Cholecystokinin system genes: associations with panic and other psychiatric disorders

The cholecystokinin (CCK) system has long been hypothesised to have a role in the pathogenesis of panic attacks. Previous research into genetic variation within the CCK gene and the genes for its two receptors, CCKAR and CCKBR, has produced mixed results. We aimed to clarify this association by investigating multiple variants within each gene and multiple phenotypes associated with panic that may have confounded the previous studies' findings.

Variants were selected for the three genes based on HapMap CEU data. Individuals from a family based cohort (n=563) were genotyped for these variations and this data was analysed in FBAT.

CCKBR showed the strongest association with panic, having multiple variants with p<0.05 (lowest: p=0.007). In CCKAR, some evidence was found for an association with panic, though further analysis suggested that the co-morbid bipolar-panic phenotype was most strongly associated. No variants in CCK were associated with panic but broader anxiety phenotypes did show associations.

Small sample size prevented thorough investigation of phenotypes, particularly pure disorders, and no correction was made for the multiple phenotypes analysed.

Our findings support the involvement of variation in the CCK system, particularly CCKBR, in the pathogenesis of panic. Our data suggest that variation in CCK may be involved in several anxiety phenotypes and CCKAR may be involved in the development of panic co-morbid with bipolar disorder. These latter findings require further investigation and highlight the importance of clearly defined phenotypes when investigating psychiatric genetics.