To assess whether bipolar disorder type I segregates into three clinically distinct sub-groups defined by age-at-onset.
Clinical data were available on 1369 individuals with DSM-IV bipolar I disorder. Mixture analysis was performed on the age-at-onset (AAO) data to determine whether they were composed of more than one normal distribution. Individuals were allocated to groups according to the results of the mixture analysis. Categorical logistic regression was then used to investigate relationships between AAO and nine clinical characteristics.
The distribution of AAOs in our sample comprised a mixture of three normal distributions with means of 18.7 (SD=3.7), 28.3 (SD=5.5) and 43.3 (SD=9.1) years, with relative proportions of 0.47, 0.39 and 0.14 respectively. Individuals were allocated into three groups dependent on their AAO: < or = 22; 25-37; and > or = 40 years, producing a sample of 1225 individuals (144 with borderline values were excluded). Eight out of the nine clinical characteristics showed evidence for a statistical association with AAO group.
Systematic and non-systematic recruitment of participants. Some data relied on retrospective recall.
Our results provide further robust evidence to suggest that the AAO distribution of individuals affected with bipolar disorder is composed of three normal distributions. Substantial clinical heterogeneity between the three AAO groups may reflect genetic heterogeneity within bipolar I disorder. Future genetic studies should consider AAO grouping as potential sub-phenotypes.
"maximum = +0.001), thus ensuring that each individual had a different AAO (Hamshere et al., 2009). To compare our theoretical distribution replicate with the theoretical distribution replicate generated using the parameters of the other admixture analysis studies we used the online version of the 2-sample KS test (http://www.physics.csbsju.edu/stats/KS-test.n.plot_form.html). "
"Nineteen studies involving 15,924 patients published since 2000 had at least one finding that was replicated in at least one other such report (Table 1). Among such studies, most (14/19, involving 9583 patients) were based outside of the United States, and used aggregated childhood/adolescent/ 7early adulthood as earlyonset groups that comprised 41.8% of these 9583 patients, with a mean onset age of 17.2 years (Azorin et al., 2013; Bellivier et al., 2001, 2003; Benazzi, 2009; Carter et al., 2003; Coryell et al., 2013; Ernst and Goldberg, 2004; Etain et al., 2012; Hamshere et al., 2009; Javaid et al., 2011; Lin et al., 2006; Manchia et al., 2008; Ortiz et al., 2011; Tozzi et al., 2011). In contrast, fewer reports (5/19, involving 6341 patients), primarily based in the United States, used separate childhood-and adolescent-onset groups that comprised 20.7% and 48.9%, respectively, of these 6341 patients, with mean onset ages of 8.6 and 13.2 years, respectively (Baldessarini et al., 2012; Leverich et al., 2007; Moor et al., 2012; Perlis et al., 2009; Rende et al., 2007). "
"The emergence of bipolar disorder involves the interaction of complex genetic mechanisms (Burmeister et al., 2008; Craddock and Sklar, 2013; Petronis, 2003) and environmental factors (Tsuchiya et al., 2003). Based on 6 studies of 2509 patients with bipolar I disorder, the weighted mean age of onset falls into 3 groups, having peaks at ages 18.1, 26.9 and 42.7 years, with 55% of patients in the middle or late onset groups (Bellivier et al., 2001, 2003; González Pinto et al., 2009; Hamshere et al., 2009; Lin et al., 2006; Manchia et al., 2008). This broad range of onset and the polygenic basis of bipolar disorder suggest that environmental factors have an influential role (Burmeister et al., 2008; Craddock and Sklar, 2013; Wright et al., 2003). "
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