title: The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels.
abstract: BACKGROUND
  Two recent and simultaneously published genome-wide association studies independently implicated clusterin (CLU), complement receptor 1 (CR1), and phosphatidylinositol binding clathrin assembly protein (PICALM) as putative novel Alzheimer disease (AD) risk loci. Despite their strong statistical support, all 3 signals emerged from heterogeneous case-control populations and lack replication in different settings.
  
  
  OBJECTIVE
  To determine whether genetic variants in CLU, CR1, and PICALM confer risk for AD in independent data sets (n = 4254) and to test the impact of these markers on cerebrospinal fluid (CSF)-Aβ42 and total-tau protein levels (n = 425).
  
  
  METHODS
  Genetic association study using family-based and case-control designs.
  
  
  METHODS
  Ambulatory or hospitalized care.
  
  
  METHODS
  Family samples originate from mostly multiplex pedigrees recruited at different centers in the United States (1245 families, 2654 individuals with AD, and 1175 unaffected relatives). Unrelated case-control subjects originate from 1 clinical center in Germany (214 individuals with AD and 211 controls). All subjects were of European descent.
  
  
  METHODS
  The association between 5 genetic variants in CLU, CR1, and PICALM and risk for AD, and the correlation between these 5 genetic variants and CSF-Aβ42 and tau levels.
  
  
  RESULTS
  All 3 investigated loci showed significant associations between risk for AD (1-tailed P values ranging from <.001 to .02) and consistent effect sizes and direction. For each locus, the overall evidence of association was substantially strengthened on meta-analysis of all available data (2-tailed P values ranging from 1.1 × 10(-16) to 4.1 × 10⁻⁷). Of all markers tested, only rs541458 in PICALM was shown to have an effect on CSF protein levels, suggesting that the AD risk allele is associated with decreased CSF Aβ42 levels (2-tailed P = .002).
  
  
  CONCLUSIONS
  This study provides compelling independent evidence that genetic variants in CLU, CR1, and PICALM are genetically associated with risk for AD. Furthermore, the CSF biomarker analyses provide a first insight into the potentially predominant pathogenetic mechanism(s) underlying the association between AD risk and PICALM.
authors.affiliation: Department Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Brit-Maren M
authors.initials: BM
authors.lastname: Schjeide
authors.forename: Cathrin
authors.initials: C
authors.lastname: Schnack
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lill
authors.forename: Julia
authors.initials: J
authors.lastname: Kirchheiner
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Tumani
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016022:Case-Control Studies; D051152:Clusterin / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011951:Receptors, Complement / Q000235:genetics*; D012307:Risk Factors; D013223:Statistics as Topic; D014481:United States; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; C495242:CLU protein, human; D051152:Clusterin; C054369:MAPT protein, human; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D010446:Peptide Fragments; D011951:Receptors, Complement; C075222:amyloid beta-protein (1-42); D016875:tau Proteins