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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.
Family history was examined to determine whether suicide in index patients is associated with suicidal behaviour or mental disorder in their first-degree relatives. Twenty-seven suicides occurred within 5½ years among 955 affectively disordered probands. Among 5042 proband relatives aged 18 years and older, 44 had committed suicide prior to proband entry to the study; however, only one was the relative of a proband suicide. Only two of the relatives who committed suicide were themselves related. As to attempted suicide of relatives, neither the number of attempts nor the severity of attempt was predictive of suicide in probands. Comparison of diagnosis between groups of relatives showed more drug abuse among relatives of proband suicides; this appears to be related to drug abuse among the proband suicides themselves. In contrast to the clustering of suicides within biological families found in other research, these data do not support the use of family history as a clinically useful indicator of suicidal potential in affectively disordered probands.
The internal construct validity of the endogenous sub-type of major depression was investigated by statistically modelling the RDC endogenous and DSM-III melancholia diagnostic criteria. Data consisted of symptom ratings on 788 patients with major depression from NIMH Collaborative Depression Study. Results indicated that the symptoms in the criteria do not specify a dichotomous classification, melancholic-non-melancholic or endogenous-nonendogenous. Results did support the existence of two sub-typings, one related to anhedonia, and one related to vegetative symptoms. The vegetative sub-type rarely occurred in non-anhedonic patients. Previous studies may have found support for a simple endogenous sub-type because of this hierarchical relationship and as a result of methodological differences.
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