Further evidence for association of GRK3 to bipolar disorder suggests a second disease mutation

OBJECTIVES: Two genome-wide linkage surveys suggest chromosome 22q12 may contain a susceptibility locus for bipolar disorder (BPD) in the immediate region of the gene G protein receptor kinase-3 (GRK3). We previously published evidence that a single nucleotide polymorphism (SNP) in the promoter region of GRK3, designated P5, was associated with BPD. This SNP, however, was too rare (allele frequency 0.007) to explain the evidence for linkage. METHODS: To identify other SNPs or haplotypes associated with illness, we have now sequenced an additional 28-kb genomic segment of GRK3 and tested an additional 35 SNPs for association with BPD in 181 Caucasian nuclear families. RESULTS: Transmission disequilibrium test analyses identified two closely related disease-associated haplotypes defined by four SNPs located upstream of the promoter region: transmission to nontransmission ratios=54:22 and 20:9, odds ratios=2.50 and 2.36, and P values=0.0009 and 0.05. The best P value remained significant after correction for multiple testing. These two haplotypes were found on an entirely different set of chromosomes from the previously identified SNP P5. They had a combined frequency of approximately 0.10 and, therefore, a much greater population attributable risk for disease than the previously identified P5 haplotype. CONCLUSIONS: These data provide evidence that at least two distinct haplotypes, and possibly two or more different underlying mutations, in GRK3 might be associated with BPD. These new findings add support for the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization and thereby predisposes to the development of BPD.