Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics, and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads, and prioritize genes for functional follow-up studies.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic and calcium signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers and antiepileptics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

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Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD. Methods: A final sample of 185 young, high-risk German adults (aged 18-35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes. Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls. Biere et al. Risk Stratification for Bipolar Disorder Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.

Background Previous studies have linked disturbances in the kynurenine pathway, responsible for the main catabolism of tryptophan and a key regulator of the immune system, to mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). However, the relationship between tryptophan catabolism and the presentation of psychiatric disorders seems to be rather complex, as up to now results have mostly been inconsistent or even contradictory. In this study, we measured plasma levels of tryptophan catabolites (TRYCATs: tryptophan, kynurenine, kynurenic acid and quinolinic acid) in a sample of in total 175 participants consisting of individuals suffering from an acute disease episode seeking inpatient treatment as well as healthy controls (HC) to investigate whether individual metabolites could serve as a biomarker for differential diagnosis. Results Significantly decreased levels of tryptophan, kynurenine, kynurenic acid and quinolinic acid were found in the patient group as a whole. This was mainly driven by the difference between BD patients and HC. Specifically, the manic symptom domain in manic and mixed phase BD patients displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between the psychiatric disorders disqualifying TRYCATs as biomarkers for differential diagnosis. None of the assessed potential demographic or pharmaceutical confounding factors revealed a significant correlation to TRYCAT concentrations. Upon reaching (partial) remission, the changes in TRYCAT levels partially normalized in the patient group. Conclusions Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD. Although we cannot prove a causal relationship, underlying mechanisms might include pro-inflammatory states in the central nervous system and/or increased neurotoxicity contributing to the immune assault. Also considering the manifold, but inconsistent previous analyses regarding TRYCAT concentrations in psychiatric disease, larger, cross-sectional and longitudinal studies will be needed for detangling the mystery about the role the tryptophan catabolism plays in the pathophysiology of mental disorders and for answering the burning question if it might constitute a possible therapeutic target in the future.