Elsevier

Biological Psychiatry

Volume 70, Issue 1, 1 July 2011, Pages 59-63
Biological Psychiatry

Archival Report
At-Risk Variant in TCF7L2 for Type II Diabetes Increases Risk of Schizophrenia

https://doi.org/10.1016/j.biopsych.2011.01.031Get rights and content

Background

Schizophrenia is associated with increased risk of type II diabetes and metabolic disorders. However, it is unclear whether this comorbidity reflects shared genetic risk factors, at-risk lifestyle, or side effects of antipsychotic medication.

Methods

Eleven known risk variants of type II diabetes were genotyped in patients with schizophrenia in a sample of 410 Danish patients, each matched with two healthy control subjects on sex, birth year, and month. Replication was carried out in a large multinational European sample of 4089 patients with schizophrenia and 17,597 controls (SGENE+) using Mantel–Haenszel test.

Results

One type II diabetes at-risk allele located in TCF7L2, rs7903146 [T], was associated with schizophrenia in the discovery sample (p = .0052) and in the replication with an odds ratio of 1.07 (95% confidence interval 1.01–1.14, p = .033).

Conclusion

The association reported here with a well-known diabetes variant suggests that the observed comorbidity is partially caused by genetic risk variants. This study also demonstrates how genetic studies can successfully examine an epidemiologically derived hypothesis of comorbidity.

Section snippets

Danish Discovery Sample

Four hundred twenty patients from the Danish Psychiatric Biobank diagnosed with International Classification of Diseases (ICD) Version 10 F20 or F25 and with no history of bipolar disorder (F30–31) were used as the discovery sample (37). For each patient, two healthy control subjects were selected among 15,000 donors in the Danish Blood Donor Corps (> 5% of the Danish population) from the same Copenhagen area as the patients. They were matched to the patients on sex and year/month of birth. At

Frequencies and Hardy–Weinberg Equilibriums

Eleven SNPs associated with T2D in GWAS before this study (published before 2008) were genotyped in the Danish sample. The allele frequencies correspond to those described in dbSNP and HapMap for Caucasians. The observed genotype distribution was not significantly different from that expected under Hardy–Weinberg proportions after correction for multiple testing (Table 1), with the exception of the SNP rs7756992 in CDKAL1 in cases (p = .002). Thus, all 11 SNPs were tested for association to

Discussion

To the best of our knowledge, this study is the first attempt to use known genetic risk factors for an epidemiologic or clinical condition to analyze a shared etiology between a somatic and a psychiatric disorder. Prompted by the increased incidence of T2D among schizophrenia patients, we analyzed the risk conferred by known T2D susceptibility variants for developing schizophrenia.

The T2D at-risk SNP in TCF7L2 (rs7903146 [T]), but not the other 10 examined T2D at-risk alleles, was associated

References (53)

  • F.H. Kooy

    Hyperglycemia in mental disorders

    Brain

    (1919)
  • T. Raphael et al.

    Blood sugar studies in dementia praecox and manic-depressive insanity

    Arch Neurol Psychiatry

    (1921)
  • C. Bushe et al.

    Prevalence of diabetes and impaired glucose tolerance in patients with schizophrenia

    Br J Psychiatry Suppl

    (2004)
  • M.J. Sernyak et al.

    Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia

    Am J Psychiatry

    (2002)
  • K. Hedenmalm et al.

    Glucose intolerance with atypical antipsychotics

    Drug Saf

    (2002)
  • L. Schwarz et al.

    Blood sugar levels in patients treated with chlorpromazine

    Am J Psychiatry

    (1968)
  • D.P. Osborn et al.

    Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom's general practice Rsearch Database

    Arch Gen Psychiatry

    (2007)
  • W.S. Fenton et al.

    Medication-induced weight gain and dyslipidemia in patients with schizophrenia

    Am J Psychiatry

    (2006)
  • M. Joukamaa et al.

    Schizophrenia, neuroleptic medication and mortality

    Br J Psychiatry

    (2006)
  • W.F. Lorenz

    Sugar tolerance in dementia praecox and other mental disorders

    Arch Neurol Psychiatry

    (1922)
  • H. Freeman et al.

    The carbohydrate tolerance of mentally disturbed soldiers

    Psychosoc Med

    (1944)
  • F.J. Braceland et al.

    Delayed action of insulin in schizophrenia

    Am J Psychiatry

    (1945)
  • K.M. Bowman

    Endocrin and biochemical studies in schizophrenia

    J Nerv Ment Dis

    (1927)
  • L.M. Spelman et al.

    Impaired glucose tolerance in first-episode drug-naive patients with schizophrenia

    Diabet Med

    (2007)
  • M.C. Ryan et al.

    Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia

    Am J Psychiatry

    (2003)
  • S.R. Marder et al.

    Physical health monitoring of patients with schizophrenia

    Am J Psychiatry

    (2004)
  • Cited by (116)

    View all citing articles on Scopus
    View full text