Nov. 11, 2016
The heritability of bipolar disorder — a severe mood disorder characterized by recurrent episodes of mania or hypomania and depression — has been estimated at around 85 percent. In the last decade, replicated genome-wide association studies have identified several risk loci, most notably ANK3, NCAN, CACNA1C and ODZ4. Genes associated with circadian rhythm patterns, including circadian locomotor output cycles kaput (CLOCK) genes, have also been linked to bipolar disorder.
Although these studies have provided valuable information about the molecular mechanisms of bipolar disorder, they don't fully explain its heritability, which is likely the result of a large number of risk genes, each conferring a small degree of disease susceptibility. Thus, more research is needed, ideally using large patient populations with precisely defined phenotypes.
To further this aim, Mayo Clinic in Rochester, Minnesota, established a bipolar biobank in collaboration with the Lindner Center of HOPE and the University of Minnesota in 2009. The goal was to create a resource for clinical and biomarker studies of disease risk and treatment response.
To date, nearly 2,000 patients have contributed medical information and blood samples to the biobank. Most participants are white and female, with diagnosed bipolar I disorder. Clinical phenotypes include a history of psychosis, attempted suicide, nicotine or alcohol addiction, and antidepressant-induced mania. Nearly 43 percent of biobank patients met the criteria for obesity (body mass index of 30 or higher).
Genetic variation regulated by BMI
The obesity phenotype has proved a fruitful area of research, according to biobank co-principal investigator and lead statistical geneticist, Joanna M. Biernacka, Ph.D., who directs the Psychiatric Genomics and Pharmacogenomics Program at Mayo Clinic's campus in Minnesota. "The way in which some genetic variations associated with bipolar disorder impact disease presentation appears to be regulated by factors related to BMI," she explains. "Our research group found that rs12772424 — a variant of the protein coding gene TCF7L2 — may help mediate the onset of bipolar disorder. The effect of the gene increases with body mass index (BMI)."
The group's initial finding was published in Molecular Psychiatry in 2014; the replication was published in Bipolar Disorders in 2016. A related 2016 study published in the Journal of Affective Disorders found an increased prevalence of obesity and binge-eating disorder in patients with bipolar disorder.
Still, the precise relationship between obesity and bipolar disorder remains unclear, says Mark A. Frye, M.D., the biobank's other principal investigator and a psychiatrist specializing in bipolar disorder at Mayo Clinic's campus in Minnesota. "Was there an elevated BMI from the beginning? Did the BMI increase over time? We want to better understand the genetic risk and interaction with obesity, yet it's very challenging due to the complexity of this disease," he says.
Nevertheless, Dr. Frye says the detailed phenotype obtained for biobank participants is an important research tool. He points out that composite measures of mood instability, comorbid anxiety and multiple drug addiction, beyond the confirmed bipolar disorder subtype, are novel quantifications that may provide more-detailed clinical disease characteristics that can be used in future biomarker genomic studies.
"Future studies that focus not on a DSM-5 bipolar disorder diagnosis but on a more-detailed phenotype such as bipolar disorder with obesity may uncover risk genes not previously identified," he explains.
For more information
Winham SJ, et al. Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2. Molecular Psychiatry. 2014;19:1010.
Cuellar-Barboza AB, et al. Accumulating evidence for a role of TCF7L2 variants in bipolar disorder with elevated body mass index. Bipolar Disorders. 2016;18:124.
McElroy SL, et al. Clinical features of bipolar spectrum with binge eating behaviour. Journal of Affective Disorders. 2016;201:95.