Susceptible loci identified for bipolar I disorder in Taiwanese

By Lucy Piper, Senior medwireNews Reporter

Researchers have identified three genetic loci that may be linked to bipolar I disorder risk in Taiwanese individuals.

These are the intergenic region rs7619173 and two markers in the MYST4 and NRXN3 genes.

“During the fine-mapping stage in which we performed individual genotyping of 96 markers, rs7619173 showed a significance level at 10^–5 of being associated with [bipolar I disorder],” report lead researcher Po-Hsiu Kuo (National Taiwan University, Taipei) and colleagues.

Their genome-wide association study involved multiple stages. For the first discovery stage, 200 patients with bipolar I disorder and 200 mentally healthy individuals were genotyped for 1 million markers. The top-ranking markers were then validated with individual genotyping.

From these studies, eight genes and 15 individual single nucleotide polymorphisms (SNPs) were identified and evaluated in a fine-mapping association study involving 240 bipolar patients and 240 mentally healthy controls.

At this stage, the SNP rs7619173 was found to have the most significant association with bipolar I disorder, followed by the four genes KCNH7, MYST4, NRXN3, and SEMA3D.

Four markers were then selected for replication in 351 bipolar patients and 341 controls. After multiple testing correction, rs7619173 remained significantly associated with bipolar I disorder, while the marker rs11001178 in the MYST4 gene and the rs2217887 marker in the NRXN3 gene showed weak associations.

The MYST4 gene encodes histone acetyltransferase, which is involved in brain development and adult neurogenesis, the researchers report in Progress in Neuro-Psychopharmacology and Biological Psychiatry. The NRXN3 gene encodes neurexin-3, which mediates neuronal positioning, axon guidance, cell migration, and adhesion.

But the rs7619173 marker does not have a known function and is not located near any genes, the researchers note.

They suggest that this marker “may exert its effects through post-translational regulation via in silico prediction.”

Given that bipolar disorder is a complex trait, the researchers believe that its risk for developing is likely to be influenced by combinations of multiple loci with small to moderate effects.

They now call for more basic and clinical research to help determine how the three novel susceptible loci for bipolar I disorder they identified are involved in the pathogenesis of bipolar disorder.

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