Researchers have found two new risk loci for bipolar disorder in a genome-wide association study of 2.3 million single-nucleotide polymorphisms (SNPs).
They are adenylate cyclase 2 (ADCY2), which plays a key role in the cyclic (c)AMP-dependent G protein-coupled receptor (GPCR) pathways, and a region between MIR2113 (encoding microRNA 2113) and POU3F2 (POU class 3 homeobox 2) that has previously been shown to be associated with variation of information processing speed.
The SNP data were obtained from 2266 patients with bipolar disorder and 5028 mentally healthy controls from the Systemic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia (MooDS) together with 7481 bipolar disorder patients and 9250 controls from the Psychiatric Genomics Consortium Bipolar Disorder Working Group (PGC-BD).
The team, led by Sven Cichon (University of Basel, Switzerland) detected 56 genome-wide significant SNPs in five chromosomal regions. These included three known loci – ANK3 (ankyrin 3), ODZ4 (odd Oz/ten-m homologue 4 alias teneurin transmembrane protein 4, TENM4) and TRANK1 (tetratricopeptide repeat and ankyrin repeat containing 1 alias lupus Brain antigen 1 homologue, LBA1) – and the two new ones.
The most significant genome-wide association signal was found for ANK3 on chromosome 10q21.2, which also had the largest number of SNPs of genome-wide significance, defined as <5 x 10–8, at 26.
This was followed by ODZ4 on chromosome 11q14.1, which had 10 genome-wide SNPs, ADCY2 on chromosome 5p15.31, which had two genome-wide SNPs, the region between MIR2113 and POU3F2 on chromosome 6q16.1, which had four genome-wide SNPs and TRANK1 on chromosome 3p22.2.
The researchers then looked up relevant databases for prior knowledge on the two new risk loci to better understand their relevance.
They found that the ADCY2 protein is primarily regulated by heterotrimeric G proteins and produces cAMP in response to extracellular hormones and neurotransmitters that bind as ligands to GPCRs.
One of the two SNPs in ADCY2 is a missense variant that possibly damages the protein, the researchers suggest. They speculate that “functional variation in ADCY2 may have a more pronounced effect on [bipolar disorder] susceptibility than functional variation in neurotransmitter receptors where a high degree of redundancy may facilitate functional compensation of one dysfunctional receptor by another.”
They add that this may explain why genome-wide association studies in neuropsychiatric disorders have failed to identify strong association signals in neurotransmitter or transporter genes.
Although a specific gene could not be identified for the region between MIR2113 and POU3F2 on chromosome 6q16.1, it did harbour a genome-wide SNP that the researchers discovered had been previously associated with information processing speed.
This cognitive function is thought to be a valid and highly specific cognitive endophenotype for bipolar disorder, note Cichon et al.
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