Shared genetic risk for bipolar disorder and BMI

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By Lucy Piper, Senior medwireNews Reporter

Researchers have found a positive association in the heritability of bipolar disorder and body mass index (BMI), supporting the theory that there is some interaction in the genetic mechanisms underlying these two traits.

They detected novel genetic variants that increased the susceptibility to bipolar disorder but only after taking into account BMI and single nucleotide polymorphisms (SNPs) that were associated with susceptibility to bipolar disorder but that were dependent on BMI.

The top ranking of these was rs12772424 in an intron of TCF7L2, which showed significant interaction between bipolar disorder risk and BMI at the genome-wide level.

“When the association between rs12772424 and [bipolar disorder] or BMI are analyzed separately, there is evidence for a marginal SNP effect on either trait; yet when examined collectively, we observe a SNP–BMI interaction on [bipolar disorder] risk where the protective effect of the minor allele becomes stronger as BMI decreases,” the team, led by Joanna Biernacka (Mayo Clinic, Rochester, Minnesota, USA) and colleagues explains.

The researchers note in Molecular Psychiatry that TCF7L2 is also the strongest genetic risk factor for Type 2 diabetes and activates the expression of target genes downstream of the Wnt/β-catenin canonical pathway. This pathway is crucial to different aspects of neuroplasticity and adult neurogenesis.

Therefore its “involvement in both neuropsychiatric disorders and [Type 2 diabetes] makes it a feasible candidate for complex shared genetic risk,” Biernacka et al say.

A total of 388 patients with bipolar I disorder participated in the study alongside 1020 mentally healthy individuals. The patients with bipolar disorder had a significantly higher maximum BMI than mentally healthy individuals, at an average of 31.3 versus 29.3 kg/m2.

Other SNPs that showed the same evidence of a bipolar disorder and BMI interaction effect included the variant rs1625975 in CDH23, which is part of the cadherin superfamily of cell–cell adhesion glycoproteins, and rs17541406 in the pseudogene SEPHS1P2, downstream of MCTP2.

Conversely, the minor allele of rs6934970, residing in an intergenic region upstream of MARCKS, was associated with an increased odds for bipolar disorder (odds ratio=1.83) after accounting for maximum BMI, but was not associated with an interaction with BMI.

The researchers acknowledge that they were unable to take into account the effects of current treatment or the possibility that BMI may be a surrogate for Type 2 diabetes predisposition in some individuals.

Nevertheless, they conclude that genetic risk for bipolar disorder may be dependent on BMI and that “investigating complex genetic relationships involving covariates and genetic interactions is necessary to better understand the genetic etiology of [bipolar disorder] and obesity.”

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