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

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• 作者：Michael W. Lutz^a ; ^b ; Robert Saul^c ; Colton Linnertz^a ; Omolara-Chinue Glenn^a ; Allen D. Roses^a ; ^b ; ^d ; Ornit Chiba-Falek^a ; ^b ; ^{o.chibafalek@duke.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：LBV/AD ; Structural variants ; Phased sequencing ; SNCA ; Lewy body ; Gene expression
• 刊名：Alzheimer's & Dementia
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：11
• 期：10
• 页码：1133-1143
• 全文大小：1500 K

文摘

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.