An Extended Swedish National Adoption Study of Bipolar Disorder Illness and Cross-Generational Familial Association With Schizophrenia and Major Depression
Authors: Kenneth S. Kendler, Henrik Ohlsson, Jan Sundquist, Kristina Sundquist
Journal: JAMA Psychiatry (2020)

<h3>Importance</h3> 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. <h3>Objective</h3> To evaluate the sources of parent-offspring transmission of bipolar disorder and its familial cross-generational association with schizophrenia and major depression. <h3>Design, Setting, and Participants</h3> 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. <h3>Exposures</h3> Three sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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. <h3>Conclusions and Relevance</h3> 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.