
NEW YORK – An international research team led by investigators in Norway, the US, and UK has uncovered genetic loci, genes, and cell types with apparent ties to bipolar disorder, starting with a multi-ancestry genome-wide association study that included almost 3 million individuals with or without the mood disorder.
"Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder," co-corresponding authors Kevin O'Connell and Ole Andreassen, with Oslo University Hospital and the University of Oslo, and their colleagues wrote in Nature on Wednesday.
The researchers began by bringing together genotyping data for 158,036 bipolar disorder cases and some 2.8 million unaffected controls from 79 prior cohorts, including participants of African American, East Asian, European, or Latino ancestry with bipolar disorder status determined in clinical, self-reported, or community settings.
In a cross-ancestry GWAS meta-analysis approach, the team identified 298 loci with genome-wide significant ties to the condition, while its ancestry-specific analyses led to bipolar disorder-linked loci that appeared to be specific to individuals of East Asian ancestry.
The investigators also identified distinct genetic contributors to the bipolar disorder type I or type II subgroups, along with genetic architecture features that varied in relation to patient ascertainment methods used to identify individuals with the condition.
"We confirmed our hypothesis that differences in ascertainment and [bipolar disorder] subtype might lead to differences in genetic architecture," the authors reported, noting that follow-up analyses "provide novel insights into the biological underpinnings and genetic architecture of [bipolar disorder] and highlight differences depending on ascertainment of participants and [bipolar disorder] subtype."
With the help of a functional annotation-informed fine-mapping approach that relied on a tool called SuSiE, the PolyFun computational framework, and reference data from the Haplotype Reference Consortium and UK Biobank project, the team flagged three dozen bipolar disorder-related candidate genes.
"Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder," the authors noted, "highlighting convergence of common and rare variant signals."
When they used published single-nucleus RNA sequencing data and other resources to look at the genes, pathways, and cell types impacted by variants unearthed in the GWAS analyses, meanwhile, the researchers found that bipolar disorder-related variant distribution and activity was overrepresented in genes involved in synaptic activity and transcription factor functions, and in neuronal cells from several brain regions — from pyramidal neurons in the hippocampus to prefrontal cortex and hippocampus interneurons.
"Together, these results implicate the synapse, interneurons of the prefrontal cortex and hippocampus, and hippocampal pyramidal neurons as particularly relevant in the molecular biology of [bipolar disorder]," the authors reported.