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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Despite apparent clinical remission, individuals with psychotic disorders often experience significant impairments across functional domains. Thus, there is a need to search beyond management of core symptoms to optimize treatment outcomes. Affective dysregulation is considered a risk factor for poor clinical and functional outcomes in many mental disorders, but research investigating such features in psychosis, particularly in schizophrenia, is limited. We aimed to investigate the level of affective lability (AL) in participants with schizophrenia- and bipolar spectrum disorders (n = 222) compared to healthy controls (n = 140), as well as clinical correlates of AL in the diagnostic groups.
The Affective Lability Scale (ALS-SF) was used to measure total score of AL and subscores covering the domains of anxiety/depression, depression/elation, and anger. An analysis of covariance was performed to compare the ALS-SF total score between groups, correcting for potential confounders, as well as standard multiple regression analyses for diagnosis-specific investigations of the relationship between AL and demographic and clinical features.
Both the schizophrenia- and bipolar spectrum group had significantly higher ALS-SF total score compared to controls (p < 0.001), and no significant differences between the patient groups were found. In the schizophrenia group, current psychotic and depressive symptoms were significantly and independently associated with AL (p = 0.012 and p = 0.024, respectively).
The findings indicate that AL is elevated in psychotic disorders and that it transcends diagnostic boundaries. Further research into the causal relationship between psychotic and affective symptoms and AL, as well as its role as a potential therapeutic target in psychosis spectrum disorders, is warranted.
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