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Editorial |

Probing the Exome in Alzheimer Disease and Other Neurodegenerative Disorders

Lars Bertram, MD1,2 ,3; Christine Klein, MD1
[+] Author Affiliations
1Platform for Genome Analytics, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
2 Institute of Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
3School of Public Health, Faculty of Medicine, Imperial College, London, United Kingdom
JAMA Neurol. 2015;72(4):389-391. doi:10.1001/jamaneurol.2014.4495.
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Alzheimer disease (AD) is a heterogeneous disorder with a substantial genetic component. A small number of cases (ie, early-onset familial AD) are caused by exceedingly rare but pathogenic and highly penetrant mutations, while most cases (ie, late-onset AD) are caused by an intricate—and still only partially understood—interplay of genetic and nongenetic risk factors.1 The past decade has seen unprecedented progress in deciphering the genetic underpinnings of late-onset AD. This advancement was achieved mostly by the application of high-throughput microarray genotyping in the context of genome-wide association studies (GWASs) comparing the allele status at millions of different base pairs on increasingly large samples of affected and unaffected individuals.2 Most AD GWAS findings to date were made with common (ie, frequency of the minor allele typically >5%) single-nucleotide polymorphisms (SNPs) typically exerting small genetic effect sizes (ie, odds ratios <1.3). In most cases, the pathogenic mechanisms underlying these associations have been difficult to discern owing to the fact that most common SNPs are located in noncoding regions of the genome.

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