UC San Diego

Objectives: Bipolar disorder (BD) is characterized by manic and depressive states that onset at various times in life. Research shows that early onset forms of BD are associated with a stronger genetic loading for the illness. We hypothesized that using age at onset to look at subsets of BD families in a genetic linkage analysis would prove useful in separating etiologically homogeneous BD sub-groups and subsequently identifying genetic susceptibility regions. Methods: We used the wave-I National Institute of Mental Health (NIMH) Genetics Initiative BD sample, which includes 540 individuals from 97 families with BD, in an ordered-subsets linkage analysis with age at onset of mania as the subset-identifying covariate. This analysis was performed using GENEHUNTER-PLUS followed by the ordered-subsets analysis program. This program generates empirical p-values for the subset with the largest LOD score to determine whether this value was significantly higher than the baseline LOD score using all families. Results: Three chromosomal regions resulted in LOD scores above 2.0: 2.21 (6q25), 3.21 (9q34), and 2.16 (20q11). The largest increase in LOD score was observed on chromosome 9q34 between markers D9S290 and D9S915 in the subset of 58 families that had mania onset before age 20. Families with a minimal mania onset less than 20 years had a significantly greater number of psychiatric comorbidities (p = 0.02) and a marginal increase in depressive symptoms (p = 0.10). Conclusions: Further investigation into chromosomal region 9q34 is necessary to determine whether this region may harbor a gene specific to families with a minimal age at onset of less than 20.