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Benefits and challenges of rare genetic variation in Alzheimer's disease

Grozeva, Detelina ORCID:, Saad, Salha, Menzies, Georgina E. ORCID: and Sims, Rebecca ORCID: 2019. Benefits and challenges of rare genetic variation in Alzheimer's disease. Current Genetic Medicine Reports 7 (1) , pp. 53-62. 10.1007/s40142-019-0161-5

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Purpose of Review It is well established that sporadic Alzheimer’s disease (AD) is polygenic with common and rare genetic variation alongside environmental factors contributing to disease. Here, we review our current understanding of the genetic architecture of disease, paying specific attention to rare susceptibility variants, and explore some of the limitations in rare variant detection and analysis. Recent Findings Rare variation has been shown to robustly associate with disease. These include potentially damaging and loss of function mutations that are easily modelled in silico, in vitro and in vivo, and represent potentially druggable targets. A number of risk genes, including TREM2, SORL1 and ABCA7 show multiple independent associations suggesting that they may influence disease via multiple mechanisms. With transcriptional regulation, inflammatory response and modification of protein production suggested to be of primary importance. Summary We are at the beginning of our journey of rare variant detection in AD. Whole exome sequencing has been the predominant technology of choice. While fruitful, this has introduced a number of challenges with regard to data integration. Ultimately the future of disease-associated rare variant identification lies in whole genome sequencing projects that will allow the testing of the full range of genomic variation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Springer
ISSN: 2167-4876
Funders: UK DRI, MRC, ABBUK, ARUK, Welsh Government, Dementia Platform UK, Innovate UK and Moondance Foundation
Date of First Compliant Deposit: 4 February 2019
Date of Acceptance: 9 January 2019
Last Modified: 09 May 2023 02:57

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