The Evidence of Bipolar Disease Risk (GWAS, functional genomics) and Cardiometabolic Disease Risk that Informs Ketogenic Studies at Mayo Clinic

Prof Mark Frye, Mayo Clinic

Abstract

Bipolar disorder (BD) is a complex illness with  high rates of obesity, cardiometabolic burden, poor diet quality, and disordered eating. The innovation of the Mayo Clinic Bipolar Biobank (n=2500), from its inception, was the concept of narrower phenotyping of bipolar illness to develop more homogeneous samples with potentially greater statistical power for subsequent genomic and pharmacogenomic analyses.  To gain greater understanding of the potential contribution of genetic factors to the comorbidity of BD and obesity, we performed a GWAS for BD risk accounting for the effect of BMI. We identified, and replicated in separate cohort ,a genome-wide significant SNP signal (“rs12772424, P=2.85E-08) mapping to an intronic region of the TCF7L2 gene, a well-established type-2 diabetes (T2D) risk gene. Functional studies of this SNP, using iPSC-derived cell line models identified a long non-coding transcript (lncRNA-TCF7L2) that, in an astrocyte knockdown model, resulted in alterations in the expression of a series of genes involved in insulin signaling and diabetes. From a clinical perspective, it is well known that BD has high rates of cardiometabolic burden. Case-controlled work from our Rochester Epidemiology Project (REP) identified that BD patients had significantly higher rates of obesity, elevated systolic blood pressure, and elevated triglycerides.

A second study, controlling for cardiovascular risk factors, additionally identified that BD patients were at increased risk for a major adverse cardiac event (MACE). Recent data would additionally suggest that poor diet quality was associated with not only increase BMI and central adiposity, but greater symptom burden of depression and disordered eating, underscoring the necessity of dietary interventions to address depressive symptoms and reduce cardiometabolic risk.  This is the evidence base that has informed the development of our study Ketogenic Intervention for Bipolar Depression: An Open-label Trial Guiding Clinical Implementation (KETO-MAYO). The study design, outcome measures and implications will be presented to the Hub for Metabolic Psychiatry.

Speaker Biography

Mark A. Frye, M.D., is a Consultant in the Department of Psychiatry & Psychology at Mayo Clinic. He is the past Chair of the Department of Psychiatry & Psychology (2010-2020) and is recognised with the distinction of the Stephen and Shelley Jackson Family Professorship in Individualised Medicine.

Prof Frye and his team established the Mayo Clinic Individualised Medicine Biobank for Bipolar Disorder to identify the underpinning mechanisms of bipolar disorder through genomic studies. An active clinical investigator, he has received research support from NIMH, NIAAA, Mayo Foundation, Brain & Behavior Research Foundation, and industry partners, and has published more than 500 peer-reviewed papers.

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