rs13166360

rs13166360 at 5p15.31 is located in an exon of adenylate cyclase 2 (ADCY2) and encodes a missense mutation (valine→leucine) in a transmembrane domain of the protein. A GWAS has associated rs13166360 with bipolar disorder in people of European ancestry. == Clinical Background == Bipolar Disorder (BD) is a severe mood disorder that is characterized by recurrent episodes of depression and mania. BD has a lifetime prevalence of 1% in the general population (4% in the United States), and therefore can be classified as a common condition. To date, there does not exist any clear associations between race or socioeconomic status, and the onset of BD. Bipolar Disorders are amongst the 10 highest burden diseases, as ranked by the World Health Organization. In particular, those suffering from bipolar disorder are at a higher risk of suicide, anxiety disorders, and substance abuse . For further information about bipolar disorder, wikipedia offers a great article: en.wikipedia.org. == SNP Data == A GWAS by Muhleisen and coworkers links rs13166360 to Bipolar Disorder. The authors were motivated by the success of a previous GWAS for bipolar disorder that had not implicated the ADCY2 gene, and added additional subjects (2,266) and controls (5,028) in order to increase the power of this study. This data primarily comes from the MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) consortium. The new data unique to the Muhleisen et al study, which helped to find rs13166360, was primarily genotyped on the Illumina Infinium assay. In all, the combined datasets analyzed ~2.3 million SNPs from 9,747 cases and 14,278 controls that are of European Ancestry, but who currently live in Europe, Australia and the USA. This represents the largest BD GWAS to date. The datasets were merged according to a standardized genomic control λ-factor (1.018) in order to control for p-value inflation. The meta-analysis found 56 SNPs that passed genome-wide significance at 5 distinct genetic loci. Of these 5 loci, 3 had been previously described (ANK3, ODZ4, and TRANK1), while two were completely novel (ADCY2 and the region between MIR2113 and POU3F2) Rs13166360 was found as a proxy to another novel SNP (rs17836816) in the ADCY2 gene (r2=0.95), and presented genome-wide significance (p-value 1.81x10-8 with an allelic odds ratio of 1.14). Neither had previously been described in the context of Bipolar Disorder, and ADCY2 SNPs had not previously been associated with BD. Rs13166360 describes a deviation from the major allele G to T (minor allele) that encodes a Valine to Leucine missense codon in ADCY2. == Relation to Disease == There is consensus amongst the scientific and medical community that Bipolar Disorder is a multifactorial disease, with both genetic and environmental causes. ADCY2 is an integral membrane protein that, upon activation by heterotrimertic G proteins, catalyzes formation of the secondary messenger cyclic adenosine monophosphate (cAMP) that then activates protein kinase A (PKA) pathways. Many neurotransmitters function through G protein-coupled receptors, that in turn signal through these heterotrimeric G proteins. GPCRs represent a large pool of candidate genes for neuropsychiatric disorders, and accordingly, many antipsychotics target multiple receptors at once. Since ADCY2 is a signal integrator that acts downstream of many of these signaling pathways, any altercation to its function would occur downstream of multiple receptors and neurotransmitter pathways. It is not currently known if the V147L mutation is deleterious to the protein. While multiple adenylate cyclase genes exist, ADCY2 is uniquely expressed in the brain.

G;G

This is the common genotype at the Rs13166360 locus. Encodes a valine at position 147 of the ADCY2 gene.

G;T

This is the heterozygous genotype at Rs13166360. One copy of the ADCY2 gene is wild-type, the other has a Val->Leu missense mutation at position 147.

T;T

Homozygous of the minor allele. Both copies of ADCY2 possess the Leu147Val missense mutation, though the physiological effects of this mutation are not yet confirmed or understood. The allelic odds ratio is 1.14