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Bipolar Disorder GWAS Meta-Analysis Points to Potential Treatment Targets

NEW YORK – Using a genome-wide association study approach, an international team led by investigators at the Icahn School of Medicine at Mount Sinai has identified dozens of loci linked to bipolar disorder in individuals of European ancestry, including subtle genetic differences between different subtypes of the disease.

"Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads, and prioritize genes for functional follow-up studies," co-first and co-corresponding author Niamh Mullins, a psychiatric genomics researcher at the Icahn School of Medicine, and her co-authors wrote in a study appearing in Nature Genetics on Monday.

Members of the Psychiatric Genomics Consortium described 33 new and 31 known loci with apparent links to bipolar disorder risk, based on data for nearly 42,000 individuals with bipolar disorder and more than 371,500 unaffected controls. The bipolar disorder-associated variants appeared to be particularly common in and around genes involved in brain cell communication and calcium signaling pathways. That, in turn, suggested it may be possible to tap into calcium channel blockers and other existing drugs to treat bipolar disorder in the future.

"It is important to note that the findings of this study do not have immediate clinical impact," Mullins explained in an email, "however they suggest several promising future research directions, which could ultimately lead to the development of new and improved treatments, preventative strategies, or precision medicine approaches to stratify patients at high genetic risk of bipolar disorder, who may benefit from targeted treatment or intervention strategies."

For their GWAS meta-analysis, the researchers brought together genotyping profiles across more than 7.5 million common SNPs for 41,917 bipolar disorder patients of European ancestry who were enrolled for prior studies in Europe, North America, and Australia. They then searched for genetic variants that distinguished these cases from 371,549 unaffected controls with the same ancestral background.

"Through this work, we prioritized some specific genes and DNA variations which can now be followed up in laboratory experiments to better understand the biological mechanisms through which they act to increase risk of bipolar disorder," senior author Ole Andreassen, a professor of psychiatry at Oslo University Hospital's Institute of Clinical Medicine, said in a statement.

For example, after narrowing in on bipolar disorder-associated alleles at 64 genomic loci — risk variants that appeared to be overrepresented in parts of the genome expressed in neurons from the brain's prefrontal cortex or hippocampus — the team used gene expression and quantitative trait locus clues to focus in on 15 potential target genes with additional expression ties to bipolar disorder.

"The results of future genome-wide association studies like this one, in larger and more diverse populations, could ultimately contribute to precision medicine approaches, which could be useful when patients initially visit a healthcare provider with nonspecific psychiatric symptoms," Mullins wrote. "In a similar way to using information on family history, genetic information could be useful to stratify patients at high genetic risk of bipolar disorder, who may benefit from targeted treatment or intervention strategies."

Even so, she cautioned that "it is crucial to recognize that while genetic information could be useful in stratifying patients at high risk, it could not be used to make a clinical diagnosis of bipolar disorder."

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