BACKGROUND: Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. It has been suggested that neurodevelopmental factors contribute to the etiology of BD, but a specific neurodevelopmental phenotype (NDP) of the disorder has not been identified. Our objective was to define and characterize an NDP in BD and validate its associations with clinical outcomes, polygenic risk scores, and treatment responses. METHODS: We analyzed the FondaMental Advanced Centers of Expertise for Bipolar Disorders cohort of 4468 patients with BD, a validation cohort of 101 patients with BD, and 2 independent replication datasets of 274 and 89 patients with BD. Using factor analyses, we identified a set of criteria for defining NDP. Next, we developed a scoring system for NDP load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and gender with bootstrap replications. RESULTS: Our study established an NDP in BD consisting of 9 clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention-deficit/hyperactivity disorder, early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, and specific learning disorders. Patients with higher NDP load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between NDP load and polygenic risk score for attention-deficit/hyperactivity disorder, suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and attention-deficit/hyperactivity disorder. CONCLUSIONS: The proposed NDP constitutes a promising clinical tool for patient stratification in BD.

• Klíčová slova
• Bipolar disorder, Genomics, Lithium response, Neurodevelopment, Neurologic soft sign, Stratification,
• MeSH
• bipolární porucha * genetika   diagnóza   klasifikace   farmakoterapie   MeSH
• dospělí MeSH
• fenotyp MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• multifaktoriální dědičnost MeSH
• neurovývojové poruchy * diagnóza   MeSH
• rizikové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

• MeSH
• běloch MeSH
• běloši genetika   MeSH
• bipolární porucha * genetika   klasifikace   patologie   patofyziologie   MeSH
• celogenomová asociační studie MeSH
• černoši nebo Afroameričané genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• genomika * MeSH
• Hispánci a Latinoameričané genetika   MeSH
• kohortové studie MeSH
• lidé MeSH
• mapování chromozomů MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

• MeSH
• bipolární porucha klasifikace   genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické lokusy * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• psychotické poruchy genetika   MeSH
• schizofrenie genetika   MeSH
• studie případů a kontrol MeSH
• systémová biologie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

Depression mood stabilisers, which stabilise mood from below the mood baseline (euthymia) without inducing switch into mania or episode acceleration, are urgently needed for the effective treatment of bipolar depression. The anticonvulsant lamotrigine, recently approved as maintenance therapy for bipolar depression, has undergone evaluation as acute and maintenance therapy for bipolar disorder in several controlled clinical trials. Data from these trials suggest that lamotrigine is effective in the treatment and prevention of bipolar depression without destabilising mood. Although the majority of evidence comes from studies in patients with bipolar I disorder, a recent naturalistic study suggests that these observations may also extend to patients with bipolar II disorder. Lamotrigine may therefore fulfil the unmet need for an effective depression mood stabiliser.

• MeSH
• antidepresiva terapeutické užití   MeSH
• bipolární porucha klasifikace   farmakoterapie   MeSH
• dvojitá slepá metoda MeSH
• kombinovaná farmakoterapie MeSH
• lamotrigin MeSH
• lidé MeSH
• psychiatrické posuzovací škály MeSH
• randomizované kontrolované studie jako téma metody   MeSH
• triaziny terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antidepresiva MeSH
• lamotrigin MeSH
• triaziny MeSH