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Original Investigation
March 18, 2020

An Extended Swedish National Adoption Study of Bipolar Disorder Illness and Cross-Generational Familial Association With Schizophrenia and Major Depression

Author Affiliations
  • 1Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond
  • 2Department of Psychiatry, Virginia Commonwealth University, Richmond
  • 3Center for Primary Health Care Research, Lund University, Malmö, Sweden
  • 4Department of Family Medicine and Community Health, Icahn School of Medicine at Mount Sinai, New York, New York
  • 5Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
  • 6Center for Community-Based Healthcare Research and Education, Department of Functional Pathology, School of Medicine, Shimane University, Matsue, Japan
JAMA Psychiatry. Published online March 18, 2020. doi:10.1001/jamapsychiatry.2020.0223
Key Points

Question  To what degree is the cross-generational transmission of bipolar disorder to bipolar disorder, bipolar disorder to schizophrenia, and bipolar disorder to major depression associated with genetics vs parental rearing effects?

Findings  In a national Swedish cohort study including 2 417 104 individuals of 4 family types, the transmission of bipolar disorder across generations appeared to be largely genetic, although rearing effects also seemed to play a modest role; however, the cross-generational transmission from bipolar illness to schizophrenia appears to be entirely the result of genes. For bipolar disorder to major depression, transmission appeared to result equally from genes and rearing.

Meaning  The sources of cross-generational transmission within and between different psychiatric disorders may differ substantially.

Abstract

Importance  Information about how risk for bipolar disorder is transmitted across generations and how parental risk for bipolar disorder relates to their children’s risk for schizophrenia and major depression is limited.

Objective  To evaluate the sources of parent-offspring transmission of bipolar disorder and its familial cross-generational association with schizophrenia and major depression.

Design, Setting, and Participants  Parents and offspring (born 1960-1990) from 4 family types were ascertained from Swedish national samples: 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). Data analysis was conducted from October 28, 2019, to January 8, 2020.

Exposures  Three sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only.

Main Outcomes and Measures  Diagnosis of bipolar disorder, broad schizophrenia (ie, schizophrenia as a 3-level variable: unaffected, nonaffective psychosis, and schizophrenia) and major depression obtained from Swedish national registries. Parent-offspring resemblance was assessed primarily by tetrachoric correlation (ie, correlation of liability) and for key results, odds ratios (ORs) from logistic regression. Cross-generational associations of bipolar disorder with broad schizophrenia and major depression were assessed by their transmission from bipolar disorder in parents and transmission to bipolar disorder in offspring.

Results  The study population included 2 417 104 individuals of 4 family types (51.8% male and 48.2% female; median age, 41 [range, 25-60] years). For bipolar disorder to bipolar disorder transmission, tetrachoric correlations for 3 types of parent-offspring relationships were statistically homogeneous across family type and mothers and fathers for genes plus rearing (0.25; 95% CI, 0.24-0.26), genes only (0.22; 95% CI, 0.18-0.26), and rearing only (0.07; 95% CI, −0.01 to 0.15). Parallel ORs were 5.20 (95% CI, 4.91-5.50), 3.66 (95% CI, 2.97-4.51), and 1.63 (95% CI, 0.96-2.78). Best-estimate, cross-disorder tetrachoric correlations for 3 types of parent-offspring relationships for bipolar disorder and broad schizophrenia 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, with parallel ORs of 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). For bipolar disorder and major depression, the parallel tetrachoric correlations were 0.09 (95% CI, 0.07-0.10) 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, 1.50-1.57), 1.23 (95% CI, 1.13-1.34), and 1.25 (95% CI, 1.09-1.42). Heritability for bipolar disorder was estimated at 0.44 (95% CI, 0.36-0.48). Genetic correlations were estimated at 0.572 (95% CI, 0.560-0.589) between bipolar disorder and broad schizophrenia and 0.302 (95% CI, 0.001-0.523) between bipolar disorder and major depression.

Conclusions and Relevance  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. 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.

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