Cross-Generational Transmission of Bipolar Disease Largely Genetic

By Will Boggs MD

March 30, 2020

NEW YORK (Reuters Health) - The transmission of bipolar disease from generation to generation depends largely on genes, researchers report.

Studies attempting to tease out the roles of genetic and environmental factors in the familial transmission of bipolar disorder have relied almost exclusively on within-generation resemblance, usually twin studies.

Dr. Kenneth S. Kendler of Virginia Commonwealth University, in Richmond, and colleagues used information from Swedish population-based registers to examine the impact of genetics versus rearing effects on cross-generational transmission of bipolar disorder (from parents to children), as well as the familial cross-generational association between bipolar disorder and schizophrenia or major depression.

The study included 2.4 million offspring residing in four types of families: intact (offspring residing in the same household with their biological mother and father); not-lived-with biological father (offspring never resided with their biological father); stepfather (children residing with a non-biologically related male); and adoptive (children adopted before age 5 years).

Across both parents and offspring, prevalence rates for bipolar disorder, major depression, nonaffective psychosis and schizophrenia were generally lowest in intact families, intermediate in stepfather families, and highest in not-lived-with biological father and adoptive families.

The magnitude of bipolar disorder transmission to offspring was 0.25 from fathers or mothers who provide genes plus rearing; 0.21 from fathers and 0.28 from mothers who provide genes only; and 0.06 from fathers and 0.10 from mothers who provide rearing only, the researchers report in JAMA Psychiatry.

Across mothers and fathers, transmission was 0.25 for genes plus rearing, 0.22 for genes only and 0.07 for rearing only relationships.

Cross-generational transmission of bipolar disorder and major depression were 0.09 for genes plus rearing, 0.04 for genes only and 0.05 for rearing only relationships.

For parent-offspring transmission of bipolar disorder and schizophrenia, estimated transmission magnitudes were 0.12 for genes plus rearing, 0.12 for genes only and -0.03 for rearing only.

Based on the available data on parental-genes-only relationships, the cross-generational genetic correlations were 0.302 between bipolar disorder and major depression and 0.572 between bipolar disorder and broad schizophrenia.

"The findings of this study suggest that genes are largely responsible for bipolar disorder transmission across generations, although modest rearing effects are also likely present," the authors conclude. "Cross-generational transmission between bipolar disorder and broad schizophrenia appears to be entirely genetic with a moderate genetic correlation; for bipolar disorder and major depression, transmission appears to result equally from genes and rearing with a modest genetic correlation."

"These results are based on clinical diagnoses and, to our knowledge, a novel extended adoption study design," they note. "However, we believe the apparent validity of our findings is supported by their consistency across family types and, with 2 modest exceptions, estimations from transmission from bipolar disorder in parents and to bipolar disorder in offspring."

Dr. John R. Kelsoe of the University of California, San Diego, in La Jolla, who studies genetic factors associated with bipolar disorder, told Reuters Health by email, "The genetic overlap between bipolar disorder and schizophrenia and major depressive disorder has been previously reported in case-control studies, but this is one of the first examining families and also using an enormous sample size. It confirms in families what has been seen in other samples."

"The clinical implication is that bipolar disorder is more like schizophrenia than major depressive disorder (which) implies that patients with the depressed phase of bipolar disorder may not respond to the treatments, antidepressants, usually used for major depressive disorder," said Dr. Kelsoe, who was not involved in the new research. "This is exactly what the clinical literature indicates."

Dr. Kendler did not respond to a request for comments.

SOURCE: JAMA Psychiatry, online March 18, 2020.