Ongoing research has identified a region of the HTR2A promoter that has been associated with a number of medical outcomes in adults and infants, including bipolar disorder, schizophrenia, chronic fatigue syndrome, borderline personality disorder, suicidality, and neurobehavioral outcomes.
Logistic regression analysis showed a significant effect of the ALDH2 and the 5-HT2A-A1438G polymorphisms, and a significant interaction effect for the A/G genotypes of the 5-HT2A-A1438G polymorphism and the ALDH2*1*1 genotypes (p=0.004) discriminated between bipolar-I patients and controls without bipolar disorder.
Higher mean serum S100B levels were associated with the risk G allele of rs3788266 in BPAD cases (P = 0.0001), unaffected relatives of BPAD cases (P < 0.0001) and unrelated controls (P < 0.0001).
These genes include GRM7, previously associated to major depression disorder and bipolar disorder, SLC6A13, in anxiety disorders, and S100B, SSTR5 and COMT in schizophrenia.
Fine-mapping analyses of 21q22 have previously identified transient receptor potential gene melastatin 2 (TRPM2), which is 2 Mb upstream of S100B, as a possible BPAD susceptibility gene at 21q22.
Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O-methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function.
This study provides new insights on the neurogenetic correlates of allelic variation at different genome-wide supported BD-risk associated ANK3 loci that support their involvement in BD and highlight the modulatory influence of increased background genetic risk for BD.
Our findings implicate abnormal perigenual and hippocampal activation as a promising intermediate phenotype for psychiatric disease and suggest a pathophysiologic mechanism conferred by a CACNA1C variant being implicated in risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.
The variants at ANK3 and CACNA1C previously known to be associated with BP were not in linkage disequilibrium with either of the two variants that we identified and these are therefore independent of the previous haplotypes implicated by genome-wide association.
In a sample of 49 patients with bipolar disorder and 633 healthy subjects, we examined possible effects of 2 risk variants within ANK3, rs10994336 and rs10761482, on 7 neurocognitive domains.
In treatment of BD with calcium channel blocking drugs, we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.
The variant at rs1006737 in the L-type voltage-gated calcium channel (alpha 1c subunit) CACNA1C gene is reliably associated with both bipolar disorder and schizophrenia.