NEW YORK (GenomeWeb News) – A genome-wide association study drawing on more than 24,000 samples has identified two new risk regions linked to bipolar disorder, as researchers led by the University of Bonn's Sven Cichon reported in Nature Communications today.
Cichon and his colleagues sifted through some 2.3 million SNPs to identify five chromosomal regions containing SNPs with genome-wide significance for disease risk. Of those regions, three had previously been linked to bipolar disorder, and two were novel.
One of these novel risk regions includes the gene ADCY2, which encodes a cell membrane-bound enzyme that is needed for the synthesis of the second-messenger molecule cAMP.
The other novel risk region couldn't be pinpointed to a specific gene; it is located between an uncharacterized microRNA gene and a transcription factor gene.
Bipolar disorder affects about 1 percent of the population, and appears to run in families. A handful of GWAS like this latest one have identified various risk loci for the disorder, and the researchers noted that there is increasing evidence for a polygenic root of the disease.
"There is no one gene that has a significant effect on the development of bipolar disorder," Markus Nöthen, the director of the Institute of Human Genetics at the University of Bonn Hospital and co-senior author, said in a statement. "Many different genes are evidently involved and these genes work together with environmental factors in a complex way."
The researchers drew on SNP data gathered by both the Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia (MooDS) and Psychiatric Genomics Consortium Bipolar Disorder Working Group (PGC-BD) consortia to pull together a cohort of 9,747 patients and 14,278 controls that they then analyzed simultaneously. All patients and controls were of European ancestry.
From this genome-wide association study, the researchers homed in on 56 SNPs at five loci that reached genome-wide significance for bipolar disorder risk. Three loci — ANK3, ODZ4, and TRANK1 — have linked to the disorder previously.
"These gene regions were, however, statistically better confirmed in our current investigation — the connection with bipolar disorder has now become even clearer," Nöthen said. Indeed, the researchers noted that the most significant association signal and the greatest number of significant SNPs could be traced to ANK3.
The novel loci, though, were linked to ADCY2, the adenylate cyclcase 2 gene, and a region falling between the microRNA gene MIR2113 and the POU class 3 homeobox 2 gene POU3F2.
The ADCY2 gene, the researchers noted, is expressed in the brain and encodes an enzyme that is needed to synthesize the second messenger cAMP. ADCY2, they added, is regulated by heterotrimeric G proteins and produces cAMP in response to extracellular transmitters and hormones that bind G-protein coupled receptors. GPCRs include a number of neurotransmitter receptors, including receptors for dopamine, norepinephrine, and serotonin.
In turn, cAMP induces the expression of downstream target genes by activating the cAMP-dependent protein kinase A and the phosphorylation of the transcription factor cAMP response element-binding protein.
One of the top ADCY2 SNPs uncovered in the GWAS, Cichon and colleagues reported, is a missense variant that may damage the ADCY2 protein and its function.
Alterations to neurotransmitter pathways, the researchers said, have long been suspected to have a role in neuropsychiatric disorders like bipolar disorder. A number of candidate gene studies have explored these pathways, they noted.
"We speculate that functional variation in ADCY2 may have a more pronounced effect on BD susceptibility than functional variation in neurotransmitter receptors where a high degree of redundancy may facilitate functional compensation of one dysfunctional receptor by another," the researchers wrote in the paper.
ADCY2, then, may be a sort of chokepoint where genetic variation can directly affect phenotype because there is a lack of the redundancy that say, neurotransmitter receptors or transports have, they added.
"This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder," Nöthen said. "Only when we know the biological foundations of this disease can [we] also identify starting points for new therapies."