A LINKAGE STUDY OF BIPOLAR ILLNESS

Background: Although genetic epidemiological studies of bipolar (BP) i llness are consistent with a heritable component, inherited risk facto rs remain unknown. The goal of the present study is to describe the lo calization of BP susceptibility loci through linkage strategies, inclu ding a genome-wide search. Methods: A linkage study of 22 BP families has been performed. These BP families include almost 400 persons, 173 of whom have been diagnosed as having BP I, schizoaffective, BP II wit h major depression, or recurrent unipolar illness. Using an autosomal dominant disease model with 85% or 50% age-dependent penetrance, and a recessive model with 85% penetrance, linkage analyses were performed assuming a narrow (BP and schizoaffective) or a broad (BP, schizoaffec tive, or unipolar) definition of the BP spectrum. Affected sibling pai rs and affected pedigree member analyses were performed when positive lod scores were observed in multiple pedigrees. The present article de scribes linkage analysis of 310 DNA markers on chromosomes 1, 5p, 6, 8 , 10q, 11q, and 12 to 18. Results: None of the loci examined disclosed compelling evidence for linkage using lod score analyses. Model-indep endent analysis by multilocus affected pedigree member method in the p ericentromeric chromosome 18 region disclosed statistically significan t evidence (P<.0001) for a BP susceptibility gene in this region. Mult ilocus analysis by affected sibling pair method also disclosed evidenc e for linkage (P<.00008). Conclusions: Our results imply that a BP sus ceptibility gene exists near the centromere of chromosome 18. Confirma tion of this finding (by independent investigators studying different pedigrees) has been published, suggesting that a valid BP disease link age may have been discovered.