Genetic Loci Associated with Alzheimer's Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort

Lyzel S. Elias-Sonnenschein, Seppo Helisalmi*, Teemu Natunen, Anette Hall, Teemu Paajanen, Sanna-Kaisa Herukka, Marjo Laitinen, Anne M. Remes, Anne M. Koivisto, Kari M. Mattila, Terho Lehtimaki, Frans R. J. Verhey, Pieter Jelle Visser, Hilkka Soininen, Mikko Hiltunen

*Corresponding author for this work

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Abstract

Objectives: 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 A beta(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-epsilon 4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased A beta(1-42) (corrected p0.05). Conclusions: We provide evidence that APOE-epsilon 4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF A beta(1-42) 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-epsilon 4, CLU and MS4A4A influence both AD risk and CSF A beta(1-42).
Original languageEnglish
Article numbere59676
JournalPLOS ONE
Volume8
Issue number4
DOIs
Publication statusPublished - 3 Apr 2013

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