Objective: To identify genetic variants that are either shared between or specific for Dementia with Lewy Bodies (DLB), REM Behavior Disorder (RBD), Parkinson’s disease (PD) and Alzheimer’s Disease (AD). A combined Genome Wide Association Study (GWAS) can potentially reveal genetic variants that are distinct or shared between the synucleinopathies that were not genome-wide significant in individual studies.

Background: GWASs in DLB, AD, PD and RBD have revealed partially overlapping genes as well as disease-specific genes that correspond to risk. In DLB, 3 out of 5 risk loci are shared with PD (SNCA, GBA and TMEM175) and 2 with AD (APOE and BIN1). In RBD, all 5 loci identified share risk for PD, but some PD loci such as LRRK2 and MAPT are not shared with RBD. The small sample sizes of the DLB and RBD GWASs prevent genetic variants to be discovered at genome-wide significance.

Method: We conducted an inverse variance weighted fixed-effects meta-analysis of GWASs from PD, DLB, RBD and AD using METAL. Quality control for each dataset included 1) filtering SNPs with minor allele frequency >0.01, 2)retain bi-allelic sites only and 3)removing variants that contained any missing data. A total of 10,910,515 variants were included with genome-wide significance set to p <5 × 10⁻⁸. SNPs with p<5×10⁻⁸ and independent from each other at r²<0.6 within 1 Mb were defined as independent significant SNPs. Lead SNPs, a subset of the independent significant SNPs, were defined if r² < 0.1.Genomic risk loci were identified by merging the LD blocks of independent significant SNPs that are closely located to each other (<250 kb).

Results: We identified 152 genome-wide significant lead SNPs in 69 loci. Nearly all loci showed association that corroborated previous GWAS results. Of the 90 GWAS significant SNPs from the original PD study, 69 of them became GWAS insignificant including VPS13C, SNCA and LRRK2. Of the 29 GWAS significant SNPs from the original AD study, 8 of them had increased significance including BIN1, KAT8, CLU, ABI3, and ECHDC3.

Conclusion: The magnitude changes in SNPs significant for PD imply that these variants may be specific to PD etiology compared to the changes in AD SNPs which increased several variants with the additional cohorts. Additional analyses that consider effect direction of variants may give an improved understanding of the genetic relationship between these neurodegenerative disorders.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/combined-gwas-of-dementia-with-lewy-bodies-rem-sleep-behavior-disorder-parkinsons-disease-and-alzheimers-disease/