Genes largely responsible for bipolar disorder transmission across generations

Cross-generational bipolar disorder transmission appeared to be caused largely by genes, with rearing effects having a modest role, according to results of an extended Swedish national adoption study published in JAMA Psychiatry.

“Attempts to quantify the role of genetic and environmental factors in the familial transmission of mood disorders — herein, specifically, bipolar disorder — have relied almost exclusively on within-generation resemblance, largely between twins,” Kenneth S. Kendler, MD, of the Virginia Institute for Psychiatric and Behavioral Genetics and the department of psychiatry at Virginia Commonwealth University, and colleagues wrote. “In the vast amount of literature on familial transmission of bipolar disorder, one small Belgian adoption study, including 29 individuals with bipolar disorder who had been adopted, focused on cross-generational transmission. However, disease transmission within and across generations does not reflect entirely the same processes.”

The researchers also referenced twin studies of major depression, which suggested that nearly all familial resemblance is linked to genetic factors; however, an expanded adoption study suggested that cross-generational transmission results almost equally from rearing and genetic effects.

In the current study, Kendler and colleagues sought to determine the magnitude of the transmission of bipolar disorder from parents to children and the degree to which this transmission results from genetic vs. rearing effects. They also investigated the familial cross generational association between bipolar disorder and schizophrenia and major depression, which they described as “key related psychiatric disorders.”

The researchers obtained data from Swedish national samples of parents and offspring born between 1960 and 1990 from four family types— intact (offspring, n = 2,175,259), not-lived-with biological father (n = 152,436), lived-with stepfather (n = 73,785) and adoptive (n = 15,624). Genes plus rearing, genes only and rearing only as related to parent-offspring resemblance served as exposures. Main outcomes and measures included diagnosis of bipolar disorder, broad schizophrenia (ie, unaffected, nonaffective psychosis and schizophrenia) and major depression obtained from Swedish national registries.

The researchers assessed parent-offspring resemblance primarily by tetrachoric correlation and determined key results and odds ratios using logistic regression. Further, they assessed cross-generational associations of bipolar disorder with broad schizophrenia and major depression by their transmission from parental bipolar disorder and transmission to offspring bipolar disorder.

The study included 2,417,104 individuals (median age, 41 years; range, 25-60; 51.8% men) of the four family categories. Tetrachoric correlations for three types of parent-offspring relationships were statistically homogeneous for bipolar disorder to bipolar disorder transmission across family type and mothers and fathers for genes plus rearing (OR = 0.25; 95% CI, 0.24-0.26), genes only (OR = 0.22; 95% CI, 0.18-0.26) and rearing only (OR = 0.07; 95% CI, 0.01 to 0.15). Parallel ORs were 5.2 (95% CI, 4.91-5.5), 3.66 (95% CI, 2.97-4.51) and 1.63 (95% CI, 0.96-2.78). For three types of parent-offspring relationships for bipolar disorder and broad schizophrenia, best-estimate, cross-disorder tetrachoric correlations were 0.12 (95% CI, 0.11-0.13) for genes plus rearing, 0.12 (95% CI, 0.09-0.14) for genes only and 0.03 (95% CI, 0.11 to 0.04) for rearing only. Parallel odds ratios were 1.95 (95% CI, 1.93-1.97), 2.04 (95% CI, 1.75-2.38) and 0.76 (95% CI, 0.43-1.35).

The parallel tetrachoric correlations for bipolar disorder and major depression were 0.09 (95% CI, 0.07-0.1) for genes plus rearing, 0.04 (95% CI, 0.01-0.07) for genes only and 0.05 (95% CI, 0.01-0.08) for rearing only. Parallel ORs were 1.53 (95% CI, 1.5-1.57), 1.23 (95% CI, 1.13-1.34) and 1.25 (95% CI, 1.09-1.42).

Kendler and colleagues estimated heritability for bipolar disorder at 0.44 (95% CI, 0.36-0.48). They estimated genetic correlations at 0.572 (95% CI, 0.56-0.589) between bipolar disorder and broad schizophrenia and 0.302 (95% CI, 0.001-0.523) between bipolar disorder and major depression.

“We believe the apparent validity of our findings is supported by their consistency across family types and, with [two] modest exceptions, estimations from transmission from bipolar disorder in parents and to bipolar disorder in offspring,” the researchers wrote. – by Joe Gramigna

Disclosures: The authors report no relevant financial disclosures.