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Meta-Analysis
. 2019 Mar;138(3):271-285.
doi: 10.1007/s00439-019-01988-9. Epub 2019 Feb 25.

Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis

Zhaozhong Zhu  1   2 , Yifei Lin  1 , Xihao Li  3 , Jane A Driver  4   5 , Liming Liang  6   7
Affiliations
Meta-Analysis

Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis

Zhaozhong Zhu et al. Hum Genet. 2019 Mar.

Erratum in

Abstract

A growing number of studies clearly demonstrate a substantial link between metabolic dysfunction and the risk of Alzheimer's disease (AD), especially glucose-related dysfunction; one hypothesis for this comorbidity is the presence of a common genetic etiology. We conducted a large-scale cross-trait GWAS to investigate the genetic overlap between AD and ten metabolic traits. Among all the metabolic traits, fasting glucose, fasting insulin and HDL were found to be genetically associated with AD. Local genetic covariance analysis found that 19q13 region had strong local genetic correlation between AD and T2D (P = 6.78 × 10- 22), LDL (P = 1.74 × 10- 253) and HDL (P = 7.94 × 10- 18). Cross-trait meta-analysis identified 4 loci that were associated with AD and fasting glucose, 3 loci that were associated with AD and fasting insulin, and 20 loci that were associated with AD and HDL (Pmeta < 1.6 × 10- 8, single trait P < 0.05). Functional analysis revealed that the shared genes are enriched in amyloid metabolic process, lipoprotein remodeling and other related biological pathways; also in pancreas, liver, blood and other tissues. Our work identifies common genetic architectures shared between AD and fasting glucose, fasting insulin and HDL, and sheds light on molecular mechanisms underlying the association between metabolic dysregulation and AD.

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Conflict of interest statement

Conflict of Interest statement

All authors declare no competing interest.

Figures

Figure 1.
Figure 1.
Partitioned genetic correlation. a. Genetic correlation between Alzheimer’s disease and sugar traits by functional category. b. Genetic correlation between Alzheimer’s disease and HDL by functional category category. Vertical axis represents the genetic correlation estimate Rg (standard error), horizontal axis represents 11 functional categories. Asterisk represents significance (P<0.05). DGF: DNaseI Digital Genomic Footprinting; DHS: DNase I hypersensitivity Site; TFBS: Transcription Factor Binding Sites. AD: Alzheimer’s disease; FG: fasting glucose; FINS: fasting insulin; FGFINSmeta: meta-analysis of fasting glucose and fasting insulin.
Figure 2.
Figure 2.
Local genetic correlation and local SNP-heritability between Alzheimer’s disease and T2D (2a), LDL (2b) and HDL (2c) respectively. For each sub-figure, top part represents local genetic correlation, middle part represents local genetic covariance, and significant local genetic correlation and covariance after multiple testing correction are highlighted in blue; bottom part represents local SNP-heritability for individual trait.
Figure 3.
Figure 3.
GTEx tissue enrichment analysis. a. GTEx tissue enrichment analysis of AD and fasting glucose. b. GTEx tissue enrichment analysis of AD and fasting insulin. c. GTEx tissue enrichment analysis of AD and HDL. Red bar represents significant tissue enrichment after Benjamin-Hochberg correction.
See this image and copyright information in PMC

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