A European DNA bank for deciphering the missing heritability of Alzheimer’s disease (EADB)
Projectomschrijving
Het EADB consortium staat voor ‘European Alzheimer’s disease DNA biobank’, bestaande uit onderzoeksinstituten uit 10 Europese landen.
Doel
Sinds februari 2016 heeft dit samenwerkingsverband het doel meer inzicht te krijgen in genetische risicofactoren belangrijk voor de ziekte van Alzheimer (ZvA).
Aanpak
EADB heeft ervoor gezorgd dat er nieuwe genetische data is gegenereerd voor 40,000 DNA samples, waardoor genetisch onderzoek verricht kan worden op 35,000 Alzheimer patiënten, 8,000 individuen met mild cognitieve klachten en 65,000 cognitief gezonde personen.
Resultaten
De voorlopige eerste resultaten laten mooie nieuwe bevindingen zien. Zo zijn er 10 nieuwe genetische risicofactoren gedetecteerd die risico voorspellingen voor het krijgen van de ZvA zullen verbeteren. Ook heeft EADB geholpen om aan te tonen dat het PLCG2 gen ertoe bijdraagt om cognitief gezond te blijven tot op zeer hoge leeftijd. De nieuw gevonden genen dragen tevens bij aan beter begrip van onderliggende biologische mechanismen die betrokken zijn bij de ontwikkeling van de ZvA. De nieuwe bevindingen wijzen bijvoorbeeld naar een belangrijke rol voor metabolisme van APP, een bekend gen betrokken bij familiaire Alzheimer.
Producten
Auteur: Itziar de Rojas, Sonia Moreno-Grau, Niccolo Tesi, Benjamin Grenier-Boley, Victor Andrade, Iris E. Jansen, Nancy L. Pedersen, Najada Stringa, Anna Zettergren, Isabel Hernández, Laura Montrreal, Carmen Antúnez, Anna Antonell, Rick M. Tankard, Joshua C. Bis, Rebecca Sims, Céline Bellenguez, Inés Quintela, Antonio González-Perez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Rafael Blesa, Laura Cervera-Carles, Manuel Menéndez-González, Ana Frank-García, Jose Luís Royo,
Magazine: Nature Communications
Link: https://www.nature.com/articles/s41467-021-22491-8
Auteur: European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration
Magazine: JAMA Network Open
Link: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805006
Verslagen
Samenvatting van de aanvraag
Understanding the genetics of Alzheimer’s disease (AD) is one of the best ways of improving our knowledge of the underlying pathophysiological processes. Indeed, genetic factors account for up to 80% of the attributable risk in common AD forms. It is likely that most of the pathophysiological pathways in AD are driven by or include genetic determinants. The advent of genomic approaches (such as genome-wide association studies, GWASs) has led to the characterization of 26 genetic determinants. However, less than 50% of the AD genetic attributable risk has been characterised; substantial additional efforts are thus still required to define the genetic landscape in AD. It will be particularly important to maximize study population sizes; studies of other multifactorial diseases have shown that the number of identified variants increases with the sample size. Our objective is thus to significantly increase the generation of GWAS-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.