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GWAS Suggests Dementia With Lewy Bodies Genetically Distinct

NEW YORK (GenomeWeb) – An international team led by investigators at University College London has identified a handful of genetic loci associated with a neurodegenerative condition known as dementia with Lewy bodies (DLB).

The researchers brought together data from dozens of centers around the world for a genome-wide association study involving more than 1,700 individuals with DLB and nearly 4,500 without. As they reported online today in the Lancet Neurology, their analysis led to three genome-wide significant DLB-linked loci — a set that was largely distinct from variants implicated in related neurological conditions, such as Alzheimer's disease or Parkinson's disease.

"Our findings clarify the disease's distinctive genetic signature, which should, in the future, help improve clinical trials, and lead to more targeted treatments," senior author Jose Bras, a molecular neuroscience researcher at University College London's Institute of Neurology and Alzheimer's Society, said in a statement.

Although DLB makes up a significant subset of overall dementia cases, the team explained, it can be tricky to distinguish it from Alzheimer's or Parkinson's due to overlap between some of the symptoms of these conditions.

"DLB and Parkinson's have many similarities, as people with DLB often develop Parkinson's symptoms, and Parkinson's often leads to dementia," Bras said. "By understanding the genetic underpinnings, we can more effectively target treatments to the different groups."

To explore the particulars of DLB genetics, the team tapped into data for 1,743 DLB cases and nearly 4,500 controls — a set that included post-mortem samples from 1,324 neuropathologically assessed individuals with pathological disease.

For the discovery stage of a GWAS aimed at uncovering DLB genetic contributors, the researchers used Illumina arrays to genotype 1,216 DLB cases and nearly 3,800 unaffected controls, all of European ancestry. Based on an analysis of directly genotyped variants and SNPs imputed with help from a Haplotype Reference Consortium panel, they narrowed in on five suspicious loci that were subsequently assessed in a replication cohort comprised of 527 cases and 663 controls.

Following the discovery and validation stages of the study, the team saw significant associations for variants in and around the APOE, SCNA, and GBA genes. A locus near the CNTN1 gene was weakly associated with DLB, while the BCL7C/STX1B locus was linked to the condition in a DLB meta-analysis. 

While some of these loci have been implicated in Alzheimer's and Parkinson's disease, though, the researchers noted that an analysis of the full suite of loci associated with those conditions did not lead to additional DLB-linked loci. Likewise, when they took a closer look at the SNCA locus — including regulatory insights gleaned from GTEx expression data — they found that the SNCA-adjacent DLB association was distinct from the SNCA locus implicated in Parkinson's disease risk.

Together, the team estimated, the new and previously known DLB risk variants appeared to explain roughly 36 percent of the condition's heritability. Along with potential insights in the biology of the disease, the group noted that the DLB-specific risk variants may help to distinguish the disease from other neurodegenerative conditions in the clinic. 

"Our findings can be used to identify more clearly which type of dementia each person has, so that they can take part in the right clinical trial, which could lead to better treatments and diagnostic tools," co-first author Rita Guerreiro, a molecular neuroscience researcher at the UCL Institute of Neurology, said in a statement.