU - Sangkuhl, Katrin

AU - Jenkins, Gregory

AU - Whaley, Ryan M.

AU - Barman, Poulami

AU - Batzler, Anthony

AU - Altman, Russ B.

AU - Arolt, Volker

AU - Brockmöller, Jürgen

AU - Chen, Chia Hui

AU - Domschke, Katharina

AU - Hall-Flavin, Daniel K.

AU - Hong, Chen Jee

AU - Illi, Ari

AU - Ji, Yuan

AU - Kampman, Olli

AU - Kinoshita, Toshihiko

AU - Leinonen, Esa

AU - Liou, Ying Jay

AU - Mushiroda, Taisei

AU - Nonen, Shinpei

AU - Skime, Michelle K.

AU - Wang, Liewei

AU - Kato, Masaki

AU - Liu, Yu Li

AU - Praphanphoj, Verayuth

AU - Stingl, Julia C.

AU - Bobo, William V.

AU - Tsai, Shih Jen

AU - Kubo, Michiaki

AU - Klein, Teri E.

AU - Weinshilboum, Richard M.

AU - Biernacka, Joanna M.

AU - Baune, Bernhard T.

PY - 2019/1/21

Y1 - 2019/1/21

N2 - 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.

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