Original Article Accumulating evidence for a role of TCF7L2 variants in bipolar disorder with elevated body mass index Cuellar-Barboza AB, Winham SJ, McElroy SL, Geske JR, Jenkins GD, Colby CL, Prieto ML, Ryu E, Cunningham JM, Frye MA, Biernacka JM. Accumulating evidence for a role of TCF7L2 variants in bipolar disorder with elevated body mass index. Bipolar Disord 2016: 18: 124–135. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives: Bipolar disorder (BD) is a complex disease associated with various hereditary traits, including a higher body mass index (BMI). In a prior genome-wide association study, we found that BMI modified the association of rs12772424 – a common variant in the gene encoding transcription factor 7-like 2 (TCF7L2) – with risk for BD. TCF7L2 is a transcription factor in the canonical Wnt pathway, involved in multiple disorders, including diabetes, cancer and psychiatric conditions. Here, using an independent sample, we evaluated 26 TCF7L2 single nucleotide polymorphisms (SNPs) to explore further the association of BD with the TCF7L2–BMI interaction. Methods: Using a sample of 662 BD cases and 616 controls, we conducted SNP-level and gene-level tests to assess the evidence for an association between BD and the interaction of BMI and genetic variation in TCF7L2. We also explored the potential mechanism behind the detected associations using human brain expression quantitative trait loci (eQTL) analysis. Results: The analysis provided independent evidence of an rs12772424– BMI interaction (p = 0.011). Furthermore, while overall there was no evidence for SNP marginal effects on BD, the TCF7L2–BMI interaction was significant at the gene level (p = 0.042), with seven of the 26 SNPs showing SNP–BMI interaction effects with p < 0.05. The strongest evidence of interaction was observed for rs7895307 (p = 0.006). TCF7L2 expression showed a significant enrichment of association with the expression of other genes in the Wnt canonical pathway. Conclusions: The current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association. Alfredo B Cuellar-Barboza a,b, *, Stacey J Winham c, *, Susan L McElroy d , Jennifer R Geske c , Gregory D Jenkins c , Colin L Colby c , Miguel L Prieto a,e,f , Euijung Ryu c , Julie M Cunningham g , Mark A Frye a and Joanna M Biernacka a,c a Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA, b Department of Psychiatry, University Hospital, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico, c Department of Health Sciences Research, Mayo Clinic, Rochester, MN, d Lindner Center of HOPE, Mason, OH, USA, e Departamento de Psiquiatr  ıa, Facultad de Medicina, Universidad de los Andes, f Cl  ınica Universidad de los Andes, Unidad de Salud Mental, Santiago, Chile, g Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, USA doi: 10.1111/bdi.12368 Key words: bipolar disorder – body mass index – obesity – TCF7L2 Received 28 April 2015, revised 3 November 2015, revised and accepted for publication 9 November 2015 Corresponding author: Joanna Biernacka Department of Psychiatry and Psychology Mayo Clinic 200 First Street, SW Rochester, MN 55905 USA Fax: 507-284-9542 E-mail: biernacka.joanna@mayo.edu *These authors contributed equally to the study. Bipolar disorder (BD) is characterized by recurrent episodes of depression, mania, and/or hypomania (1), and has devastating clinical consequences (2) and high mortality (3). It has a high heritability of approximately 60–85% (4), most likely explained by multiple common variants with small-to-moder- ate effects (5). Early linkage and candidate-gene studies provided inconsistent findings; however, an 124 Bipolar Disorders 2016: 18: 124–135 © 2016 John Wiley & Sons A/S Published by John Wiley & Sons Ltd. BIPOLAR DISORDERS