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

作者：Lutz MichaelW; Saul Robert; Linnertz Colton; Glenn Omolara Chinue; Roses Allen D; Chiba Falek Ornit^*

来源：Alzheimer's and Dementia, 2015, 11(10): 1133-1143.

DOI：10.1016/j.jalz.2015.05.011

• LBV/AD
• Structural variants
• Phased sequencing
• SNCA
• Lewy body
• Gene expression

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.

• 出版日期2015-10