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; 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

doi:10.1007/s00702-018-01966-x

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 journal › Article › peer-review

6 Scopus citations

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 (P_T) 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 language	English (US)
Pages (from-to)	35-45
Number of pages	11
Journal	Journal of Neural Transmission
Volume	126
Issue number	1
DOIs	https://doi.org/10.1007/s00702-018-01966-x
State	Published - Jan 21 2019

Keywords

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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10.1007/s00702-018-01966-x

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Amare, A. T., Schubert, K. O., Tekola-Ayele, F., Hsu, Y. H., Sangkuhl, K., Jenkins, G., Whaley, R. M., Barman, P., Batzler, A., Altman, R. B., Arolt, V., Brockmöller, J., Chen, C. H., Domschke, K., Hall-Flavin, D. K., Hong, C. J., Illi, A., Ji, Y., Kampman, O., ... 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, 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

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

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.",

keywords = "Antidepressants, Body mass index, Coronary artery disease, Major depression, Obesity, Pharmacogenomics, Pleiotropy, Polygenic score, SSRIs",

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.}",

note = "Funding Information: Funding 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. Funding Information: Acknowledgements 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/. Funding Information: 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/. Publisher Copyright: {\textcopyright} 2019, Springer-Verlag GmbH Austria, part of Springer Nature.",

year = "2019",

month = jan,

day = "21",

doi = "10.1007/s00702-018-01966-x",

language = "English (US)",

volume = "126",

pages = "35--45",

journal = "Journal of Neural Transmission",

issn = "0300-9564",

publisher = "Springer Verlag",

number = "1",

}

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.

N1 - Funding Information: Funding 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. Funding Information: Acknowledgements 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/. Funding Information: 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/. Publisher Copyright: © 2019, Springer-Verlag GmbH Austria, part of Springer Nature.

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.

AB - 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.

KW - Antidepressants

KW - Body mass index

KW - Coronary artery disease

KW - Major depression

KW - Obesity

KW - Pharmacogenomics

KW - Pleiotropy

KW - Polygenic score

KW - SSRIs

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

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