Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer's disease and Parkinson's disease: a large-scale multi-trait association analysis

Abstract

Background: The current genome-wide association study (GWAS) of Lewy body dementia (LBD) suffers from low power due to a limited sample size. In addition, the genetic determinants underlying LBD and the shared genetic etiology with Alzheimer's disease (AD) and Parkinson's disease (PD) remain poorly understood.

Methods: Using the largest GWAS summary statistics of LBD to date (2591 cases and 4027 controls), late-onset AD (86,531 cases and 676,386 controls), and PD (33,674 cases and 449,056 controls), we comprehensively investigated the genetic basis of LBD and shared genetic etiology among LBD, AD, and PD. We first conducted genetic correlation analysis using linkage disequilibrium score regression (LDSC), followed by multi-trait analysis of GWAS (MTAG) and association analysis based on SubSETs (ASSET) to identify the trait-specific SNPs. We then performed SNP-level functional annotation to identify significant genomic risk loci paired with Bayesian fine-mapping and colocalization analysis to identify potential causal variants. Parallel gene-level analysis including GCTA-fastBAT and transcriptome-wide association analysis (TWAS) was implemented to explore novel LBD-associated genes, followed by pathway enrichment analysis to understand underlying biological mechanisms.

Results: Pairwise LDSC analysis found positive genome-wide genetic correlations between LBD and AD (rg = 0.6603, se = 0.2001; P = 0.0010), between LBD and PD (rg = 0.6352, se = 0.1880; P = 0.0007), and between AD and PD (rg = 0.2136, se = 0.0860; P = 0.0130). We identified 13 significant loci for LBD, including 5 previously reported loci (1q22, 2q14.3, 4p16.3, 4q22.1, and 19q13.32) and 8 novel biologically plausible genetic associations (5q12.1, 5q33.3, 6p21.1, 8p23.1, 8p21.1, 16p11.2, 17p12, and 17q21.31), among which APOC1 (19q13.32), SNCA (4q22.1), TMEM175 (4p16.3), CLU (8p21.1), MAPT (17q21.31), and FBXL19 (16p11.2) were also validated by gene-level analysis. Pathway enrichment analysis of 40 common genes identified by GCTA-fastBAT and TWAS implicated significant role of neurofibrillary tangle assembly (GO:1902988, adjusted P = 1.55 × 10^-2).

Conclusions: Our findings provide novel insights into the genetic determinants of LBD and the shared genetic etiology and biological mechanisms of LBD, AD, and PD, which could benefit the understanding of the co-pathology as well as the potential treatment of these diseases simultaneously.

Keywords: Alzheimer’s disease; Lewy body dementia; Multi-trait association analysis; Parkinson’s disease; Shared genetics.

Fig. 1

Overall study design. Pairwise genome-wide genetic correlation analysis among LBD, AD, and PD was first performed by linkage disequilibrium score regression (LDSC), followed by multi-trait meta-analysis of LBD, AD, and PD GWASs using MTAG. Based on the MTAG_LBD results, SNP-level analysis and gene-level analysis were further implemented to investigate the genetic basis of LBD and shared genetics underlying LBD, AD, and PD. GWAS, genome-wide association study; MTAG, multi-trait analysis of genome-wide association studies; LBD, Lewy body dementia; AD, Alzheimer’s disease; PD, Parkinson’s disease

Fig. 2

Manhattan plots of GWAS_LBD (a) and MTAG_LBD (b). The x-axis denotes the chromosomal position, and the y-axis shows the −log10 P value. The horizontal black line corresponds to the genome-wide significance threshold (P < 5 × 10⁻⁸). Labels are the chromosome regions where genomic risk loci are located. Note that the Manhattan plots were plotted at P values truncated by 1 × 10⁻⁶⁰ for better visualization

Fig. 3

GARFIELD enrichment of SNPs with P_mtag < 5 × 10⁻⁸ in MTAG_LBD. Enrichment in genic regions (a), DHS (hotspots) regions of different tissues (b), chromatin states of different tissues (c), and histone modified regions of different tissues (d). The horizontal axis represents the enrichment odds ratios of each annotation category derived from logistic regression, and the vertical axis shows the corresponding −log10 P values. The dashed line corresponds to the significance threshold of P = 0.05/1005. The size of the dots indicates the number of independent SNPs in a specific annotation. The color of the dots in c and d indicates different tissue types