Different familial transmission patterns in bipolar I disorder with onset before and after age 25

Gene identification in common disorders such as Alzheimer disease and breas t cancer has greatly profited from the use of age of onset as criterion to delineate subgroups of disease characterized by different inheritance patte rns. In bipolar affective disorder, where the majority of linkage studies h ave produced conflicting results, studies reporting clinical characteristic s and familial occurrence of disease have suggested that age of onset might serve as an indicator for identifying more homogeneous subgroups of diseas e. Our study was the first to examine this hypothesis by the means of segre gation analysis. We investigated a sample of 177 bipolar I probands recruit ed from consecutive admissions and their first- and second-degree relatives (2,407 subjects). Probands were subdivided into an early-onset (n = 107) a nd a late-onset group (n = 70) using an age of onset of 25 as a cut-off poi nt. This age was chosen because the observed age of onset distribution was bimodal with a cut-off of 25 years. Morbid risks for affective disorder wer e found significantly higher (P = 0.01) in relatives of probands with an ea rly onset than in probands with late onset of disease. The segregation anal ysis showed that the disease is transmitted differently in early- and late- onset groups. In the early-onset group, a non-Mendelian major gene with a p olygenic component was favored while the data in the late-onset group were compatible with a multifactorial model. This result may have important impl ications for future molecular studies aiming at the identification of disea se-associated genes. (C) 2001 Wiley-Liss, Inc.