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Genetic validation study of protein tyrosine phosphatase receptor type D (PTPRD) gene variants and risk for antipsychotic-induced weight gain

  • Translational Neurosciences - Original Article
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Abstract

Schizophrenia is a severe, debilitating disorder with a lifetime prevalence of 1% irrespective of gender or ethnicity and is typically treated with antipsychotic drugs. Antipsychotic-induced weight gain (AIWG) is a leading factor of patient non-compliance and has previously been shown to increase the risk of type 2 diabetes, metabolic syndrome, and cardiovascular events. The current study intends to replicate findings from a recent genome-wide association study in Han-Chinese patients implicating two gene variants (rs10977144 and rs10977154) of the protein tyrosine phosphatase receptor type D (PTPRD) in antipsychotic-induced weight gain (AIWG). We investigated a sample of European and African American ancestry (n = 201) and calculated percentage of weight change using linear regression corrected for type of antipsychotics, duration of treatment and principal components from ancestry checks. As secondary goal, we investigated additional gene variants of PTPRD previously not associated with AIWG. We found no association with rs10977144 and rs10977154. However, we found nominally significant results between PTPRD and AIWG with rs73398242 in Europeans (BETA = − 0.267, p = 0.002) and rs13294608 in African Americans (BETA = 0.423, p = 0.003). According to Haploreg, both SNPs are histone marks for enhancers and promoters across various brain regions including the cingulate gyrus and dorsolateral prefrontal cortex. In summary, our results tentatively suggest that PTPRD might be associated with AIWG although different SNPS might be involved in different ethnic groups.

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References

  • 1000 Genomes Project Consortium, Abecasis GR, Altshuler D et al (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073

    Article  CAS  Google Scholar 

  • Anderson CA, Pettersson FH, Clarke GM et al (2010) Data quality control in genetic case-control association studies. Nat Protoc 5:1564–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belfort-DeAguiar R, Seo D, Lacadie C et al (2018) Obese humans have disordered brain responses to food images during physiological hyperglycemia. Am J Physiol Endocrinol Metab. https://doi.org/10.1152/ajpendo.00335.2017

    Article  PubMed  PubMed Central  Google Scholar 

  • Below JE, Gamazon ER, Morrison JV et al (2011) Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals. Diabetologia 54:2047–2055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang Y-C, Chiu Y-F, Liu P-H et al (2012) Replication of genome-wide association signals of type 2 diabetes in Han Chinese in a prospective cohort. Clin Endocrinol 76:365–372

    Article  CAS  Google Scholar 

  • Cheke LG, Bonnici HM, Clayton NS, Simons JS (2017) Obesity and insulin resistance are associated with reduced activity in core memory regions of the brain. Neuropsychologia 96:137–149

    Article  PubMed  PubMed Central  Google Scholar 

  • Clarke GM, Anderson CA, Pettersson FH et al (2011) Basic statistical analysis in genetic case-control studies. Nat Protoc 6:121–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Delaneau O, Marchini J, Zagury J-F (2011) A linear complexity phasing method for thousands of genomes. Nat Methods 9:179–181

    Article  CAS  PubMed  Google Scholar 

  • Gonçalves VF, Zai CC, Tiwari AK et al (2014) A hypothesis-driven association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 39:1347–1354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeda M, Tanaka S, Saito T et al (2018) Re-evaluating classical body type theories: genetic correlation between psychiatric disorders and body mass index. Psychol Med 48:1745–1748

    Article  PubMed  PubMed Central  Google Scholar 

  • Imamura M, Iwata M, Maegawa H et al (2013) Replication study for the association of rs391300 in SRR and rs17584499 in PTPRD with susceptibility to type 2 diabetes in a Japanese population. J Diabetes Investig 4:168–173

    Article  CAS  PubMed  Google Scholar 

  • Kang SH, Lee J-I, Han HR et al (2014) Polymorphisms of the leptin and HTR2C genes and clozapine-induced weight change and baseline BMI in patients with chronic schizophrenia. Psychiatr Genet 24:249–256

    Article  CAS  PubMed  Google Scholar 

  • Kim S-H, Chung J-H, Kim T-H et al (2017) The effects of repetitive transcranial magnetic stimulation on eating behaviors and body weight in obesity: a randomized controlled study. Brain Stimul. https://doi.org/10.1016/j.brs.2017.11.020

    Article  PubMed  PubMed Central  Google Scholar 

  • Kircher M, Witten DM, Jain P et al (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lett TAP, Wallace TJM, Chowdhury NI et al (2012) Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry 17:242–266

    Article  CAS  PubMed  Google Scholar 

  • Lieberman JA, Stroup TS, McEvoy JP et al (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Chen L, Li Z et al (2014) Association between gene polymorphisms of seven newly identified loci and type 2 diabetes and the correlate quantitative traits in Chinese Dong populations. Iran J Public Health 43:1345–1355

    PubMed  PubMed Central  Google Scholar 

  • Machiela MJ, Chanock SJ (2015) LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31:3555–3557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacNeil RR, Müller DJ (2016) Genetics of common antipsychotic-induced adverse effects. Mol Neuropsychiatry 2:61–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malhotra AK, Correll CU, Chowdhury NI et al (2012) Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug—induced weight gain. Arch Gen Psychiatry 69:904–912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marchini J, Howie B (2010) Genotype imputation for genome-wide association studies. Nat Rev Genet 11:499–511

    Article  CAS  PubMed  Google Scholar 

  • Nurmi EL, Spilman SL, Whelan F et al (2013) Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies. Transl Psychiatry 3:e274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Opgen-Rhein C, Brandl EJ, Müller DJ et al (2010) Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics 11:773–780

    Article  CAS  PubMed  Google Scholar 

  • Owen MJ, Sawa A, Mortensen PB (2016) Schizophrenia. Lancet 388:86–97

    Article  PubMed  PubMed Central  Google Scholar 

  • Price AL, Patterson NJ, Plenge RM et al (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909

    Article  CAS  PubMed  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiwari AK, Brandl EJ, Weber C et al (2013) Association of a functional polymorphism in neuropeptide Y with antipsychotic-induced weight gain in schizophrenia patients. J Clin Psychopharmacol 33:11–17

    Article  CAS  PubMed  Google Scholar 

  • Tiwari AK, Brandl EJ, Zai CC et al (2016) Association of orexin receptor polymorphisms with antipsychotic-induced weight gain. World J Biol Psychiatry 17:221–229

    Article  PubMed  Google Scholar 

  • Tsai F-J, Yang C-F, Chen C-C et al (2010) A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6:e1000847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  • Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934

    Article  CAS  PubMed  Google Scholar 

  • Ward J, Strawbridge RJ, Bailey MES et al (2017) Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia. Transl Psychiatry 7:1264

    Article  PubMed  PubMed Central  Google Scholar 

  • Winter SR, Yokum S, Stice E et al (2017) Elevated reward response to receipt of palatable food predicts future weight variability in healthy-weight adolescents. Am J Clin Nutr 105:781–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Wang L, Lv L et al (2016) Genome-Wide Association Study suggested the PTPRD polymorphisms were associated with weight gain effects of atypical antipsychotic medications. Schizophr Bull 42:814–823

    Article  PubMed  Google Scholar 

  • Zhang J-P, Lencz T, Zhang RX et al (2016) Pharmacogenetic associations of antipsychotic drug-related weight gain: a systematic review and meta-analysis. Schizophr Bull 42:1418–1437

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This investigation received approval from the Centre of Addiction and Mental Health Research Ethics Board. We are indebted to all patients participating in our research. All included participants gave informed consent to participate.

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Authors and Affiliations

  1. Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, R-132, Toronto, ON, M5T1R8, Canada

    Malgorzata Maciukiewicz, Ilona Gorbovskaya, Arun K. Tiwari, Clement C. Zai, Natalie Freeman, James L. Kennedy & Daniel J. Müller

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

    Arun K. Tiwari, Clement C. Zai & Daniel J. Müller

  3. Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    James L. Kennedy & Daniel J. Müller

  4. Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA

    Herbert Y. Meltzer

Authors
  1. Malgorzata Maciukiewicz
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  2. Ilona Gorbovskaya
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  3. Arun K. Tiwari
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  4. Clement C. Zai
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  5. Natalie Freeman
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  6. Herbert Y. Meltzer
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  7. James L. Kennedy
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  8. Daniel J. Müller
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Correspondence to Daniel J. Müller.

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Maciukiewicz, M., Gorbovskaya, I., Tiwari, A.K. et al. Genetic validation study of protein tyrosine phosphatase receptor type D (PTPRD) gene variants and risk for antipsychotic-induced weight gain. J Neural Transm 126, 27–33 (2019). https://doi.org/10.1007/s00702-018-1921-1

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  • DOI: https://doi.org/10.1007/s00702-018-1921-1

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