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Journal of Neural Transmission

, Volume 126, Issue 1, pp 35–45 | Cite as

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. BauneEmail author
Psychiatry and Preclinical Psychiatric Studies - Original Article

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

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

Notes

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

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.

Compliance with ethical standards

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.

Supplementary material

702_2018_1966_MOESM1_ESM.pdf (45 kb)
Supplementary material 1 (PDF 45 KB)
702_2018_1966_MOESM2_ESM.pdf (35 kb)
Supplementary material 2 (PDF 36 KB)

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Azmeraw T. Amare
    • 1
    • 2
  • Klaus Oliver Schubert
    • 1
    • 3
  • Fasil Tekola-Ayele
    • 4
  • Yi-Hsiang Hsu
    • 5
    • 6
  • Katrin Sangkuhl
    • 7
  • Gregory Jenkins
    • 8
  • Ryan M. Whaley
    • 7
  • Poulami Barman
    • 8
  • Anthony Batzler
    • 8
  • Russ B. Altman
    • 9
  • Volker Arolt
    • 10
  • Jürgen Brockmöller
    • 11
  • Chia-Hui Chen
    • 12
  • Katharina Domschke
    • 13
  • Daniel K. Hall-Flavin
    • 14
  • Chen-Jee Hong
    • 15
    • 16
  • Ari Illi
    • 17
  • Yuan Ji
    • 18
  • Olli Kampman
    • 17
    • 19
  • Toshihiko Kinoshita
    • 20
  • Esa Leinonen
    • 17
    • 21
  • Ying-Jay Liou
    • 15
    • 16
  • Taisei Mushiroda
    • 22
  • Shinpei Nonen
    • 23
  • Michelle K. Skime
    • 14
  • Liewei Wang
    • 18
  • Masaki Kato
    • 20
  • Yu-Li Liu
    • 24
  • Verayuth Praphanphoj
    • 25
  • Julia C. Stingl
    • 26
  • William V. Bobo
    • 14
  • Shih-Jen Tsai
    • 15
    • 16
  • Michiaki Kubo
    • 22
  • Teri E. Klein
    • 7
  • Richard M. Weinshilboum
    • 18
  • Joanna M. Biernacka
    • 8
    • 14
  • Bernhard T. Baune
    • 1
    Email author
  1. 1.Discipline of Psychiatry, School of MedicineUniversity of AdelaideAdelaideAustralia
  2. 2.South Australian Academic Health Science and Translation CentreSouth Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
  3. 3.Northern Adelaide Local Health Network, Mental Health ServicesAdelaideAustralia
  4. 4.Epidemiology Branch, Division of Intramural Population Health Research, National Institute of Child Health and Human Development, InstituteNational Institutes of HealthBethesdaUSA
  5. 5.HSL Institute for Aging ResearchHarvard Medical SchoolBostonUSA
  6. 6.Program for Quantitative GenomicsHarvard School of Public HealthBostonUSA
  7. 7.Biomedical Data ScienceStanford UniversityStanfordUSA
  8. 8.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  9. 9.Department of BioengineeringStanford UniversityStanfordUSA
  10. 10.Department of Psychiatry and PsychotherapyUniversity of MuensterMuensterGermany
  11. 11.Department of Clinical PharmacologyUniversity GöttingenGöttingenGermany
  12. 12.Department of PsychiatryTaipei Medical University-Shuangho HospitalNew Taipei CityTaiwan
  13. 13.Department of Psychiatry and Psychotherapy, Faculty of MedicineUniversity of FreiburgFreiburgGermany
  14. 14.Department of Psychiatry and PsychologyMayo ClinicRochesterUSA
  15. 15.Department of PsychiatryTaipei Veterans General HospitalTaipeiTaiwan
  16. 16.Division of Psychiatry, School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  17. 17.Department of Psychiatry, Faculty of Medicine and Life SciencesUniversity of TampereTampereFinland
  18. 18.Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterUSA
  19. 19.Department of PsychiatrySeinäjoki Hospital DistrictSeinäjokiFinland
  20. 20.Department of NeuropsychiatryKansai Medical UniversityOsakaJapan
  21. 21.Department of PsychiatryTampere University HospitalTampereFinland
  22. 22.RIKEN Center for Integrative Medical SciencesYokohamaJapan
  23. 23.Department of PharmacyHyogo University of Health SciencesKobeJapan
  24. 24.Center for Neuropsychiatric ResearchNational Health Research InstitutesMiaoliTaiwan
  25. 25.Center for Medical Genetics Research, Department of Mental Health, Ministry of Public Health BangkokRajanukul InstituteBangkokThailand
  26. 26.Research Division Federal Institute for Drugs and Medical DevicesBonnGermany

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