title: Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2.
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.
authors: Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, MN, USA.
authors: S J
authors: SJ
authors: Winham
authors: 1] Department of Psychiatry, University Hospital, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico [2] Department of Psychiatry and Psychology, Mayo Clinic Rochester, Rochester, MN, USA.
authors: A B
authors: AB
authors: Cuellar-Barboza
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN, USA.
authors: A
authors: A
authors: Oliveros
authors: 1] Lindner Center of HOPE, Mason, OH, USA [2] University of Cincinnati, College of Medicine, Cincinnati, OH, USA.
authors: S L
authors: SL
authors: McElroy
authors: Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
authors: S
authors: S
authors: Crow
authors: Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, MN, USA.
authors: C
authors: C
authors: Colby
authors: 1] Department of Psychiatry and Psychology, Mayo Clinic Rochester, Rochester, MN, USA [2] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN, USA.
authors: D-S
authors: DS
authors: Choi
authors: Department of Psychiatry and Psychology, Mayo Clinic Health Systems Austin, Austin, MN, USA.
authors: M
authors: M
authors: Chauhan
authors: Department of Psychiatry and Psychology, Mayo Clinic Rochester, Rochester, MN, USA.
authors: M
authors: M
authors: Frye
authors: 1] Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, MN, USA [2] Department of Psychiatry and Psychology, Mayo Clinic Rochester, Rochester, MN, USA.
authors: J M
authors: JM
authors: Biernacka
mesh_terms: D001741:Black or African American / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology*; D015992:Body Mass Index; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide; D011795:Surveys and Questionnaires; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein