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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.
A Set of Six (1908) is one of Conrad's most versatile and varied compositions, embracing diverse interests and settings, multiple tonal qualities and a medley of short-story forms (ranging from the novella in 'The Duel' to the anecdotal tale in 'The Informer'). The volume's wide-ranging introduction offers a careful evaluation of the origins and sources of the individual stories, while also measuring their early reception as a published collection. Explanatory notes clarify literary and historical references, identify real-life places and people, and indicate borrowings and Gallicisms. The lengthy textual essay and its accompanying apparatus lay out the history of composition and publication, detailing interventions made by Conrad's typists, compositors and editors. Also included are appendices, allowing the reader first-hand access to Conrad's source material; glossaries of nautical and foreign terms; and illustrations in the form of maps and reproductions of early drafts. By returning to (and respecting) Conrad's own early manuscript and typescript forms, this edition presents the collection and its preface in a form more authoritative than any so far printed.