Role of the Wnt signaling pathway in bipolar disorder susceptibility: Gene-set analysis of SNP-BMI interaction effects. M. A. Simonson1, S. J. Winham1, G. D. Jenkins1, A. Cuellar Barboza2, M. H. Jang3, S. McElroy4, M. A. F. Frye1, 5, J. M. Biernacka1, 5 1) Health Sciences Research, Mayo Clinic, Rochester, MN; 2) Universidad Autonoma de Nuevo Leon, Monterrey, Mexico; 3) Neurologic Surgery, and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN; 4) Lindner Center of Hope, Mason, OH; 5) Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN.

   The Wnt signaling pathway is essential for the maturation and functioning of the central nervous system and may play a role in the etiology of bipolar disorder (BD), although the precise genetic mechanisms of this relationship remain unknown. BD is associated with higher body mass index (BMI) and increased metabolic comorbidity. In a previous GWAS that examined interaction effects between BMI and potential BD risk alleles, we identified a significant SNPxBMI interaction in the gene TCF7L2, a critical member of the Wnt signaling pathway. Here we built upon those results by performing a gene-set analysis of this pathway to elucidate relevant genetic factors that influence BD susceptibility, potentially via an interaction with BMI. Using data from the Genetic Association Information Network (GAIN) genome-wide association study of BD, we performed gene-set analyses to evaluate both genetic main effects and SNP-BMI interaction effects. The analysis included 388 cases and 1,020 controls of European American ancestry with available BMI data. The gene set consisted of 3,761 SNPs in 148 genes in the pathway. Gene-set analysis was performed using Interval Based Enrichment Analysis (INRICH), and a modification of the PC-gamma method previously developed for testing SNP main effects at the pathway level. In addition to pathway-level results, the PC-gamma approach provides gene-level tests of association, and INRICH identifies specific genes that contribute to pathway enrichment for associations, which were used to evaluate both gene main effects and BMI-gene interactions. Both methods provided evidence of association for both the SNP main effects and BMI-SNP interactions at the pathway level. Additionally, both methods identified several of the same genes or gene-BMI interactions as top associations with BD. In addition to the gene TCF7L2, FZD7 was identified as having for both main and interaction effects by INRICH and the PC-gamma approach. These genes also contain SNPs previously associated with psychiatric or neurological disorders. Further functional work is needed to determine the neurobiological mechanisms underlying the identified associations with BD, particularly the identified interaction with BMI.

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