Study highlights ‘complex genetic architecture’ of Lewy body dementia

A genome-wide analysis of patients with Lewy body dementia and healthy controls identified five independent risk loci associated with Lewy body dementia, according to findings published in Nature Genetics.

Genetic risk scores also demonstrated that Lewy body dementia shared “risk profiles and pathways” with Alzheimer’s disease and Parkinson’s disease, a finding that provides “a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition,” the researchers wrote.

“Lewy body dementia (LBD) is a poorly understood form of dementia. Recent evidence has shown us that genetic factors play a role in the pathogenesis of LBD,” Sonja W. Scholz, MD, PhD, investigator and chief in the neurodegenerative diseases research unit, neurogenetics branch, at the National Institute of Neurological Disorders and Stroke, told Healio Neurology. “To perform a comprehensive genetic evaluation of LBD and to generate a foundational resource for the dementia research community, we undertook whole-genome sequencing of a large cohort of LBD cases and neurologically healthy controls.”

Scholz and colleagues conducted whole-genome sequencing in a cohort of 2,981 patients with LBD and 4,391 healthy individuals. They also completed gene-aggregation tests and modeled the relative contributions of AD and PD risk variants to LBD.

Following quality control measures, the researchers had access to whole-genome sequencing data from 2,591 individuals with LBD and 4,027 neurologically healthy individuals. Participants came from 44 institutions and consortia and were diagnosed according to established consensus criteria, according to the study results.

The results revealed five loci that “surpassed the genome-wide significance threshold, three of which were located at known LBD risk loci within the genes GBA, APOE and SNCA. The other signals, in BIN1 and TMEM175, “represented new LBD risk loci,” according to the findings from Scholz and colleagues, though these loci have been implicated in other age-related neurodegenerative diseases, including AD (BIN1) and PD (TMEM175).

Genome-wide, gene-based aggregation tests implicated mutations in GBA as “critical” to the pathogenesis of LBD, according to the study results. The researchers observed strong cis-expression quantitative trait loci colonization signals at the TMEM175 and SNCA-AS1 loci, a finding that demonstrated that the risk for disease at these genomic regions “may be driven by expression changes of these particular genes.” Additionally, results from Scholz and colleagues showed “definitive evidence” that risk for LBD is driven, at least partially, by genetic variants associated with the risk for developing Alzheimer’s disease and Parkinson’s disease.

“We found that LBD is a genetically complex disease that intersects molecularly with AD and PD. Our study highlights several risk genes and pathways that are shared with related neurodegenerative diseases,” Scholz said. “This knowledge is crucial to prioritize targets for developing new therapies. We hope that increased insights into the pathogenesis of LBD will ultimately pave the way for disease-modifying treatments of this understudied disease.”