Association study between the corticotropin-releasing hormone receptor 2 gene and suicidality in bipolar disorder

Family, adoption and twin studies show that genetics influences suicidal behavior, but does not indicate specific susceptibility variants. Stress response is thought to be mediated by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway (HPA). Alterations in HPA system have been related to impulsivity, aggression and suicidal behaviour, that are common features in Bipolar Disorder (BD). CRH is a hypothalamic factor that stimulates the pituitary gland. Two CRH receptors are known, CRHR1 and CRHR2. To search for markers conferring genetic susceptibility to suicide, we typed three polymorphisms of the CRHR2 gene, CRHR2(CA), CRHR2(GT), and CRHR2(GAT), in 312 families where at least one subject had DSM-IV bipolar disorder. Family based association analyses in the suicide attempters using FBAT yielded no difference in the distribution of the alleles for all three markers. HBAT analysis for quantitative measures on suicide-related traits showed association between haplotype 5-2-3 and higher severity. The current results show that haplotype variation at the CRHR2 locus is associated with suicidal behaviour. This is to our knowledge the first investigation on suicidal behavior and genetic variation at the CRHR2 locus, an important regulator of the HPA axis.