Systematic review of genetic association studies in people with Lewy body dementia
Rajkumar, Anto P.
MetadataShow full item record
OBJECTIVES: Lewy body dementia (LBD) causes more morbidity, disability and earlier mortality than Alzheimer's disease. Molecular mechanisms underlying neurodegeneration in LBD are poorly understood. We aimed to do a systematic review of all genetic association studies that investigated people with LBD for improving our understanding of LBD molecular genetics and for facilitating discovery of novel biomarkers and therapeutic targets for LBD. METHODS: We systematically reviewed five online databases (PROSPERO protocol: CRD42018087114) and completed the quality assessment using the Quality of genetic association studies tool. RESULTS: 8521 articles were screened, and 75 articles were eligible to be included. Genetic associations of LBD with APOE, GBA and SNCA variants have been replicated by two or more good quality studies. Our meta-analyses confirmed that APOE-epsilon4 is significantly associated with dementia with Lewy bodies (pooled odds ratio (POR)= 2.70; 95%CI 2.37-3.07; p<0.001) and Parkinson's disease dementia (POR=1.60; 95%CI 1.21-2.11; p=0.001). Other reported genetic associations that need further replication include variants in A2M, BCHE-K, BCL7C, CHRFAM7A, CNTN1, ESR1, GABRB3, MAPT, mtDNA Haplogroup-H, NOS2A, PSEN1, SCARB2, TFAM, TREM2, and UCHL1. CONCLUSIONS: The reported genetic associations and their potential interactions indicate the importance of alpha-synuclein, amyloid, and tau pathology, autophagy lysosomal pathway, ubiquitin proteasome system, oxidative stress and mitochondrial dysfunction in LBD. There is a need for larger GWAS for identifying more LBD associated genes. Future hypothesis-driven studies should aim to replicate reported genetic associations of LBD, and to explore their functional implications. This article is protected by copyright. All rights reserved.