Shared genetic architecture between leukocyte telomere length and Alzheimer's disease

Abstract

Background: Epidemiological and clinical studies have reported an association between leukocyte telomere length (LTL) and Alzheimer's disease (AD). However, genetic association between the two phenotypes remains largely unknown. We aimed to elucidate the potential shared genetic architecture between LTL and AD.

Methods: Summary statistics from genome-wide association studies were obtained from large-scale biobank in European-ancestry populations for LTL (N = 472,174) and AD (71,880 cases, 383,378 controls). We examined the global and local genetic correlation between LTL and AD using linkage-disequilibrium score regression and ρ-HESS. We applied the bivariate causal mixture model (MiXeR) to calculate the number of shared genetic causal variants, and the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework to identify specific shared loci between LTL and AD. Bidirectional two-sample Mendelian randomization (MR) were used to explore the causal associations between LTL and AD.

Results: We detected a significant genetic correlation between LTL and AD (r_g = -0.168). Partitioning the whole genome into 1703 almost independent regions, we observed a significant local genetic correlation for LTL and AD at 19q13.32. MiXeR estimated a total of 360 variants affecting LTL, of which 16 was estimated to influence AD. The condFDR revealed an essential genetic enrichment in LTL conditional on associations with AD, and vice versa. We next identified 8 shared genomic loci between LTL and AD using conjFDR method, of which 4 are novel loci for both the phenotypes. Moreover, 3 shared loci were identified as eQTLs (rs3098168, rs4780338 and rs2680702). All shared loci mapped a subset of 48 credible genes, including USP8, DEXI and APOE. Gene-set analysis identified 18 putative gene sets enriched with the genes mapped to the shared loci. MR analysis suggested that genetically determined AD was causally associated with LTL.

Conclusion: Our study identified specific shared loci between LTL and AD, providing new insights for polygenic overlap and molecular mechanisms, and highlighting new opportunities for future experimental validation.

Keywords: Alzheimer’s disease; Genetic architecture; Leukocyte telomere length.

Fig. 1

Outline of the current study

Fig. 2

Local genetic correlation between LTL and AD. Manhattan plot showing the estimates of local genetic correlation, genetic covariance, and SNP heritability between LTL and AD overall. Blue bars represent loci showing significant local genetic correlation after multiple testing adjustment (p < 0.05/1,703)

Fig. 3

Common genetic variants jointly associated with LTL and AD at conjFDR < 0.05. Manhattan plots showing the–log10 transformed conjunctional FDR values for LTL and AD for each SNP (y-axis) against chromosomal position (x-axis). The dotted line represents the conjFDR threshold for significant association < 0.05. Black outlined circles represent independent lead SNPs. Details for genomic loci and candidate single-nucleotide variants are provided in Table 1 and Supplementary Table S5

Fig. 4

Distribution of the annotation for all candidate SNPs jointly associated between LTL and AD. (a) Distribution of functional consequences of SNPs in the shared genomic risk loci. (b) Distribution of RegulomeDB scores for SNPs in the shared genomic loci, with a low score indicating a higher likelihood of having a regulatory function. (c) The minimum chromatin state across 127 tissue and cell types for SNPs in shared genomic loci, with lower states indicating higher accessibility and states 1–7 referring to open chromatin states

Fig. 5

Spatiotemporal gene expression of credible genes of shared loci between LTL and AD. Among all mapping candidate SNPs of the shared loci between LTL and AD, 48 credible genes were mapped by at least 2 strategies: positional mapping, expression quantitative trait locus mapping, and chromatin interaction mapping. The gene expression data were acquired from the Genotype Tissue Expression (GTEx) v8 resource and the figure was generated using the GENE2FUNC procedure of FUMA. Gene expression was based on data from 948 individuals and is presented as the averaged log2 transformed expression per tissue for each gene. Darker red means higher gene expression compared to a darker blue color

Fig. 6

Bidirectional MR results for the relationship between LTL and AD