Abstract
Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.
Highlights
Regarding APOE, the strongest genetic risk factor for Alzheimer’s disease (AD), we showed that the APOE ε4 allele increases and the APOE ε2 allele decreases the risk of developing DLB14
We nominate a novel genetic locus near ZFPM1 as suggestively associated with Dementia with Lewy Bodies (DLB)
We recently demonstrated that this variant accounts for the GBA top-hit from a Parkinson’s disease (PD) meta-GWAS23
Summary
Previous genetic studies have suggested associations of APOE, GBA, SNCA and SCARB2 with DLB in both neuropathologically and clinically diagnosed cases[12]. None of the AD associated common variants identified in large genome-wide association studies (GWAS) have been associated to DLB besides APOE. Notwithstanding these interesting results from early genetic studies, the individual genetic risk factors that contribute to the common and sporadic late onset form of DLB have remained relatively unexplored compared to PD and AD, largely due to the lack of large sample series providing adequate statistical power for GWAS. We investigated whether common genetic variants are associated with DLB, aiming to elucidate the molecular mechanisms underlying the disease
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