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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.
It is widely accepted that it counts for a metaphysical theory when the theory is in accord with common sense and against a metaphysical theory when the theory clashes with common sense. It is unclear, however, why this should be the case. When engaging in metaphysics, why should we give common sense any weight? This chapter maintains that it is only against the backdrop of a particular metametaphysical stance that questions about metaphysical best practices become tractable. From the perspective of a metaphysics-as-modelling approach, common sense ought to play a significant, though defeasible, role in metaphysical theorizing. According with common sense is one of a number of theoretical virtues that metaphysicians should strive for. Nevertheless, it is important for the metaphysician to be cautious when appealing to common sense. She should distinguish what actually falls within the bounds of common sense as such from what a particular researcher happens to find intuitive. Furthermore, our best scientific theories may undercut the evidence provided by common sense. Finally, the metaphysician should attend to the context in which she invokes common sense. For some topics of inquiry, common sense ought to play a more expansive role in our metaphysical theorizing than for others.