Genetic Vulnerability to Mood Disorders Shared by Bipolar Disorder, MDD

Individuals with high genetic liability to major depressive disorder (MDD) may be at lower risk for psychosis and greater risk for anxiety disorders compared with those with high genetic liability to bipolar disorder (BD), according to study findings published in Journal of the American Medical Association Psychiatry.

Researchers conducted a cohort study using data from 2,736,950 individuals who were born in Sweden to Swedish parents between 1960 and 1990. Follow-up lasted through December 2018 (mean age at follow-up, 43.9±9.1 years). Data comprised family genetic risk scores for MDD and BD as well as codes from International Classification of Disease that were reported in hospital, specialist, and primary care registries. The upper and lower 2 risk deciles were used to define high and low genetic liability.

Researchers compared risk in individuals at high genetic liability to:

• BD only;
• MDD only;
• MDD and BD together;
• MDD and low genetic liability to BD; and
• BD and low genetic liability to MDD.

Primary endpoints included risk for schizoaffective disorder (SAD), obsessive-compulsive disorder, anxiety disorders, psychotic MDD and BD, and nonpsychotic MDD and BD.

Increased risk was observed for SAD, psychotic BD, and nonpsychotic BD with high genetic liability to BD only. Risk was amplified for nonpsychotic MDD, anxiety disorders, and nonpsychotic BD with high genetic liability to MDD only. The strongest association with risk for nonpsychotic BD, anxiety disorders, and nonpsychotic MDD was with high genetic liability to MDD and BD together.

High genetic liability to MDD and low genetic liability to BD resulted in increased risk for anxiety disorders, nonpsychotic BD, and nonpsychotic MDD without increased risk for psychotic BD. There was high genetic liability to BD and low genetic liability to MDD, which resulted in increased risk for SAD, nonpsychotic BD, and psychotic BD without increased risk for anxiety disorders or nonpsychotic MDD.

Limitations of the study include the fact that final genetic risk scores are not highly sensitive to various corrections, and that validity of analysis is dependent on the quality of diagnoses in Swedish registries. The incorporation of only Swedish-born individuals may result in lack of generalizability to populations with varying ethnicities.

Study authors conclude ”These results suggest that BD and MD have both shared and relatively distinct genetic liabilities, with BD risk associated largely with mood and psychotic disorders while MD risk affects mood and anxiety disorders. […] High genetic risk for BD is associated with increased risk for BD more than MD risk and vice versa.” They note the results are not consistent with prior genetically informative design analyses and not consistent with hypotheses that MDD and BD are either genetically closely interrelated or genetically distinct.