Examination of the clock gene Cryptochrome 1 in bipolar disorder: mutational analysis and absence of evidence for linkage or association.

Bipolar disorder is associated with malfunctions of the circadian system, which regulates individual circadian rhythms and which enables the adaptation to a daily 24-h cycle and seasonal change. One of the human circadian clock genes, cryptochrome 1 (Cry1) (located on 12q23-q24.1) was analyzed because of its close correspondence to a linkage hotspot for bipolar disorder. We found no evidence for linkage of 52 bipolar families to two Cry1 flanking microsatellites under several parametric and non-parametric models. In order to employ association for a more sensitive test, 25 affected subjects selected from families with positive LOD scores were screened for mutations by sequencing 9.5% of the Cry1 gene. A total of 16 single nucleotide polymorphisms (SNPs) and a 3 base pair insertion were identified. However, no mutations with probable functional impact were found. These novel SNPs and data on allele frequency and linkage disequilibrium structure will be useful for future association analyses. Nine SNPs have been analyzed in a set of 159 parent proband triads. Linkage disequilibrium analyses using single SNPs and haplotypes showed no association to bipolar disease.Additional, more powerful, studies involving Cry1 and other circadian clock genes need to be tested before an association of circadian abnormalities with bipolar disorder can be excluded.