A collaborative study offers the first large-scale glimpse into the genetics of dementia with Lewy bodies. Researchers led by José Bras, University College London, genotyped 1,743 patients to search for genome-wide associations. Published in the December 15 Lancet Neurology, the study confirms links to known Alzheimer’s and Parkinson’s disease genes, but also hints at a profile distinct from both. Alzforum covered preliminary data from the GWAS, which were reported at the 2015 International Dementia with Lewy Body Conference in Fort Lauderdale, Florida (Dec 2015 news).
“Drs. Guerreiro, Bras, and colleagues should be congratulated on … publishing the first genome-wide association study of dementia with Lewy bodies, which confirms previously reported associations with APOE, SNCA, and GBA, and suggests other novel loci, namely CNTN1,” wrote Ian McKeith, Newcastle University, U.K. (see full comment below).
Dementia with Lewy bodies (DLB), the second-most-common form of dementia after Alzheimer’s disease, mimics aspects of both AD and Parkinson’s disease (PD). DLB patients suffer not only from dementia, but also from parkinsonism, cognitive fluctuations, and certain psychiatric symptoms, most prominently visual hallucinations. As is the case for AD and PD, scientists believe genetic variation plays an important role in DLB (Guerreiro et al., 2016). However, to date, only a handful of studies, most focused on candidate genes and relying on very small cohorts, have explored genetic associations. Obtaining large numbers of reliably diagnosed DLB patients has proven difficult.
To obtain sufficient samples for GWAS, Bras and collaborators enlisted volunteers at 22 centers across 10 countries in Europe, North America, and Australia. “We all agreed to join forces. It’s the only way we could have succeeded,” said Bras. Co-first authors Rita Guerreiro, also at UCL, and Owen Ross, Mayo Clinic, Jacksonville, Florida, analyzed DNA from 1,743 white patients of European ancestry.
Using genotyping arrays and imputation, an approach to infer alleles based on co-inheritance of nearby variants, the researchers surveyed approximately 8.3 million single-nucleotide polymorphisms (SNPs), including common and not-so-common variants. They first genotyped 1,216 patients with DLB and 3,791 controls, and then replicated the analysis on an independent group of 527 patients and 663 controls. All patients were diagnosed according to established clinical or pathological criteria (McKeith et al., 2005). From the discovery and replication cohorts, 80 and 65 percent, respectively, also had a postmortem neuropathological diagnosis.
The researchers calculated that, overall, genetic variants account for about 36 percent of the risk for DLB in this sample. This is roughly the same as for PD, but much less than that for late-onset AD (Keller et al., 2012; Aug 2017 news).
The APOE locus emerged as the most strongly associated with DLB, with the SNCA gene for α-synuclein next. Interestingly, though, the particular SNCA SNPs were different from the ones associated with PD. “Since [synuclein] pathology occurs in different brain regions in each disease, it is tempting to speculate that the variants are involved in differential expression [of the gene],” said Bras. If true, this may provide a way to begin differentiating both diseases at the molecular level, he added.
No new DLB variants met the statistical threshold for genome-wide significance. However, CNTN1, a gene encoding the neuronal cell-adhesion molecule contactin-1, came close in both the discovery and replication stages of the analysis. Bras noted that at AAIC last July in London, researchers led by Charlotte Teunissen at VU University Medical Center, Amsterdam, reported that contactin-1 levels in cerebrospinal fluid discriminated DLB from AD and non-demented controls. However, he cautioned the genetic association result needs to be replicated and could be driven by variation at the LRRK2 locus, a PD risk factor only 500,000 base pairs away from CNTN1.
The authors found no other known AD or PD variants associated with DLB. This suggests that “DLB does not simply sit between PD and AD,” as the authors put it, but has a distinct combination of risk alleles. Bras predicts that unique DLB genes will surface in the future. The key will be to assemble larger cohorts of reliably diagnosed patients, he said.
McKeith said that newly updated guidelines for DLB diagnosis should help, because they provide more than 90 percent predictive accuracy (Jun 2017 news). James Galvin, Florida Atlantic University, Boca Raton (see full comment below), noted that additional GWAS might finally bring DLB-specific animal models and therapeutic targets within reach.—Marina Chicurel
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