Whole genome sequencing of late-onset Alzheimer's disease patients from genetic isolate

Abstract

Alzheimer's disease (AD) is a common heritable neurodegenerative disorder. However, aside from ApoEe4, the genetic factors contributing to common late-onset AD remain to be elucidated. In addition to known single genetic risk factor (ApoEe4 allele) and highly penetrant missense-mutations in APP and PSEN1/PSEN2 genes, many other genetic variations with incomplete penetrance may potentially be risk factors for AD. The role of such rare variations in AD would be difficult or impossible to identify by GWAS using a standard population case-control design. Thus, we employed the direct whole-genome sequencing of AD patients from a genetically isolated population from the southwestern area of The Netherlands. We have performed a whole-genome sequencing of pairs of distantly-related late-onset AD patients from extra-large pedigree branches from genetically isolated Dutch population, described previously (Liu et al, Am J Hum Genet,2007). The genome sequencing data were combined with the previously reported data of genetic linkage analysis in these pedigrees, which identified a set of AD susceptibility chromosomal loci, including 1q25, 1q21, 11q24 and 3q23 loci. We selected rare single nucleotide variations (SNV) and insertion deletion (indel) mutations shared between at least two AD patients in each pedigree branch. We searched only for the rare variations with MAF<0.05 that potentially affect protein structure. We filtered out potential sequencing errors and also removed the SNV/indels found in “controls,” including genomes of centenarians with no AD symptoms (Illumina sequencing data). The deleterious effects were verified by computational programs. In the primary analysis, we selected the genes with SNVs/indels located on 1q25, 1q21, 11q24 and 3q23 loci. In a broader whole-genome scanning, we listed all the rare variations that had an effect on protein structure and which are shared between at least two affected, distantly-related individuals. The data suggested that not a single, but many genetic variations may be involved in risk and modulation of AD pathway, even in a genetic isolate with common genetic founders. A set of candidate genes bearing rare variations in AD patients which are involved in Abeta/tau–metabolism and regulation and in neurodegeneration-related biological processes were revealed and their role will be discussed.