First Genome-Wide Association Study of Dementia with Lewy Bodies

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

Comments

  1. Although dementia with Lewy bodies (DLB) is the second-most-common cause of dementia, research into the underlying pathophysiology lags behind Alzheimer’s and Parkinson’s disease. Guerreiro and colleagues recently conducted the first large-scale genome-wide association study and identified three previously known associations: apolipoprotein E (ApoE), α-synuclein (SCNA), and glucocerebrosidase (GBA). In addition, a novel locus was found in discovery and validation assays—CNTN1, a glycosylphophotidyl inositol-anchored neuronal membrane protein that may serve as a cell-adhesion molecule. Even more interesting, the CNTN1 locus is located near the Lrrk2 locus, which has been linked to Parkinson’s disease. While additional GWAS studies are needed, with this new knowledge it may be possible to design experimental paradigms to ultimately model DLB pathophysiology and develop DLB-specific targets for new therapeutic interventions.

    View all comments by James Galvin

  2. The recently published Fourth Report of the DLB Consortium, which updated recommendations about DLB diagnosis and management, prioritized “strategies to progress critical areas of biological research, include collecting samples from large population-based cohorts, and developing a publically available DLB genetic database and a repository for DLB exome data” (July 2017 news). Drs. Guerreiro, Bras, and colleagues should be congratulated on progressing this agenda by publishing the first genome-wide association study of DLB, which confirms previously reported associations with ApoE, SNCA, and GBA and suggests other novel loci, namely CNTN1.

    We now know from their work that the heritable component of DLB is approximately 36 percent, similar to both AD and PD, and although the three disorders may share common genes, the specific mutations or combinations of them appear to differ. DLB families will of course ask whether they should now come forward for clinical genetic testing and risk profiling, but it is still too early to advocate this. New and larger samples are required to continue the search/validation for other DLB genes.  Although the gold standard will always be pathologically verified cases, my view is that since clinical diagnostic criteria for DLB, properly applied, have greater than 90 percent positive predictive accuracy, the goal can be achieved using well-characterized clinical cases. As the DLB4 report concluded, “In order to best advance DLB research, global harmonization efforts are required to create networks of researchers and research participants that share common platforms for data and biomarker collection, outcome measures for clinical-translational research, and shared terminology across language, cultures, and traditions.”  

    View all comments by Ian McKeith

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References

News Citations

  1. Genetics of DLB: Setting Up to Fill a Mostly Empty Canvas
  2. Searching for New AD Risk Variants? Move Beyond GWAS
  3. DLB Guidelines Get a Makeover

Paper Citations

  1. Guerreiro R, Escott-Price V, Darwent L, Parkkinen L, Ansorge O, Hernandez DG, Nalls MA, Clark L, Honig L, Marder K, van der Flier W, Holstege H, Louwersheimer E, Lemstra A, Scheltens P, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Ortega-Cubero S, Pastor P, Ferman TJ, Graff-Radford NR, Ross OA, Barber I, Braae A, Brown K, Morgan K, Maetzler W, Berg D, Troakes C, Al-Sarraj S, Lashley T, Compta Y, Revesz T, Lees A, Cairns NJ, Halliday GM, Mann D, Pickering-Brown S, Powell J, Lunnon K, Lupton MK, International Parkinson's Disease Genomics Consortium, Dickson D, Hardy J, Singleton A, Bras J. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging. 2016 Feb;38:214.e7-10. Epub 2015 Nov 2 PubMed.
  2. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005 Dec 27;65(12):1863-72. PubMed.
  3. Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simón-Sánchez J, Mittag F, Büchel F, Sharma M, Gibbs JR, Schulte C, Moskvina V, Durr A, Holmans P, Kilarski LL, Guerreiro R, Hernandez DG, Brice A, Ylikotila P, Stefánsson H, Majamaa K, Morris HR, Williams N, Gasser T, Heutink P, Wood NW, Hardy J, Martinez M, Singleton AB, Nalls MA, International Parkinson's Disease Genomics Consortium (IPDGC), Wellcome Trust Case Control Consortium 2 (WTCCC2). Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Hum Mol Genet. 2012 Nov 15;21(22):4996-5009. Epub 2012 Aug 13 PubMed.

Further Reading

Papers

  1. Hardy J, Crook R, Prihar G, Roberts G, Raghavan R, Perry R. Senile dementia of the Lewy body type has an apolipoprotein E epsilon 4 allele frequency intermediate between controls and Alzheimer's disease. Neurosci Lett. 1994 Nov 21;182(1):1-2. PubMed.
  2. Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP. APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013 Feb;70(2):223-8. PubMed.
  3. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K. alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003 Oct 31;302(5646):841. PubMed.
  4. Bras J, Guerreiro R, Darwent L, Parkkinen L, Ansorge O, Escott-Price V, Hernandez DG, Nalls MA, Clark LN, Honig LS, Marder K, Van Der Flier WM, Lemstra A, Scheltens P, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Ortega-Cubero S, Pastor P, Ferman TJ, Graff-Radford NR, Ross OA, Barber I, Braae A, Brown K, Morgan K, Maetzler W, Berg D, Troakes C, Al-Sarraj S, Lashley T, Compta Y, Revesz T, Lees A, Cairns N, Halliday GM, Mann D, Pickering-Brown S, Dickson DW, Singleton A, Hardy J. Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet. 2014 Dec 1;23(23):6139-46. Epub 2014 Jun 27 PubMed.
  5. Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Trojanowski JQ, Schellenberg GD, Yearout D, Huston H, Fritts-Penniman A, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP. GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology. 2012 Nov 6;79(19):1944-50. PubMed.
  6. Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D, Cras P, Engelborghs S, De Deyn PP, Van Broeckhoven C, Mann DM, Snowden J, Pickering-Brown S, Halliwell N, Davidson Y, Gibbons L, Harris J, Sheerin UM, Bras J, Hardy J, Clark L, Marder K, Honig LS, Berg D, Maetzler W, Brockmann K, Gasser T, Novellino F, Quattrone A, Annesi G, De Marco EV, Rogaeva E, Masellis M, Black SE, Bilbao JM, Foroud T, Ghetti B, Nichols WC, Pankratz N, Halliday G, Lesage S, Klebe S, Durr A, Duyckaerts C, Brice A, Giasson BI, Trojanowski JQ, Hurtig HI, Tayebi N, Landazabal C, Knight MA, Keller M, Singleton AB, Wolfsberg TG, Sidransky E. A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies. JAMA Neurol. 2013 Apr 15;:1-9. PubMed.

Primary Papers

  1. Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD, Shepherd CE, Parkkinen L, Darwent L, Heckman MG, Scholz SW, Troncoso JC, Pletnikova O, Ansorge O, Clarimon J, Lleo A, Morenas-Rodriguez E, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Troakes C, Al-Sarraj S, Lashley R, Holton J, Compta Y, Van Deerlin V, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana I, Pastor P, Diez-Fairen M, Aguilar M, Tienari PJ, Myllykangas L, Oinas M, Revesz R, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Cairns NJ, Morris JC, Pickering-Brown S, Mann D, Halliday GM, Hardy J, Trojanowski JQ, Dickson DW, Singleton A, Stone DJ, Bras J. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. The Lancet Neurol, Dec 15, 2107.

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