NEW YORK – New research suggests rare, loss-of-function changes in two genes with ties to a suspected lithium treatment target gene can increase the risk of developing bipolar disorder in individuals of European ancestry.
The findings, published in Nature Genetics on Tuesday, point to the possibility of developing bipolar disorder therapies that directly target such genes to avoid complications linked to long-term use of existing treatments.
"The pharmacological treatments of bipolar disorder can all be accompanied by serious side effects, and better treatments are urgently needed," first and co-corresponding author Thorgeir Thorgeirsson, a researcher with Amgen subsidiary Decode Genetics, and his colleagues explained, noting that the genes identified "have to be considered as promising targets in the search for new treatments for bipolar disorder."
For their new study, Thorgeirsson and colleagues from Decode, the University of Iceland, and Landspitali University Hospital analyzed whole-genome sequence data for 58,449 individuals from Iceland, including 4,197 bipolar disorder cases. They also considered genome sequence data for 1,881 European ancestry cases and 426,6222 controls from the UK Biobank project, before bringing in findings from a Bipolar Exome study published in Nature Genetics in 2022 for a bipolar disorder meta-analysis.
Despite the high heritability of bipolar disorder, which has been estimated at around 60 percent to 85 percent, the investigators explained, genome-wide association studies centered on common variant contributors can only explain a subset of this heritability so far.
The team's new analyses, which focused on the mutational burden associated with rare, loss-of-function alterations, led to two genes: HECTD2 and AKAP11 — associations that were further supported by data from a previous Bipolar Exome study that implicated AKAP11 in schizophrenia risk.
The authors noted that proteins encoded by both AKAP11 and HECTD2 appear to interact with an enzyme produced by the glycogen synthase kinase-3 beta (GSK3-beta) gene.
Though they noted that the biology behind lithium response in bipolar disorder has not been fully delineated, a serine threonine kinase enzyme encoded by GSK3-beta has been proposed as a target of lithium treatment, which can cause kidney damage when used for long-term management of bipolar disorder.
"[O]ne of the limiting aspects of lithium in long-term treatment of bipolar disorder is nephrotoxicity, which is common and somewhat dose-dependent," the authors wrote, noting that the development of targeted gene treatments may help in avoiding such toxicity.
The team did not see cognitive differences in individuals with or without rare, loss-of-function variants in either of the genes, though cognitive performance appeared to dip in bipolar disorder cases in general that were included in the Icelandic and UK Biobank projects compared to control individuals.
Overall, the authors argued that findings from the Icelandic and UK Biobank cohorts, combined with data from the Bipolar Exome study, "will be useful resources for those conducting analyses of bipolar disorder in the future," though they emphasized that "[l]arger samples are needed for further discovery of variants."