Association Between the Serotonin 2A Receptor Gene and Bipolar Affective Disorder in an Australian Cohort

Objective: The serotonin 2A receptor gene (HTR2A) is involved in serotonergic neurotransmission, and has been targeted as a functional candidate for mood disorders because of the extensive support for the involvement of serotonin in mood regulation. We previously reported linkage evidence for a bipolar affective disorder susceptibility locus on chromosome 13q, which harbours HTR2A, thus making the gene both a positional and functional candidate. We assessed HTR2A for association in an Australian bipolar disorder case-control cohort.

Methods: Single nucleotide polymorphisms (SNPs) were selected across HTR2A exons and introns, and were investigated for association in an Australian cohort of 218 cases and 166 healthy controls. SNP haplotypes were also examined for association.

Results: Significant association of rs2224721 (P = 0.02) and borderline significance of rs1923886 (P = 0.05) were observed. The former remained significant after multiple testing corrections using the rough False Discovery Rate method, but did not exceed the more conservative Bonferroni's correction threshold. Haplotype association analysis suggests that the haplotype CCGCA (at SNPs rs3125, rs6314, rs1923886, rs2224721 and rs2770296) is protective against bipolar disorder (P = 0.021, odds ratio 0.63) and the rarer haplotype CCACG confers risk to the disorder (P = 0.0065, odds ratio 3.08).

Conclusion: We found that HTR2A is associated with bipolar disorder. The HTR2A gene should not be excluded as a potential susceptibility gene for bipolar disorder despite a number of conflicting association results.