Objective: Previous linkage and allelic association studies using DNA polymorphisms, cosegregation of cytogenetic abnormalities with psychiatric illness, and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness. The authors examined linkage in the families of 14 probands with bipolar illness, with the candidate genes tyrosine hydroxylase (TH), D4 dopamine receptor (DRD4) at 11p15, tyrosinase (TYR) at 11q14-q21, and D2 dopamine receptor (DRD2) at 11q22-q23, as well as with the c-Harvey-ras oncogene (HRAS) and insulin gene (INS), both located at 11p15, a region that previously showed linkage to bipolar illness.
Method: The genetic data were analyzed with both lod score analysis (parametric) and affected-sib-pair analysis (nonparametric); both narrow and broad definitions of the clinical phenotype were used. Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype.
Results: Two-point linkage results excluded close linkage of bipolar illness to each candidate gene; negative results were also obtained when the narrow definition of the clinical phenotype was used. Moreover, multipoint linkage analysis of HRAS and INS excluded the 11p15 region encompassing both DRD4 and TH. In agreement with the negative linkage results, affected-sib-pair analysis did not show preferential sharing of marker alleles at any of the candidate genes.
Conclusions: The negative results obtained under different genetic models exclude a frequent role for DRD4, TH, TYR, and DRD2 in the pathogenesis of bipolar illness.