A cytosine‐thymine (CT)‐rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression. Issue 10 (13th June 2015)

• Record Type: Journal Article
• Authors: Lutz, Michael W.; Saul, Robert; Linnertz, Colton; Glenn, Omolara‐Chinue; Roses, Allen D.; Chiba‐Falek, Ornit
• Is Part Of: Alzheimer's & dementia. Volume 11:Issue 10(2015)
• Page Start: 1133
• Page End: 1143
• Publication Date: 2015-06-13
• Subjects: LBV/AD -- Structural variants -- Phased sequencing -- SNCA -- Lewy body -- Gene expression; Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1016/j.jalz.2015.05.011
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Introduction: We recently showed that tagging single‐nucleotide polymorphisms across the SNCA locus were significantly associated with increased risk for Lewy body (LB) pathology in Alzheimer's disease (AD) cases. However, the actual genetic variant(s) that underlie the observed associations remain elusive. Methods: We used a bioinformatics algorithm to catalog structural variants in a region of SNCA intron 4, followed by phased sequencing. We performed a genetic association analysis in autopsy series of LB variant of Alzheimer's disease (LBV/AD) cases compared with AD‐only controls. We investigated the biological functions by expression analysis using temporal‐cortex samples. Results: We identified four distinct haplotypes within a highly polymorphic low‐complexity cytosine‐thymine (CT)‐rich region. We showed that a specific haplotype conferred risk to develop LBV/AD. We demonstrated that the CT‐rich site acts as an enhancer element, where the risk haplotype was significantly associated with elevated levels of SNCA messenger RNA. Discussion: We have discovered a novel haplotype in a CT‐rich region in SNCA that contributes to LB pathology in AD patients, possibly via cis ‐regulation of the gene expression.