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Multicenter Study
. 2014 Dec 1;23(23):6139-46.
doi: 10.1093/hmg/ddu334. Epub 2014 Jun 27.

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Jose Bras  1 , Rita Guerreiro  2 , Lee Darwent  2 , Laura Parkkinen  3 , Olaf Ansorge  3 , Valentina Escott-Price  4 , Dena G Hernandez  5 , Michael A Nalls  5 , Lorraine N Clark  6 , Lawrence S Honig  7 , Karen Marder  7 , Wiesje M Van Der Flier  8 , Afina Lemstra  8 , Philip Scheltens  8 , Ekaterina Rogaeva  9 , Peter St George-Hyslop  10 , Elisabet Londos  11 , Henrik Zetterberg  12 , Sara Ortega-Cubero  13 , Pau Pastor  13 , Tanis J Ferman  14 , Neill R Graff-Radford  15 , Owen A Ross  16 , Imelda Barber  17 , Anne Braae  17 , Kristelle Brown  17 , Kevin Morgan  17 , Walter Maetzler  18 , Daniela Berg  18 , Claire Troakes  19 , Safa Al-Sarraj  19 , Tammaryn Lashley  20 , Yaroslau Compta  21 , Tamas Revesz  20 , Andrew Lees  20 , Nigel Cairns  22 , Glenda M Halliday  23 , David Mann  24 , Stuart Pickering-Brown  24 , Dennis W Dickson  16 , Andrew Singleton  5 , John Hardy  25
Affiliations
Multicenter Study

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Jose Bras et al. Hum Mol Genet. .

Abstract

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

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Figures

Figure 1.
Figure 1.
Genomic overview of the association at 54 genomic regions in a cohort of 788 DLB cases and 2624 controls. These loci correspond to 500 kb flanking regions of each top association hit from the latest PD and AD GWAS (32 regions from PD and 22 from AD GWAS). The dotted horizontal red line represents our study-wise Bonferroni correction threshold of 3.7 × 10−5.
Figure 2.
Figure 2.
Genomic overview of the association using only neuropathologically confirmed DLB cases at the previously reported association hits for PD and AD. These loci correspond to 500 kb flanking regions of each top association hit from the latest PD and AD GWAS (32 regions from PD and 22 from AD GWAS). The dotted horizontal red line represents our study-wise Bonferroni correction threshold of 3.7 × 10−5.
Figure 3.
Figure 3.
Regional association plot of the APOE genomic locus (the top hit from GWAS in AD) in a cohort of 788 DLB cases and 2624 controls. Coloring is based on linkage disequilibrium (LD) with the most associated SNP.
Figure 4.
Figure 4.
Regional association plot at the SNCA locus (the top hit from GWAS in PD) in a cohort of 788 DLB cases and 2624 controls. Interestingly, the top hit at this locus for PD is not significant in our DLB study (in purple) and the association seems to be 5′ of the gene. Coloring represents LD with the top reported hit for PD.
Figure 5.
Figure 5.
Regional association plot at the SCARB2 locus (one of the top hits from GWAS in PD) in a cohort of 788 DLB cases and 2624 controls. The top hit in DLB is not in high LD with the reported hit for PD (in purple). Coloring represents LD with the top reported hit for PD.
Figure 6.
Figure 6.
Comparison of the regional association at the SNCA and SCARB2 loci between DLB and PD. Red symbols represent the PD association (restricted to the top hits per region), while the blue ones represent DLB. P-values were normalized for each region/study to allow for a better comparison of regional association.
See this image and copyright information in PMC

References

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