JPND:A European DNA bank for deciphering the missing heritability of Alzheimer's disease
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Medicine
Abstract
Understanding the genetics of Alzheimer's disease is one of the best ways of improving our knowledge of the biology underpinning the disease. Genes are thought to account for around 80% of disease risk. Advances in the field of biomedical genetics have allowed the identification of 26 genes that act to increase a person's risk of developing disease. However, it is believed that there are at least the same number of genes that also contribute to disease risk are yet to be discovered.
To identify new disease related genes substantial additional efforts are required. It is particularly important to maximise sample numbers; studies of other complex genetic diseases have shown that the number of disease genes a study can identify increases with the sample size of the study.
Our primary objective is therefore to increase the number of Alzheimer's disease samples with genetic data to identify new risk genes for disease. We will achieve this via the creation of a European Alzheimer's Disease DNA BioBank (EADB). We have identified a European cohort of 31,911 AD cases (of which 24,049 have no genetic data) and 40,802 controls (of which 15,638 have no genetic data) from 11 countries. We will undertake genotyping of these 39,687 samples with no genetic data and analyse the new data along with existing genetic data via standard methods. This study plan will allow us to identify new Alzheimer's disease risk genes and the biological pathways in which these genes function. This initiative will increase the number of Alzheimer's disease samples available for genetic studies in Europe by more than 4-fold and worldwide by almost 2-fold.
In parallel, the EADB will collect samples from Europe's largest cohort of mild cognitive impairment cases, with a view to identifying genes that change the rate of disease progression and cognitive decline. We have available to us 9,109 mild cognitive impairment cases (of which 6,952 have no genetic data). The cohort includes data on conversion to Alzheimer's disease, cognitive and non-cognitive parameters, cerebrospinal fluid proteins and brain imaging.
The identification of genes that are functional in pathways that act to modify Alzheimer's disease risk and increase the rate of disease progression, or increase cognitive decline in mild cognitive impairment, is essential to allow the development and testing of novel treatments.
To identify new disease related genes substantial additional efforts are required. It is particularly important to maximise sample numbers; studies of other complex genetic diseases have shown that the number of disease genes a study can identify increases with the sample size of the study.
Our primary objective is therefore to increase the number of Alzheimer's disease samples with genetic data to identify new risk genes for disease. We will achieve this via the creation of a European Alzheimer's Disease DNA BioBank (EADB). We have identified a European cohort of 31,911 AD cases (of which 24,049 have no genetic data) and 40,802 controls (of which 15,638 have no genetic data) from 11 countries. We will undertake genotyping of these 39,687 samples with no genetic data and analyse the new data along with existing genetic data via standard methods. This study plan will allow us to identify new Alzheimer's disease risk genes and the biological pathways in which these genes function. This initiative will increase the number of Alzheimer's disease samples available for genetic studies in Europe by more than 4-fold and worldwide by almost 2-fold.
In parallel, the EADB will collect samples from Europe's largest cohort of mild cognitive impairment cases, with a view to identifying genes that change the rate of disease progression and cognitive decline. We have available to us 9,109 mild cognitive impairment cases (of which 6,952 have no genetic data). The cohort includes data on conversion to Alzheimer's disease, cognitive and non-cognitive parameters, cerebrospinal fluid proteins and brain imaging.
The identification of genes that are functional in pathways that act to modify Alzheimer's disease risk and increase the rate of disease progression, or increase cognitive decline in mild cognitive impairment, is essential to allow the development and testing of novel treatments.
Technical Summary
Our objective is to significantly increase the generation of Genome Wide Association Study-based population data via the creation of a European Alzheimer's Disease DNA BioBank (EADB). We shall be able to collate 31,911 AD cases (of which 24,049 have yet to be genotyped) and 40,802 controls (of which 15,638 have yet to be genotyped) from 11 countries. GWASs and complementary statistical studies (based on genotype and imputation data) will be performed, in order to capture the missing heritability and identify potential disease pathways. This initiative will increase the number of AD samples available for genetic studies in Europe by more than 4-fold and worldwide by almost 2-fold.
In parallel, the EADB will collect DNA samples from Europe's largest longitudinal cohort of MCI cases, with a view to identifying genetic markers that modulate the rate of disease progression and cognitive decline. At present, we have compiled approximately 9,109 MCI cases (of which 6,952 have yet to be genotyped) and have data on AD conversion, neuropsychological parameters, cerebrospinal fluid biomarkers and neuroimaging for most of these samples. We shall investigate the influence of genetic risk factors for AD in a genome-wide- or hypothesis-based manner.
From a translational perspective, the identification of genetic factors in pathways that modulate the AD risk and increase the rate of disease progression/cognitive decline in MCI will be pivotal for the development and testing of therapeutic approaches.
In parallel, the EADB will collect DNA samples from Europe's largest longitudinal cohort of MCI cases, with a view to identifying genetic markers that modulate the rate of disease progression and cognitive decline. At present, we have compiled approximately 9,109 MCI cases (of which 6,952 have yet to be genotyped) and have data on AD conversion, neuropsychological parameters, cerebrospinal fluid biomarkers and neuroimaging for most of these samples. We shall investigate the influence of genetic risk factors for AD in a genome-wide- or hypothesis-based manner.
From a translational perspective, the identification of genetic factors in pathways that modulate the AD risk and increase the rate of disease progression/cognitive decline in MCI will be pivotal for the development and testing of therapeutic approaches.
Planned Impact
As a global and growing problem associated with an increasing aged population, studies to improve, focus and streamline research on Alzheimer's disease will have a universal impact.
In addition to the vast academic impact of this study, we anticipate a significant impact on the delivery of clinical trials for AD therapies, and any commercial private sector companies involved in these trials will benefit. Participants can be selected for trials based on their genetic profile, increasing the likelihood of success using a smaller study cohort. In addition, the biomarkers used to measure trial outcome will be more accurately defined leading to clearer interpretation of results. This will impact on study design and the financial investment required finding drugs effective in targeting AD.
The identification of as yet unaccounted for AD genetic risk factors will help guide the research undertaken by, or funded by, commercial companies, government agencies and charities. A better, more comprehensive, genetic profile of AD will improve research focus and deliver better value for money from AD research. This should lead to more impactful research studies for minimal investment.
In the long term, the accurate and early prediction of AD risk has impact for the entire general public through the implementation of early detection and development of personalised medicine. Those at high risk of AD can be identified, together with the specific pathophysiological pathways involved, before providing a personalised medicine to specifically target the manifestation of disease in the individual.
In addition to the vast academic impact of this study, we anticipate a significant impact on the delivery of clinical trials for AD therapies, and any commercial private sector companies involved in these trials will benefit. Participants can be selected for trials based on their genetic profile, increasing the likelihood of success using a smaller study cohort. In addition, the biomarkers used to measure trial outcome will be more accurately defined leading to clearer interpretation of results. This will impact on study design and the financial investment required finding drugs effective in targeting AD.
The identification of as yet unaccounted for AD genetic risk factors will help guide the research undertaken by, or funded by, commercial companies, government agencies and charities. A better, more comprehensive, genetic profile of AD will improve research focus and deliver better value for money from AD research. This should lead to more impactful research studies for minimal investment.
In the long term, the accurate and early prediction of AD risk has impact for the entire general public through the implementation of early detection and development of personalised medicine. Those at high risk of AD can be identified, together with the specific pathophysiological pathways involved, before providing a personalised medicine to specifically target the manifestation of disease in the individual.
People |
ORCID iD |
Rebecca Sims (Principal Investigator) |
Publications
Bellenguez C
(2020)
New insights on the genetic etiology of Alzheimer's and related dementia
Bellenguez C
(2022)
New insights into the genetic etiology of Alzheimer's disease and related dementias.
in Nature genetics
Carpanini SM
(2021)
The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's Disease.
in Genes
De Rojas I
(2023)
Author Correction: Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
in Nature communications
Sims R
(2016)
Defining the Genetic Architecture of Alzheimer's Disease: Where Next.
in Neuro-degenerative diseases
Sims R
(2020)
The multiplex model of the genetics of Alzheimer's disease.
in Nature neuroscience
Sims R
(2017)
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
in Nature genetics
Torvell M
(2021)
Genetic Insights into the Impact of Complement in Alzheimer's Disease.
in Genes
Description | Detecting simple repeat sequences in the genome and their effects in dementias |
Amount | £48,507 (GBP) |
Funding ID | ARUK-PPG2018A-015 |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2018 |
End | 04/2019 |
Description | Expanding the DPUK resource via genotyping |
Amount | £100,000 (GBP) |
Funding ID | EM9 |
Organisation | MRC Dementias Platform UK |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2018 |
End | 12/2019 |
Description | Leveraging human genetics to identify target populations for dementia therapeutics |
Amount | £200,134 (GBP) |
Organisation | UK Dementia Research Institute |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2019 |
End | 09/2022 |
Description | The development and implementation of polygenic risk scoring algorithms for stratifying individuals for future cognitive decline due to Alzheimer's Disease in non-symptomatic and early cognitive impaired subjects. |
Amount | £386,341 (GBP) |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 02/2020 |
Title | New insights into the genetic etiology of Alzheimer's disease and related dementias |
Description | Abstract: Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE e4 allele. |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | Latest GWAS dataset for AD |
URL | https://www.repository.cam.ac.uk/handle/1810/336882 |
Description | Illumina Chip Development |
Organisation | Illumina Inc. |
Country | United States |
Sector | Private |
PI Contribution | We are working with a Illumina to get chips for SNP detection into production. These chips will be the best and most up to date methods for detection of AD, and will be future-proofed for tailored experiments into pathways of disease and personalised medicines. |
Collaborator Contribution | Confidential |
Impact | Illumina Neurochip |
Start Year | 2016 |
Description | International Genomics of Alzheimer's Project |
Organisation | Boston University |
Country | United States |
Sector | Academic/University |
PI Contribution | Multiway access to data and knowledge, analytical expertise, funding collaborative meetings. |
Collaborator Contribution | Multiway access to data and knowledge, analytical expertise, funding collaborative meetings. |
Impact | Multiple publications Lambert et al 2013 Sims et al 2017 Kunkle et al 2019 Basis for EADB consortium |
Start Year | 2014 |
Description | International Genomics of Alzheimer's Project |
Organisation | Pasteur Institute, Lille |
Country | France |
Sector | Charity/Non Profit |
PI Contribution | Multiway access to data and knowledge, analytical expertise, funding collaborative meetings. |
Collaborator Contribution | Multiway access to data and knowledge, analytical expertise, funding collaborative meetings. |
Impact | Multiple publications Lambert et al 2013 Sims et al 2017 Kunkle et al 2019 Basis for EADB consortium |
Start Year | 2014 |
Description | International Genomics of Alzheimer's Project |
Organisation | University of Pittsburgh |
Country | United States |
Sector | Academic/University |
PI Contribution | Multiway access to data and knowledge, analytical expertise, funding collaborative meetings. |
Collaborator Contribution | Multiway access to data and knowledge, analytical expertise, funding collaborative meetings. |
Impact | Multiple publications Lambert et al 2013 Sims et al 2017 Kunkle et al 2019 Basis for EADB consortium |
Start Year | 2014 |
Description | Interview for National News |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Broadcast for BBC Wales on the research undertake |
Year(s) Of Engagement Activity | 2018 |
Description | Piece for 'The Conversation' |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Lay person piece on the genetics of Alzheimer's disease |
Year(s) Of Engagement Activity | 2016 |
URL | https://theconversation.com/if-you-develop-alzheimers-will-your-children-get-it-too-62986 |
Description | Press release for new manuscript |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Press release for the Nature Genetics publication (2017) |
Year(s) Of Engagement Activity | 2017 |