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Article: Are Alzheimer's and coronary artery diseases genetically related to longevity?

Bellou, Eftychia / Escott-Price, Valentina

2023 Volume 13, Page(s) 1102347

Abstract: Introduction: In the last decade researchers have attempted to investigate the shared genetic architecture of longevity and age-related diseases and assess whether the increased longevity in certain people is due to protective alleles in the risk genes ... ...

Abstract	Introduction: In the last decade researchers have attempted to investigate the shared genetic architecture of longevity and age-related diseases and assess whether the increased longevity in certain people is due to protective alleles in the risk genes for a particular condition or whether there are specific "longevity" genes increasing the lifespan independently of age-related conditions' risk genes. The aim of this study was to investigate the shared genetic component between longevity and two age-related conditions. Methods: We performed a cross-trait meta-analysis of publicly available genome-wide data for Alzheimer's disease, coronary artery disease and longevity using a subset-based approach provided by the R package ASSET. Results: Despite the lack of strong genetic correlation between longevity and the two diseases, we identified 38 genome-wide significant lead SNPs across 22 independent genomic loci. Of them 6 were found to be potentially shared among the three traits mapping to genes including Discussion: In summary, we have been able to advance in the knowledge of the genetic overlap existing among longevity and the two most common age-related disorders.
Language	English
Publishing date	2023-01-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2022.1102347
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Article ; Online: Genome-wide association studies for Alzheimer's disease: bigger is not always better.

Escott-Price, Valentina / Hardy, John

Brain communications

2022 Volume 4, Issue 3, Page(s) fcac125

Abstract: As the size of genome-wide association studies increase, the number of associated trait loci identified inevitably increase. One welcomes this if it allows the better delineation of the pathways to disease and increases the accuracy of genetic prediction ...

Abstract	As the size of genome-wide association studies increase, the number of associated trait loci identified inevitably increase. One welcomes this if it allows the better delineation of the pathways to disease and increases the accuracy of genetic prediction of disease risk through polygenic risk score analysis. However, there are several problems in the continuing increase in the genome-wide analysis of 'Alzheimer's disease'. In this review, we have systematically assessed the history of Alzheimer's disease genome-wide association studies, including their sample sizes, age and selection/assessment criteria of cases and controls and heritability explained by these disease genome-wide association studies. We observe that nearly all earlier disease genome-wide association studies are now part of all current disease genome-wide association studies. In addition, the latest disease genome-wide association studies include (i) only a small fraction (∼10%) of clinically screened controls, substituting for them population-based samples which are systematically younger than cases, and (ii) around 50% of Alzheimer's disease cases are in fact 'proxy dementia cases'. As a consequence, the more genes the field finds, the less the heritability they explain. We highlight potential caveats this situation creates and discuss some of the consequences occurring when translating the newest Alzheimer's disease genome-wide association study results into basic research and/or clinical practice.
Language	English
Publishing date	2022-05-17
Publishing country	England
Document type	Journal Article ; Review
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcac125
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Article ; Online: Comparison of long-term effects of metformin on longevity between people with type 2 diabetes and matched non-diabetic controls.

Stevenson-Hoare, Joshua / Leonenko, Ganna / Escott-Price, Valentina

BMC public health

2023 Volume 23, Issue 1, Page(s) 804

Abstract: Background: Metformin, a medication for type 2 diabetes, has been linked to many non-diabetes health benefits including increasing healthy lifespan. Previous work has only examined the benefits of metformin over periods of less than ten years, which may ...

Abstract	Background: Metformin, a medication for type 2 diabetes, has been linked to many non-diabetes health benefits including increasing healthy lifespan. Previous work has only examined the benefits of metformin over periods of less than ten years, which may not be long enough to capture the true effect of this medication on longevity. Methods: We searched medical records for Wales, UK, using the Secure Anonymised Information Linkage dataset for type 2 diabetes patients treated with metformin (N = 129,140) and sulphonylurea (N = 68,563). Non-diabetic controls were matched on sex, age, smoking, and history of cancer and cardiovascular disease. Survival analysis was performed to examine survival time after first treatment, using a range of simulated study periods. Findings: Using the full twenty-year period, we found that type 2 diabetes patients treated with metformin had shorter survival time than matched controls, as did sulphonylurea patients. Metformin patients had better survival than sulphonylurea patients, controlling for age. Within the first three years, metformin therapy showed a benefit over matched controls, but this reversed after five years of treatment. Interpretation: While metformin does appear to confer benefits to longevity in the short term, these initial benefits are outweighed by the effects of type 2 diabetes when patients are observed over a period of up to twenty years. Longer study periods are therefore recommended for studying longevity and healthy lifespan. Evidence before this study: Work examining the non-diabetes outcomes of metformin therapy has suggested that there metformin has a beneficial effect on longevity and healthy lifespan. Both clinical trials and observational studies broadly support this hypothesis, but tend to be limited in the length of time over which they can study patients or participants. Added value of this study: By using medical records we are able to study individuals with Type 2 diabetes over a period of two decades. We are also able to account for the effects of cancer, cardiovascular disease, hypertension, deprivation, and smoking on longevity and survival time following treatment. Implications of all the available evidence: We confirm that there is an initial benefit to longevity of metformin therapy, but this benefit does not outweigh the negative effect on longevity of diabetes. Therefore, we suggest that longer study periods are required for inference to be made about longevity in future research.
MeSH term(s)	Humans ; Metformin/therapeutic use ; Diabetes Mellitus, Type 2/drug therapy ; Hypoglycemic Agents/therapeutic use ; Cardiovascular Diseases/chemically induced ; Longevity ; Sulfonylurea Compounds/adverse effects
Chemical Substances	Metformin (9100L32L2N) ; Hypoglycemic Agents ; Sulfonylurea Compounds
Language	English
Publishing date	2023-05-02
Publishing country	England
Document type	Observational Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041338-5
ISSN	1471-2458 ; 1471-2458
ISSN (online)	1471-2458
ISSN	1471-2458
DOI	10.1186/s12889-023-15764-y
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Article ; Online: Pitfalls of predicting age-related traits by polygenic risk scores.

Escott-Price, Valentina / Schmidt, Karl Michael

Annals of human genetics

2023 Volume 87, Issue 5, Page(s) 203–209

Abstract: Polygenic risk scores (PRS) are a method increasingly used to capture the combined effect of genome-wide significant variants and those which individually do not show genome-wide significant association but are likely to contribute to the risk of ... ...

Abstract	Polygenic risk scores (PRS) are a method increasingly used to capture the combined effect of genome-wide significant variants and those which individually do not show genome-wide significant association but are likely to contribute to the risk of developing diseases. However, their practical use incurs complications and inconsistencies that so far limit their clinical applicability. The aims of the present review are to discuss the PRS for age-related diseases and to highlight pitfalls and limitations of PRS prediction accuracy due to ageing and mortality effects. We argue that the PRS is widely used but the individual's PRS values differ substantially depending on the number of genetic variants included, the discovery GWAS and the method employed to generate them. Moreover, for neurodegenerative disorders, although an individual's genetics do not change with age, the actual score depends on the age of the sample used in the discovery GWAS and is likely to reflect the individual's disease risk at this particular age. Improvement of PRS prediction accuracy for neurodegenerative disorders will come from two sides, both the precision of clinical diagnoses, and a careful attention to the age distribution in the underlying samples and validation of the prediction in longitudinal studies.
MeSH term(s)	Risk Factors ; Phenotype ; Multifactorial Inheritance ; Aging ; Humans ; Genome-Wide Association Study ; Allergens
Chemical Substances	Allergens
Language	English
Publishing date	2023-07-07
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	333-5
ISSN	1469-1809 ; 0003-4800
ISSN (online)	1469-1809
ISSN	0003-4800
DOI	10.1111/ahg.12520
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Article ; Online: Overlapping brain correlates of superior cognition among children at genetic risk for Alzheimer's disease and/or major depressive disorder.

Petrican, Raluca / Paine, Amy L / Escott-Price, Valentina / Shelton, Katherine H

Scientific reports

2023 Volume 13, Issue 1, Page(s) 984

Abstract: Early life adversity (ELA) tends to accelerate neurobiological ageing, which, in turn, is thought to heighten vulnerability to both major depressive disorder (MDD) and Alzheimer's disease (AD). The two conditions are putatively related, with MDD ... ...

Abstract	Early life adversity (ELA) tends to accelerate neurobiological ageing, which, in turn, is thought to heighten vulnerability to both major depressive disorder (MDD) and Alzheimer's disease (AD). The two conditions are putatively related, with MDD representing either a risk factor or early symptom of AD. Given the substantial environmental susceptibility of both disorders, timely identification of their neurocognitive markers could facilitate interventions to prevent clinical onset. To this end, we analysed multimodal data from the Adolescent Brain and Cognitive Development study (ages 9-10 years). To disentangle genetic from correlated genetic-environmental influences, while also probing gene-adversity interactions, we compared adoptees, a group generally exposed to substantial ELA, with children raised by their biological families via genetic risk scores (GRS) from genome-wide association studies. AD and MDD GRSs predicted overlapping and widespread neurodevelopmental alterations associated with superior fluid cognition. Specifically, among adoptees only, greater AD GRS were related to accelerated structural maturation (i.e., cortical thinning) and higher MDD GRS were linked to delayed functional neurodevelopment, as reflected in compensatory brain activation on an inhibitory control task. Our study identifies compensatory mechanisms linked to MDD risk and highlights the potential cognitive benefits of accelerated maturation linked to AD vulnerability in late childhood.
MeSH term(s)	Adolescent ; Humans ; Child ; Depressive Disorder, Major/diagnosis ; Genome-Wide Association Study ; Alzheimer Disease/genetics ; Alzheimer Disease/complications ; Brain ; Risk Factors ; Cognition
Language	English
Publishing date	2023-01-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-28057-6
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Article ; Online: Diabetes and Alzheimer's disease: shared genetic susceptibility?

Hardy, John / de Strooper, Bart / Escott-Price, Valentina

The Lancet. Neurology

2022 Volume 21, Issue 11, Page(s) 962–964

MeSH term(s)	Humans ; Genetic Predisposition to Disease/genetics ; Alzheimer Disease/genetics ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Diabetes Mellitus/epidemiology ; Diabetes Mellitus/genetics
Language	English
Publishing date	2022-10-04
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2081241-3
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(22)00395-7
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Article ; Online: Polygenic Risk Scores in Alzheimer's Disease: Current Applications and Future Directions.

Baker, Emily / Escott-Price, Valentina

Frontiers in digital health

2020 Volume 2, Page(s) 14

Abstract: Genome-wide association studies have identified nearly 40 genome-wide significant single nucleotide polymorphisms (SNPs) which are associated with Alzheimer's Disease (AD). Due to the polygenicity of AD, polygenic risk scores (PRS) have shown high ... ...

Abstract	Genome-wide association studies have identified nearly 40 genome-wide significant single nucleotide polymorphisms (SNPs) which are associated with Alzheimer's Disease (AD). Due to the polygenicity of AD, polygenic risk scores (PRS) have shown high potential for AD risk prediction. PRSs have been shown to successfully discriminate between AD cases and controls achieving a prediction accuracy of up to 84% based on area under the receiver operating curve. The prediction accuracy in AD is higher compared with other complex genetic disorders. PRS can be restricted to SNPs which reside in biologically relevant gene-sets; the predictive value of these gene-sets in the general population is not as high as genome-wide PRS, but they may play an important role to identify mechanisms of disease development and inform biological experiments. Multiple methods are available to derive PRSs, such as selecting SNPs based on statistical evidence of association with the disease or using prior evidence for SNP selection. All methods have advantages, but PRS produced using different methodologies are often not comparable, and results should be interpreted with care. Similarly, this is true when PRS is based on different background populations. With the exponential growth in development of digital electronic devices it is easy to calculate an individual's disease risk using public databases. A major limitation for the utility of PRSs is that the risk score is sample and method dependent. Therefore, replicability and interpretability of PRS is an important issue. PRS can be used to determine the probability of developing disease which incorporates information about disease risk in the general population or in a specific AD risk group. It is essential to consult with genetic counselors to ensure genetic risk is communicated appropriately.
Language	English
Publishing date	2020-08-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ISSN	2673-253X
ISSN (online)	2673-253X
DOI	10.3389/fdgth.2020.00014
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Article ; Online: Probability of Alzheimer's disease based on common and rare genetic variants.

Escott-Price, Valentina / Schmidt, Karl Michael

Alzheimer's research & therapy

2021 Volume 13, Issue 1, Page(s) 140

Abstract: Background: Alzheimer's disease, among other neurodegenerative disorders, spans decades in individuals' life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. ...

Abstract	Background: Alzheimer's disease, among other neurodegenerative disorders, spans decades in individuals' life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer's disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE-ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals. Methods: We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups. Results: The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+, the probability of AD grows from 0.03 to 0.18 (without APOE) and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08-0.6 and 0.3-0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3. Conclusions: Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach has potential for use in a clinical setting and can easily be updated for novel rare variants and for other populations or confounding factors when appropriate genome-wide association data become available.
MeSH term(s)	Alzheimer Disease/epidemiology ; Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Membrane Glycoproteins ; Receptors, Immunologic ; Risk Factors
Chemical Substances	Apolipoproteins E ; Membrane Glycoproteins ; Receptors, Immunologic ; TREM2 protein, human
Language	English
Publishing date	2021-08-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-021-00884-7
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Article ; Online: Challenges of Adjusting Single-Nucleotide Polymorphism Effect Sizes for Linkage Disequilibrium.

Escott-Price, Valentina / Schmidt, Karl Michael

Human heredity

2021 , Page(s) 1–11

Abstract: Background: Genome-wide association studies (GWAS) were successful in identifying SNPs showing association with disease, but their individual effect sizes are small and require large sample sizes to achieve statistical significance. Methods of post-GWAS ...

Abstract	Background: Genome-wide association studies (GWAS) were successful in identifying SNPs showing association with disease, but their individual effect sizes are small and require large sample sizes to achieve statistical significance. Methods of post-GWAS analysis, including gene-based, gene-set and polygenic risk scores, combine the SNP effect sizes in an attempt to boost the power of the analyses. To avoid giving undue weight to SNPs in linkage disequilibrium (LD), the LD needs to be taken into account in these analyses. Objectives: We review methods that attempt to adjust the effect sizes (β-coefficients) of summary statistics, instead of simple LD pruning. Methods: We subject LD adjustment approaches to a mathematical analysis, recognising Tikhonov regularisation as a framework for comparison. Results: Observing the similarity of the processes involved with the more straightforward Tikhonov-regularised ordinary least squares estimate for multivariate regression coefficients, we note that current methods based on a Bayesian model for the effect sizes effectively provide an implicit choice of the regularisation parameter, which is convenient, but at the price of reduced transparency and, especially in smaller LD blocks, a risk of incomplete LD correction. Conclusions: There is no simple answer to the question which method is best, but where interpretability of the LD adjustment is essential, as in research aiming at identifying the genomic aetiology of disorders, our study suggests that a more direct choice of mild regularisation in the correction of effect sizes may be preferable.
Language	English
Publishing date	2021-02-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2424-7
ISSN	1423-0062 ; 0001-5652
ISSN (online)	1423-0062
ISSN	0001-5652
DOI	10.1159/000513303
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Article ; Online: Genes, pathways and risk prediction in Alzheimer's disease.

Hardy, John / Escott-Price, Valentina

Human molecular genetics

2019 Volume 28, Issue R2, Page(s) R235–R240

Abstract: The failure of recent clinical trials in Alzheimer's disease has highlighted the need for the development of a more complete understanding of the pathogenesis of the disorder and also a belief that therapies may only work if given very early in the ... ...

Abstract	The failure of recent clinical trials in Alzheimer's disease has highlighted the need for the development of a more complete understanding of the pathogenesis of the disorder and also a belief that therapies may only work if given very early in the disease process before overt symptoms occur. The rare, early onset forms of the disease are all caused by mutations which make amyloid deposition a more likely event. Here we discuss the recent data showing that, in contrast, much of the risk of late onset disease is encoded by loci involved in lipid metabolism and/or encoded by microglia. We discuss these finding and suggest that amyloid induced membrane damage may be a key factor in disease and also review the evidence that genome wide genetic analysis can substantially help in the prediction of those individuals at high risk of disease in the general population.
MeSH term(s)	Alzheimer Disease/genetics ; Amyloid beta-Peptides/metabolism ; Apolipoproteins E/genetics ; Brain/metabolism ; Epistasis, Genetic ; European Continental Ancestry Group/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lipid Metabolism/genetics ; Presenilin-1/genetics ; Presenilin-2/genetics ; Risk Factors
Chemical Substances	Amyloid beta-Peptides ; Apolipoproteins E ; PSEN1 protein, human ; PSEN2 protein, human ; Presenilin-1 ; Presenilin-2
Language	English
Publishing date	2019-07-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddz163
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