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Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment., (© 2024. The Author(s).)

Background: Being adopted early in life, an indicator of exposure to early-life adversity, has been consistently associated with poor mental health outcomes in adulthood. Such associations have largely been attributed to stressful environments, e.g., exposure to trauma, abuse, or neglect. However, mental health is substantially heritable, and genetic influences may contribute to the exposure to childhood adversity, resulting in potential genetic confounding of such associations., Methods: Here, we explored associations between childhood adoption and mental health-related outcomes in midlife in 243,797 UK Biobank participants (n adopted = 3151). We used linkage disequilibrium score regression and polygenic risk scores for depressive symptoms, schizophrenia, neuroticism, and subjective well-being to address potential genetic confounding (gene-environment correlations) and gene-environment interactions. As outcomes, we explored depressive symptoms, bipolar disorder, neuroticism, loneliness, and mental health-related socioeconomic and psychosocial measures in adoptees compared with nonadopted participants., Results: Adoptees were slightly worse off on almost all mental, socioeconomic, and psychosocial measures. Each standard deviation increase in polygenic risk for depressive symptoms, schizophrenia, and neuroticism was associated with 6%, 5%, and 6% increase in the odds of being adopted, respectively. Significant genetic correlations between adoption status and depressive symptoms, major depression, and schizophrenia were observed. No evidence for gene-environment interaction between genetic risk and adoption on mental health was found., Conclusions: The association between childhood adoption and mental health cannot fully be attributed to stressful environments but is partly explained by differences in genetic risk between adoptees and those who have not been adopted (i.e., gene-environment correlation)., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h 2 g = 10.6%). The genetic correlation (r 2 g = 10.6%). The genetic correlation (r g ) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h 2 g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)