Journal
MOLECULAR PSYCHIATRY
Volume 8, Issue 5, Pages 546-557Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.mp.4001268
Keywords
bipolar disorder; mania; depression; linkage disequilibrium; transmission disequilibrium test; SNP; chromosome 22; genetic association; G protein receptor kinases; receptor desensitization
Funding
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000827] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [P30MH030914, P50MH030914] Funding Source: NIH RePORTER
- NCRR NIH HHS [M01 RR00827] Funding Source: Medline
- NIMH NIH HHS [MH20914-14, MH59567, MH47612, MH30914] Funding Source: Medline
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In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 50-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2) = 9.6, one-sided P value = 0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.
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