title: Linkage disequilibrium and haplotype analysis of the ATP7B gene in Alzheimer's disease.
abstract: Copper dyshomeostasis leading to a labile Cu(2+) not bound to ceruloplasmin ("free" copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n=515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two "strong LD" blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR]=1.52, 95% confidence interval [CI]=1.10-2.09, p=0.010; rs2147363, OR=1.58, 95% CI=1.11-2.25, p=0.010; rs1061472, OR=1.73, 95% CI=1.23-2.43, p=0.002; rs732774, OR=2.31, 95% CI=1.41-3.77, p<0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.
authors.affiliation: Department of Neurology, Campus Bio-Medico University, Rome, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Squitti
authors.forename: Renato
authors.initials: R
authors.lastname: Polimanti
authors.forename: Serena
authors.initials: S
authors.lastname: Bucossi
authors.forename: Mariacarla
authors.initials: M
authors.lastname: Ventriglia
authors.forename: Stefania
authors.initials: S
authors.lastname: Mariani
authors.forename: Dario
authors.initials: D
authors.lastname: Manfellotto
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vernieri
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cassetta
authors.forename: Francesca
authors.initials: F
authors.lastname: Ursini
authors.forename: Paolo Maria
authors.initials: PM
authors.lastname: Rossini
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide
chemical_list: D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases