Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample

The Pharmacogenomics Journal volume 16, pages 352–356 (2016)Cite this article

Subjects

Abstract

Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10−8. We observed interesting trends for rs9346455 (P=6.49x10−6) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10−5) and rs1012650 (P=1.47 × 10−5), and rs1059778 (P=1.49x10−5) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10−7. Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Newcomer JW . Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19: 1–93.

    Article  CAS  PubMed  Google Scholar 

  2. Das C, Mendez G, Jagasia S, Labbate LA . Second-generation antipsychotic use in schizophrenia and associated weight gain: a critical review and meta-analysis of behavioral and pharmacologic treatments. Ann Clin Psychiatry 2012; 24: 225–239.

    PubMed  Google Scholar 

  3. Lett TA, Wallace TJ, Chowdhury NI, Tiwari AK, Kennedy JL, Muller DJ . Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry 2012; 17: 242–266.

    Article  CAS  PubMed  Google Scholar 

  4. Shams TA, Muller DJ . Antipsychotic induced weight gain: genetics, epigenetics, and biomarkers reviewed. Curr Psychiatry Rep 2014; 16: 473.

    Article  PubMed  Google Scholar 

  5. Wallace TJ, Zai CC, Brandl EJ, Muller DJ . Role of 5-HT(2C) receptor gene variants in antipsychotic-induced weight gain. Pharmgenom Pers Med 2011; 4: 83–93.

    CAS  Google Scholar 

  6. Malhotra AK, Correll CU, Chowdhury NI, Muller DJ, Gregersen PK, Lee AT et al. Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry 2012; 69: 904–912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Czerwensky F, Leucht S, Steimer W . MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain? Int J Neuropsychopharmacol 2013; 16: 2103–2109.

    Article  CAS  PubMed  Google Scholar 

  8. Nurmi EL, Spilman SL, Whelan F, Scahill LL, Aman MG, McDougle CJ et al. Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies. Transl Psychiatry 2013; 3: e274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

    Article  CAS  PubMed  Google Scholar 

  10. Need AC, Keefe RS, Ge D, Grossman I, Dickson S, McEvoy JP et al. Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis. Eur J Hum Genet 2009; 17: 946–957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tiwari HK, Patki A, Lieberman J, Stroup TS, Allison DB, Leibel RL et al. Association of allelic variation in genes mediating aspects of energy homeostasis with weight gain during administration of antipsychotic drugs (CATIE Study). Front Genet 2011; 2: 56.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Adkins DE, Aberg K, McClay JL, Bukszar J, Zhao Z, Jia P et al. Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Mol Psychiatry 2011; 16: 321–332.

    Article  CAS  PubMed  Google Scholar 

  13. Tiwari AK, Brandl EJ, Weber C, Likhodi O, Zai CC, Hahn MK et al. Association of a functional polymorphism in neuropeptide Y with antipsychotic-induced weight gain in schizophrenia patients. J Clin Psychopharmacol 2013; 33: 11–17.

    Article  CAS  PubMed  Google Scholar 

  14. Brandl EJ, Tiwari AK, Chowdhury NI, Zai CC, Lieberman JA, Meltzer HY et al. Genetic variation in the GCG and in the GLP1R genes and antipsychotic-induced weight gain. Pharmacogenomics 2014; 15: 423–431.

    Article  CAS  PubMed  Google Scholar 

  15. Pinheiro J, Bates D, DebRoy S, Sarkar D, Team RC nlme: Linear and Nonlinear Mixed Effects Models. R package version 3.1-117. 2014; Available at: http://CRAN.R-project.org/package=nlme; last accessed on 15 December, 2014.

  16. Willer CJ, Li Y, Abecasis GR . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 2010; 26: 2190–2191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Oeschger FM, Wang WZ, Lee S, Garcia-Moreno F, Goffinet AM, Arbones ML et al. Gene expression analysis of the embryonic subplate. Cereb Cortex 2012; 22: 1343–1359.

    Article  PubMed  Google Scholar 

  18. Buchser WJ, Smith RP, Pardinas JR, Haddox CL, Hutson T, Moon L et al. Peripheral nervous system genes expressed in central neurons induce growth on inhibitory substrates. PLoS One 2012; 7: e38101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Barragan I, Abd El-Aziz MM, Borrego S, El-Ashry MF, O'Driscoll C, Bhattacharya SS et al. Linkage validation of RP25 using the 10 K genechip array and further refinement of the locus by new linked families. Ann Hum Genet 2008; 72: 454–462.

    Article  CAS  PubMed  Google Scholar 

  20. Abd El-Aziz MM, Patel RJ, El-Ashry MF, Barragan I, Marcos I, Borrego S et al. Exclusion of four candidate genes, KHDRBS2, PTP4A1, KIAA1411 and OGFRL1, as causative of autosomal recessive retinitis pigmentosa. Ophthalmic Res 2006; 38: 19–23.

    Article  CAS  PubMed  Google Scholar 

  21. Sheftel AD, Wilbrecht C, Stehling O, Niggemeyer B, Elsasser HP, Muhlenhoff U et al. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4 S] protein maturation. Mol Biol Cell 2012; 23: 1157–1166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ajit Bolar N, Vanlander AV, Wilbrecht C, Van der Aa N, Smet J, De Paepe B et al. Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. Hum Mol Genet 2013; 22: 2590–2602.

    Article  CAS  PubMed  Google Scholar 

  23. Goncalves VF, Zai CC, Tiwari AK, Brandl EJ, Derkach A, Meltzer HY et al. A hypothesis-driven association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 2014; 39: 1347–1354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Harper AR, Topol EJ . Pharmacogenomics in clinical practice and drug development. Nat Biotechnol 2012; 30: 1117–1124.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The principal investigators of the CATIE trial were Jeffrey A Lieberman, MD, T Scott Stroup, MD, MPH, and Joseph P McEvoy, MD. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. AKT: recipient of NARSAD 2010 young investigator award. CCZ: recipient of NARSAD Young Investigator Award; postdoctoral fellowship from the American Foundation for Suicide Prevention (2PDF-00065-1208-0609-1209); and Eli Lilly Canada. ELN: supported by the NIMH Career Development Award K23 MH094613-01. NIC: OMHF Research Studentship. DJM: CIHR operating grant (Genetics of antipsychotics induced metabolic syndrome, MOP 89853 and Development, validation, and benefits of a genetic risk model for AIWG; MOP 142192); NARSAD Independent Investigator Award, Early Researcher Award by the Ministry of Research and Innovation of Ontario, CIHR Michael Smith New Investigator Salary Prize for Research in Schizophrenia and OMHF New Investigator Fellowship. JLK: recipient of a CIHR operating grant (Strategies for gene discovery in schizophrenia: subphenotypes, deep sequencing and interactions, MOP 115097), recipient of a Genome Canada grant. The funding sources did not have any influence on study design, data analysis and writing of the manuscript.

Author information

Author notes

  1. E J Brandl and A K Tiwari: These authors contributed equally to this work.

Authors and Affiliations

  1. Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    E J Brandl, A K Tiwari, C C Zai, N I Chowdhury, T Arenovich, M Sanches, V F Goncalves, J L Kennedy & D J Müller

  2. Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany

    E J Brandl

  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    C C Zai, V F Goncalves, J L Kennedy & D J Müller

  4. Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Semel Institute for Neuroscience, Los Angeles, CA, USA

    E L Nurmi

  5. Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China

    J J Shen

  6. Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York City, NY, USA

    J A Lieberman

  7. Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL, USA

    H Y Meltzer

Authors
  1. E J Brandl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A K Tiwari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C C Zai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E L Nurmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N I Chowdhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Arenovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Sanches
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V F Goncalves
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J J Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J A Lieberman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Y Meltzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J L Kennedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D J Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D J Müller.

Ethics declarations

Competing interests

EJB/AKT/CCZ/VFG/NIC/DJM/JLK are authors on a patent application for a multigene model (not including SNPs presented here) predicting antipsychotic-induced weight gain. TA/MS/JJS/ELN: no competing interests. HYM has received grants or is or was a consultant to: Abbott Labs, ACADIA, Alkemes, Bristol Myers Squibb, DaiNippon Sumitomo, Eli Lilly, EnVivo, Janssen, Otsuka, Pfizer, Roche, Sunovion and BiolineRx. HYM is a shareholder of ACADIA and Glaxo Smith Kline. In the past 3 years JAL reports having received research funding or is a member of the advisory board of Allon, Alkermes Bioline, GlaxoSmithKline Intracellular Therapies, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Psychogenics, F Hoffmann-La Roche, Sepracor (Sunovion) and Targacept. JAL received no direct financial compensation or salary support for participation in these researches, consulting or advisory board activities. JLK has been a consultant to GSK, Sanofi-Aventis and Dainippon-Sumitomo.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brandl, E., Tiwari, A., Zai, C. et al. Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample. Pharmacogenomics J 16, 352–356 (2016). https://doi.org/10.1038/tpj.2015.59

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.59

This article is cited by

Search

Advanced search

Quick links