Journal
HUMAN MOLECULAR GENETICS
Volume 28, Issue 16, Pages 2675-2685Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddz085
Keywords
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Funding
- Swedish Research Council
- Center for Innovative Medicine
- Swedish Alzheimer foundation
- Stockholm County Council
- Karolinska Institutet
- Strategic Research Program in Neuroscience at Karolinska Institutet
- Swedish Medical Research Council
- Swedish Brain Foundation
- Old Servants foundation
- Gun and Bertil Stohne's foundation
- Schorling Foundation - Swedish FTD Initiative
- StratNeuro at the Karolinska Institutet
- Swedish Brain Power and Stockholm County Council
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Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Familial cases suggest genetic components; however, monogenetic causes are few, and the vast majority of incidences have unknown cause. Sequencing efforts have focused on germline mutations, but improved technology has opened up for studies on somatic mutations in affected brain tissue samples. Here we use ultra-deep sequencing on brain and blood from early-onset AD (EOAD) and late-onset AD (LOAD) patients and non-AD individuals (n = 16). In total, 2.86 Mb of genomic regions, previously associated with AD, were targeted included 28 genes and upstream and downstream regulatory regions. Tailored downstream bioinformatics filtering identified 11 somatic single nucleotide variants in the temporal cortex in AD patients and none in the controls. One variant was validated to be present at 0.4% allele frequency in temporal cortex of a LOAD patient. This variant was predicted to affect transcription factor binding sites upstream of the CD55 gene, contributing to AD pathogenesis by affecting the complement system. Our results suggest that future studies targeting larger portions of the genome for somatic mutation analysis are important to obtain an increased understanding for the molecular basis of both EOAD and LOAD.
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