Genetic heterogeneity according to age at onset in bipolar disorder: a combined positional cloning and candidate gene approach.

This study is the first that formally tests for genetic heterogeneity of bipolar disorder (BD) according to age at onset (AAO) sub-groups by combining positional cloning and candidate gene approaches. Our previous genome-wide linkage-scan identified five genomic regions linked to early-onset form of BD. The present study uses association analysis to test genetic heterogeneity of candidate genes located in these five regions in a sample of 443 unrelated bipolar patients and 1,731 controls. The study involved the following steps: (1) test of heterogeneity by comparing early-onset BD patients versus later-onset BD patients; and (2) for significant results in step 1, comparison of early-onset BD patients and later-onset BD patients separately to controls. Two types of analyses were used: the single SNP test and the gene-based association test. We provide evidence for genetic heterogeneity within the ADRB2 (beta-2adrenoreceptor) gene region that is specifically associated with the early onset form of BD with an OR of 1.8. Unfortunately, the genotyping coverage of ADRB2 in the Wellcome Trust Case Control Consortium sample meant undermined our efforts to undertake a replication. However, as the ADRB2 gene product directly interacts with the CACNA1C gene product, and is known to be implicated in BD susceptibility, we conclude that further exploration of the relationships between ADRB2 and BD needs to be undertaken.