title: Genetic loci associated with Alzheimer's disease and cerebrospinal fluid biomarkers in a Finnish case-control cohort.
abstract: OBJECTIVE
  To understand the relation between risk genes for Alzheimer's disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers Aβ(1-42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF).
  
  
  METHODS
  We tested 25 SNPs for genetic association with clinical AD in our cohort comprised of 890 AD patients and 701-age matched healthy controls using logistic regression. For the correlational study with biomarkers, we tested 36 SNPs in a subset of 222 AD patients with available CSF using mixed models. Statistical analyses were adjusted for age, gender and APOE status. False discovery rate for multiple testing was applied. All participants were from academic hospital and research institutions in Finland.
  
  
  RESULTS
  APOE-ε4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased Aβ(1-42) (corrected p<0.05). At an uncorrected p<0.05, PPP3R1 rs1868402 and MAPT rs2435211 were related with increased t-tau; while SORL1 rs73595277 and MAPT rs16940758, with increased p-tau. Only TOMM40 rs2075650 showed association with clinical AD after adjusting for APOE-ε4 (p = 0.007), but not after multiple test correction (p>0.05).
  
  
  CONCLUSIONS
  We provide evidence that APOE-ε4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF Aβ1-42 in AD. None of the other AlzGene and GWAS loci showed significant effects on CSF tau. The effects of other SNPs on CSF biomarkers and clinical AD diagnosis did not reach statistical significance. Our findings suggest that APOE-ε4, CLU and MS4A4A influence both AD risk and CSF Aβ1-42.
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
authors.forename: Lyzel S
authors.initials: LS
authors.lastname: Elias-Sonnenschein
authors.forename: Seppo
authors.initials: S
authors.lastname: Helisalmi
authors.forename: Teemu
authors.initials: T
authors.lastname: Natunen
authors.forename: Anette
authors.initials: A
authors.lastname: Hall
authors.forename: Teemu
authors.initials: T
authors.lastname: Paajanen
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.forename: Marjo
authors.initials: M
authors.lastname: Laitinen
authors.forename: Anne M
authors.initials: AM
authors.lastname: Remes
authors.forename: Anne M
authors.initials: AM
authors.lastname: Koivisto
authors.forename: Kari M
authors.initials: KM
authors.lastname: Mattila
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Frans R J
authors.initials: FR
authors.lastname: Verhey
authors.forename: Pieter Jelle
authors.initials: PJ
authors.lastname: Visser
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000235:genetics*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D051152:Clusterin / Q000235:genetics*; D005260:Female; D005387:Finland; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D012307:Risk Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; C495242:CLU protein, human; D051152:Clusterin; C424714:MS4A4A protein, human; D008565:Membrane Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins