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

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?

SUBMITTER: Zhu Z

PROVIDER: S-EPMC7193309 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Zhu Zhaozhong Z Lin Yifei Y Li Xihao X Driver Jane A JA Liang Liming L

Human genetics 20190225 3

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. L ...[more]

PMID: 30805717

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Project description:BackgroundTo study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved.MethodsBased on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations.ResultsOur research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10-8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL.ConclusionsOur research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.

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Dataset Information

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

Publications

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

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