A Genetic Risk Adoption Design for Psychiatric and Substance Use Disorders

Traditional adoption studies examine disorder-to-disorder parent-offspring transmission. The role of parental genetic risk in offspring disorder transmission can capture indirect genetic effects from parental genotype to parental phenotype to offspring risk.

To assess the relative importance of genetic and rearing effects from paternal family genetic risk scores (FGRSs) in 3 pairs of disorders: internalizing (major depression [MD] and anxiety disorders [AD]), substance use (alcohol use disorder [AUD] and drug use disorder [DUD]), and severe (bipolar disorder [BD] and schizophrenia [SZ]).

This cohort study examined fathers in intact families, not-lived-with fathers, stepfathers, adoptive fathers of adoptees, and biological fathers of adoptees, all born in Sweden, and their biological and adoptive offspring born between 1955 and 1990 using data from Swedish National Registries. Follow-up extended through December 2018. Data were analyzed from May to August 2025.

Paternal FGRSs for MD, AD, AUD, DUD, BD, and SZ.

Cox proportional hazard ratios (HRs) for offspring diagnoses focusing on the paternal effect of genes-and-rearing fathers in intact families, genes only (not-lived-with fathers and biological fathers of adoptees), and rearing only (stepfathers and adoptive fathers of adoptees).

The study sample included 2 584 384 offspring (mean [SD] age at follow-up, 41.7 [10.5] years; 1 329 558 [51.5%] male). We present results for MD, AUD, and BD with findings broadly similar for, respectively, AD, DUD, and SZ. The HRs (95% CIs) for genes and rearing fathers, genes-only, and rearing-only relationships were, respectively, for MD 1.19 (1.18-1.19), 1.13 (1.12-1.15), and 1.02 (1.01-1.04); for AUD 1.25 (1.25-1.26), 1.16 (1.14-1.18), and 1.08 (1.06-1.09), and for BD, 1.19 (1.18-1.20), 1.17 (1.14-1.20), and 1.01 (0.98-1.05). In rearing-only relationships, offspring risks for MD and AUD were significantly predicted by paternal genetic risk for DUD, AUD, AD, and MD, while offspring risk for BD was not predicted by any paternal genetic risk.

Using a more incisive measure of genetic effects, the novel adoption design used in this cohort study provides findings broadly similar to traditional adoption models. Rearing effects were strongest for substance use disorders, modest for internalizing disorders, and absent for severe disorders. Indirect genetic effects in the father on offspring risk were clearly observed and were not diagnostically specific. In rearing-only paternal-offspring relationships, elevated paternal genetic risk for internalizing and substance use disorders increased offspring risk for MD and AUD.