Linking Alzheimer's disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach

Wang, Xia-Fang; Lin, Xu; Li, Ding‐You; Zhou, Ruanbao; Greenbaum, Jonathan; Chen, Yuancheng; Zeng, Chun‐Ping; Peng, Lin-Ping; Wu, Kai-Kai; Ao, Zeng-Xin; Lu, Jun-Min; Guo, Yan-Fang; Shen, Jie; Deng, Hong‐Wen

doi:10.1016/j.jns.2017.07.044

Cited by 42 publications

(29 citation statements)

References 85 publications

(104 reference statements)

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“…They found an enrichment for SNPs associated with cognitive impairment conditional on plasma CRP and lipids, and significant associations for the APOE extended locus 36 . Shared genetic etiology for LOAD using the cFDR method was also investigated for Type 2 diabetes (T2D) 37 . In this study, multiple known and novel associated SNPs were identified by conditioning LOAD association on T2D and by the reverse direction, and mitochondrial dysfunction was highlighted as a common pathway 37 .…”

Section: Discussionmentioning

confidence: 99%

“…The pleiotropy analysis strategy, based on conditional false discovery rates, fold-enrichment plots, and conditional quantile-quantile (Q-Q) plots, is described in detail elsewhere 28,37 . In brief, for two phenotypes A and B, pleiotropic enrichment of phenotype A conditional on phenotype B exists if the proportion of variants (SNPs) statistically significantly associated with phenotype A increases as a function of increased statistically significant SNP associations with phenotype B.…”

Section: Statistical and Bioinformatics Analysis Pleiotropy Analysismentioning

confidence: 99%

“…Following the prior analysis strategy 28 , we focused the analysis for polygenic enrichment on SNPs below the standard GWAS Bonferroni-corrected P-value thresholds. Following the example of Wang et al 37 and Desikan et al 28 , the SNP data were pruned to eliminate correlated pairs of SNPs based on linkage disequilibrium (LD) measured in the 1000 Genomes data set (Phase 3, version 5 of the 1000 Genomes Project, European panel). If R 2 value for a pair of SNPs was >0.2, the SNP with the lower minor allele frequency (MAF) was removed.…”

Section: Statistical and Bioinformatics Analysis Pleiotropy Analysismentioning

confidence: 99%

“…For identification of specific SNPs conditionally associated with LOAD and MDD, a conditional false discovery rate (FDR) statistic (Q value) was calculated as described in the prior implementation of this analysis strategy 28,37 and other publications [25][26][27][30][31][32][33] . This framework was an extension of the standard analysis for FDR calculations and uses information from the secondary phenotype to re-rank the P-values for the primary phenotype.…”

Section: Statistical and Bioinformatics Analysis Pleiotropy Analysismentioning

confidence: 99%

“…Recently, a statistical method to evaluate genetic pleiotropic effects using GWAS summary statistics (P-values and odds ratios) was developed [25][26][27][28] , and has been utilized to examine genetic pleiotropy between multiple diverse diseases and phenotypes [25][26][27][29][30][31][32][33][34][35] , including LOAD with other conditions. Most prominent, polygenic overlaps were reported for LOAD with modulation of c-reactive protein (CRP) and plasma lipids 28,36 , and with type 2 diabetes 37 . Here, we utilize this statistical framework to investigate the genetic overlap between LOAD and MDD.…”

Section: Introductionmentioning

confidence: 99%

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Shared genetic etiology underlying Alzheimer’s disease and major depressive disorder

et al. 2020

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Patients with late-onset Alzheimer's disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with major depressive disorder (MDD) have an increased prevalence of LOAD. This suggests shared etiologies and intersecting pathways between LOAD and MDD. We performed pleiotropy analyses using LOAD and MDD GWAS data sets from the International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium (PGC), respectively. We found a moderate enrichment for SNPs associated with LOAD across increasingly stringent levels of significance with the MDD GWAS association (LOAD| MDD), of maximum four and eightfolds, including and excluding the APOE-region, respectively. Association analysis excluding the APOE-region identified numerous SNPs corresponding to 40 genes, 9 of which are known LOAD-risk loci primarily in chromosome 11 regions that contain the SPI1 gene and MS4A genes cluster, and others were novel pleiotropic risk-loci for LOAD conditional with MDD. The most significant associated SNPs on chromosome 11 overlapped with eQTLs found in whole-blood and monocytes, suggesting functional roles in gene regulation. The reverse conditional association analysis (MDD|LOAD) showed a moderate level,~sevenfold, of polygenic overlap, however, no SNP showed significant association. Pathway analyses replicated previously reported LOAD biological pathways related to immune response and regulation of endocytosis. In conclusion, we provide insights into the overlapping genetic signatures underpinning the common phenotypic manifestations and inter-relationship between LOAD and MDD. This knowledge is crucial to the development of actionable targets for novel therapies to treat depression preceding dementia, in an effort to delay or ultimately prevent the onset of LOAD.

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Section: Discussionmentioning

confidence: 99%

Section: Statistical and Bioinformatics Analysis Pleiotropy Analysismentioning

confidence: 99%

Section: Statistical and Bioinformatics Analysis Pleiotropy Analysismentioning

confidence: 99%

Section: Statistical and Bioinformatics Analysis Pleiotropy Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Shared genetic etiology underlying Alzheimer’s disease and major depressive disorder

et al. 2020

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Shared genetic etiology underlying late‐onset Alzheimer's disease and posttraumatic stress syndrome

Lutz

Luo

Williamson

et al. 2020

Alzheimer's & Dementia

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Introduction: Late-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies. Methods: We performed genetic pleiotropy analysis using LOAD and PTSD genomewide association study (GWAS) datasets from white and African-American populations, followed by functional-genomic analyses. Results: We found an enrichment for LOAD across increasingly stringent levels of significance with the PTSD GWAS association (LOAD|PTSD) in the discovery and replication cohorts and a modest enrichment for the reverse conditional association (PTSD|LOAD). LOAD|PTSD association analysis identified and replicated the MS4A genes region. These genes showed similar expression pattern in brain regions affected in LOAD, and across-brain-tissue analysis identified a significant association for MS4A6A. The African-American samples showed moderate enrichment; however, no false discovery rate-significant associations. Discussion: We demonstrated common genetic signatures for LOAD and PTSD and suggested immune response as a common pathway for these diseases.

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Phytotherapic use of the Crocus sativus L. (Saffron) and its potential applications: A brief overview

Leone

Recinella

Chiavaroli

et al. 2018

Phytotherapy Research

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Crocus sativus L. (Saffron) has long been known for multiple target therapeutic uses. The plant metabolism is well investigated and the main metabolites related to saffron organoleptic qualities are crocin, crocetin, picrocrocin, and safranal. Particularly, the most abundant of them, such as crocin and safranal, are investigated for their multiple biological activities and known as potential drugs. We aimed to review the constituent features of the plant, along with its potential therapeutic effects in depression, neurodegenerative diseases, diabetes mellitus, atherosclerosis, cancer, and sexual dysfunction. A systematic literature search was conducted in PubMed, Medline, Scopus, and EMBASE, with particular attention to preclinical and clinical studies. Although saffron and its components showed potential clinical applications, further investigations are necessary to confirm the effective use of "Red Gold" and its real applications in clinical practice.

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Linking Alzheimer's disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach

Abstract: Our study provided evidence for shared genetic loci between T2D and AD in European subjects by using cFDR and ccFDR analyses. These results may provide novel insight into the etiology and potential therapeutic targets of T2D and/or AD.

Cited by 42 publications

References 85 publications

Shared genetic etiology underlying Alzheimer’s disease and major depressive disorder

Shared genetic etiology underlying Alzheimer’s disease and major depressive disorder

Shared genetic etiology underlying late‐onset Alzheimer's disease and posttraumatic stress syndrome

Phytotherapic use of the Crocus sativus L. (Saffron) and its potential applications: A brief overview

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