title: 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.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC, USA; Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Department of Neurology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lutz
authors.affiliation: Polymorphic DNA Technologies, Alameda, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Saul
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Colton
authors.initials: C
authors.lastname: Linnertz
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Omolara-Chinue
authors.initials: OC
authors.lastname: Glenn
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC, USA; Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Department of Neurology, Duke University Medical Center, Durham, NC, USA; Zinfandel Pharmaceuticals, Chapel Hill, NC, USA.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Roses
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC, USA; Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Department of Neurology, Duke University Medical Center, Durham, NC, USA. Electronic address: o.chibafalek@duke.edu.
authors.forename: Ornit
authors.initials: O
authors.lastname: Chiba-Falek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D003596:Cytosine; D005260:Female; D005786:Gene Expression Regulation; D006239:Haplotypes; D006801:Humans; D007438:Introns; D020961:Lewy Body Disease / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger; D012306:Risk; D013941:Thymine; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C497604:SNCA protein, human; D051844:alpha-Synuclein; D003596:Cytosine; D013941:Thymine
keywords: Gene expression; LBV/AD; Lewy body; Phased sequencing; SNCA; Structural variants