Study Shows Significant Genetic Overlap Between Type 2 Diabetes and Depression

A study of Swedish and Danish twins concluded that the long-observed association between type 2 diabetes mellitus (T2DM) and depression has a significant genetic component.

Investigators looked for diagnoses of T2DM and clinical depression — as measured by national hospital discharge registries — in 68,606 Swedish twins and 95,403 Danish twins. They then used structural equation model fitting to determine how much of the correlation between the 2 diagnoses stemmed from genetic overlap and how much stemmed from other factors.

“The phenotypic correlation between T2DM and depression is modest in both samples,” the study authors wrote in Molecular Psychiatry. “In the Swedish sample, unique environmental effects explain a greater proportion of the covariance in males, whereas the association is primarily attributed to genetic effects in females. In the Danish sample, genetic effects account for the majority of the covariance in both males and females. Qualitative genetic sex differences are observed in both samples. We believe this is the first study to demonstrate significant genetic overlap between T2DM and depression.”

Previous studies have reported that T2DM patients are about 15% more likely than others to develop depression and that people with depression are wildly more likely than others — up to 60% more likely — to develop T2DM, wrote the authors of the new study, who went on to note that very few of those earlier studies tried to evaluate how much of the connection between the diseases is genetic and how much is environmental. (That said, at least 3 prior studies have found the comorbidity of T2DM and depression to be significantly higher in women than it is in men.)

The investigators who conducted the new study used the Danish and Swedish twin cohorts both because they include nearly all twins born in either country since the late 1800s and because they include both (and differentiate between) monozygotic (identical) twins and dizygotic (fraternal) twins. Having both kinds of twins allows investigators to compare comorbidity among genetically identical pairs and pairs that typically share 50% of separating genes.

Many statistical models assuming different levels of genetic, gender and environmental involvement were tested to see which best predicted actual results in the Swedish cohort. The winning model was a full sex-limitation bivariate AE model.

The heritability estimates for clinical diagnoses of T2DM and depression were 66% (95% confidence interval [CI], 58% to 73%) and 45% (95% CI, 32% to 56%) in men and 71% (95% CI, 65% to 77%) and 38% (95% CI, 30% to 47%) in women. The genetic correlation between T2DM and depression was not significant in men (0.06; 95% CI, −0.13 to 0.25), but it was significant in women (0.23; 95% CI, 0.07 to 0.38).

Among men, moreover, the phenotypic correlation between T2DM and depression was 31% due to genetic factors and 69% due to individual-specific environmental factors, whereas, in women, the correlation was 75% genetic and 25% individual environment.

The study investigators found that the same model produced the best fit in the Danish cohort as well. The heritability estimates for clinical diagnoses of T2DM and depression were 67% (95% CI, 61% to 73%) and 45% (95% CI, 35% to 54%) in men and 66% (95% CI, 59% to 72%) and 53% (95% CI, 46% to 59%) in women.

For both men and women, the genetic correlation between T2DM and depression was moderate and significant (men: 0.25; 95% CI, 0.23 to 0.41; women: 0.18; 95% CI, 0.06 to 0.31). The phenotypic correlation was primarily attributed to shared genetic effects in both sexes (men: 87%; women: 74%).

“Our finding of qualitative genetic sex differences implies that although the comorbidity is mainly due to correlated genetic risk factors, these factors are not necessarily the same in males and females,” the study authors wrote. “Possible biological support for this observed latent effect is given by findings regarding the activation of the hypothalamic—pituitary adrenal axis, which has been postulated to have a major role in the T2DM and depression.”