Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics

Feng, Yen Chen Anne; Cho, Kelly; Lindström, Sara; Kraft, Peter; Cormack, Jean; Discovery, Biology; Liang, Liming; Driver, Jane A.

doi:10.1007/s00439-017-1831-6

Cited by 39 publications

(42 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data suggested that the observed inverse association between dementia and cancer might be a true finding, but the underlying mechanisms are still largely unknown (15). Differential regulation of common genes and pathways might be related to the inverse association between cancer and dementia.…”

Section: Discussionmentioning

confidence: 67%

“…Survival bias, which means that cancer survivors may be more likely to die before they can develop dementia, has been suggested to confound the observed association (2,14). A potential mechanism is that biological pathway to cancer might be protective against dementia (15)(16)(17)(18), but the existing evidence remains inconclusive. The observed inverse association is further complicated by the medical treatments of various types of cancer, which have been reported to be associated with either a higher or lower risk of dementia (5,(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Association Between Cancer and Dementia: A National Cohort Study in Sweden

et al. 2020

View full text Add to dashboard Cite

Background: Previous studies have found that the incidence of dementia is lower in patients with cancer. However, the impact of survival bias, as well as the confounding by medical treatment, have not been fully addressed. We aimed to explore the subsequent risk of dementia in different follow-up intervals among patients with cancer, as well as the risk before the diagnosis of cancer.Methods: By using the Swedish Cancer Register and the Swedish Hospital Discharge Register, we systematically examined the risk of dementia among patients diagnosed with 35 different types of cancer. Standardized incidence ratios (SIRs) were used to calculate the relative risk. Results:The subsequent risk of dementia in patients with cancer decreased by 21% compared to matched cancer-free controls (SIR = 0.79, 95% CI 0.78-0.80). For specific cancer sites, 21 of them had a significantly lower risk of subsequent dementia. The decreased risk of dementia was also significant before the diagnosis of cancer. However, the risk was higher among patients with cancer who survived for more than 10 years' post-diagnosis (SIR = 1.37, 95% CI 1.32-1.41). Conclusions:In this population-based study, we found that the risk of dementia was lower among patients with cancer, and the risk was also lower before the diagnosis of cancer. This suggests that lower dementia risk is not simply due to bias. However, the underlying mechanisms need to be explored further.

show abstract

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

The Association Between Cancer and Dementia: A National Cohort Study in Sweden

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Evaluation of the genetic overlap between dementia and cancer could reveal the true direction of the association between cancer and dementia. One study used genomewide association study summary statistics showed a positive genetic correlation between these diseases, implying that cancer and dementia share some genetic background . Shared genetic variants could modulate the risk of cancer and dementia in the same direction, thereby pointing towards pleiotropic effects.…”

Section: The Risk Of Cancer In Dementia Patients and The Risk Of Demementioning

confidence: 99%

“…One study used genomewide association study summary statistics showed a positive genetic correlation between these diseases, implying that cancer and dementia share some genetic background. 76 Shared genetic variants could modulate the risk of cancer and dementia in the same direction, thereby pointing towards pleiotropic effects. The strongest positive genetic correlations were found in regions representing enhancer marks on the genome, indicating a possible role of gene expression regulation in the pathogenesis of both diseases.…”

Section: Geneticsmentioning

confidence: 99%

Cancer and dementia: Two sides of the same coin?

Willik

Schagen

Ikram

2018

Eur J Clin Investigation

View full text Add to dashboard Cite

Noncentral nervous system cancer and the brain share an interesting and complex relation, with an emerging body of evidence showing that cancer patients are at an increased risk of developing cognitive problems. In contrast, population‐based studies consistently find an inverse link between cancer and dementia, that is patients with dementia having a lower risk of subsequently developing cancer, and cancer patients being less often diagnosed with dementia. Different biological processes such as inversely activated cell proliferation and survival pathways have been suggested to have an important role underlying this inverse association. However, the effect of methodological biases including surveillance or survival bias has not been completely ruled out, calling into question the inverse direction of the association between cancer and dementia. In fact, emerging evidence now suggests that cancer and dementia might share a positive association. This narrative review summarises the current literature on cancer, cognitive problems and dementia. Moreover, different strategies will be discussed to reduce the impact of potential methodological biases on the association between cancer and dementia, trying to reveal the true direction of this link.

show abstract

“…Increasing evidence suggest that there are common pathophysiological features in both diseases, such as DNA damage, oxidative stress, mitochondrial dysfunction, metabolic dysregulation, and inflammation (Driver, 2014;Houck et al, 2018). Moreover, single nucleotide polymorphism (SNP)-trait genome-wide association studies (GWAS) have shown positive genetic correlations between AD and cancer (Feng et al, 2017). Although the relationship between AD and cancer remains controversial, the analysis of large cancer multi-omics datasets and associated clinical information should provide insights into developing new drugs for AD.…”

Section: Introductionmentioning

confidence: 99%

A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease

et al. 2020

View full text Add to dashboard Cite

Numerous clinical trials of drug candidates for Alzheimer's disease (AD) have failed, and computational drug repositioning approaches using omics data have been proposed as effective alternative approaches to the discovery of drug candidates. However, little multiomics data is available for AD, due to limited availability of brain tissues. Even if omics data exist, systematic drug repurposing study for AD has suffered from lack of big data, insufficient clinical information, and difficulty in data integration on account of sample heterogeneity derived from poor diagnosis or shortage of qualified post-mortem tissue. In this study, we developed a proteotranscriptomic-based computational drug repositioning method named Drug Repositioning Perturbation Score/Class (DRPS/C) based on inverse associations between disease-and drug-induced gene and protein perturbation patterns, incorporating pharmacogenomic knowledge. We constructed a Drug-induced Gene Perturbation Signature Database (DGPSD) comprised of 61,019 gene signatures perturbed by 1,520 drugs from the Connectivity Map (CMap) and the L1000 CMap. Drugs were classified into three DRPCs (High, Intermediate, and Low) according to DRPSs that were calculated using drug-and disease-induced gene perturbation signatures from DGPSD and The Cancer Genome Atlas (TCGA), respectively. The DRPS/C method was evaluated using the area under the ROC curve, with a prescribed drug list from TCGA as the gold standard. Glioblastoma had the highest AUC. To predict anti-AD drugs, DRPS were calculated using DGPSD and AD-induced gene/protein perturbation signatures generated from RNA-seq, microarray and proteomic datasets in the Synapse database, and the drugs were classified into DRPCs. We predicted 31 potential anti-AD drug candidates commonly belonged to high DRPCs of transcriptomic and proteomic signatures. Of these, four drugs classified into the nervous system group of Anatomical Therapeutic Chemical (ATC) system are voltage-gated sodium channel blockers (bupivacaine, topiramate) and monamine oxidase inhibitors (selegiline, iproniazid), and their mechanism of action was inferred from a potential anti-AD drug perspective. Our approach suggests a shortcut to discover new efficacy of drugs for AD.

show abstract

Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics

Cited by 39 publications

References 32 publications

The Association Between Cancer and Dementia: A National Cohort Study in Sweden

The Association Between Cancer and Dementia: A National Cohort Study in Sweden

Cancer and dementia: Two sides of the same coin?

A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease

Contact Info

Product

Resources

About