Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2

Stacey J Winham, A. B. Cuellar-Barboza, A. Oliveros, S. L. McElroy, S. Crow, C. Colby, Doo Sup Choi, M. Chauhan, Mark A Frye, Joanna M Biernacka

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Abstract

Bipolar disorder (BD) is associated with higher body mass index (BMI) and increased metabolic comorbidity. Considering the associated phenotypic traits in genetic studies of complex diseases, either by adjusting for covariates or by investigating interactions between genetic variants and covariates, may help to uncover the missing heritability. However, obesity-related traits have not been incorporated in prior genome-wide analyses of BD as covariates or potential interacting factors. To investigate the genetic factors underlying BD while considering BMI, we conducted genome-wide analyses using data from the Genetic Association Information Network BD study. We analyzed 729 454 genotyped single-nucleotide polymorphism (SNP) markers on 388 European-American BD cases and 1020 healthy controls with available data for maximum BMI. We performed genome-wide association analyses of the genetic effects while accounting for the effect of maximum BMI, and also evaluated SNP-BMI interactions. A joint test of main and interaction effects demonstrated significant evidence of association at the genome-wide level with rs12772424 in an intron of TCF7L2 (P=2.85E-8). This SNP exhibited interaction effects, indicating that the bipolar susceptibility risk of this SNP is dependent on BMI. TCF7L2 codes for the transcription factor TCF/LF, part of the Wnt canonical pathway, and is one of the strongest genetic risk variants for type 2 diabetes (T2D). This is consistent with BD pathophysiology, as the Wnt pathway has crucial implications in neurodevelopment, neurogenesis and neuroplasticity, and is involved in the mechanisms of action of BD and depression treatments. We hypothesize that genetic risk for BD is BMI dependent, possibly related to common genetic risk with T2D.Molecular Psychiatry advance online publication, 10 December 2013; doi:10.1038/mp.2013.159.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Dec 10 2013

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Genome-Wide Association Study
Bipolar Disorder
Body Mass Index
Alleles
Single Nucleotide Polymorphism
Wnt Signaling Pathway
Genome
Type 2 Diabetes Mellitus
Transcription Factor 7-Like 2 Protein
Neuronal Plasticity
Information Services
Neurogenesis
Introns
Psychiatry
Publications
Comorbidity
Obesity
Joints

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Molecular Biology

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Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2. / Winham, Stacey J; Cuellar-Barboza, A. B.; Oliveros, A.; McElroy, S. L.; Crow, S.; Colby, C.; Choi, Doo Sup; Chauhan, M.; Frye, Mark A; Biernacka, Joanna M.

In: Molecular Psychiatry, 10.12.2013.

Research output: Contribution to journalArticle

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