Benefits and Challenges of Rare Genetic Variation in Alzheimer ’s Disease

AbstractPurpose of ReviewIt 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 limitati ons in rare variant detection and analysis.Recent FindingsRare 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, includingTREM2,SORL1 andABCA7 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.SummaryWe 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.

Source: Current Genetic Medicine Reports - February 1, 2019 Category: Genetics & Stem Cells Source Type: research