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Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort
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 cand...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616106/ https://www.ncbi.nlm.nih.gov/pubmed/23573206 http://dx.doi.org/10.1371/journal.pone.0059676 |
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author | Elias-Sonnenschein, Lyzel S. Helisalmi, Seppo Natunen, Teemu Hall, Anette Paajanen, Teemu Herukka, Sanna-Kaisa Laitinen, Marjo Remes, Anne M. Koivisto, Anne M. Mattila, Kari M. Lehtimäki, Terho Verhey, Frans R. J. Visser, Pieter Jelle Soininen, Hilkka Hiltunen, Mikko |
author_facet | Elias-Sonnenschein, Lyzel S. Helisalmi, Seppo Natunen, Teemu Hall, Anette Paajanen, Teemu Herukka, Sanna-Kaisa Laitinen, Marjo Remes, Anne M. Koivisto, Anne M. Mattila, Kari M. Lehtimäki, Terho Verhey, Frans R. J. Visser, Pieter Jelle Soininen, Hilkka Hiltunen, Mikko |
author_sort | Elias-Sonnenschein, Lyzel S. |
collection | PubMed |
description | 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 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 Aβ(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-ε4, CLU and MS4A4A influence both AD risk and CSF Aβ(1–42). |
format | Online Article Text |
id | pubmed-3616106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36161062013-04-09 Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort Elias-Sonnenschein, Lyzel S. Helisalmi, Seppo Natunen, Teemu Hall, Anette Paajanen, Teemu Herukka, Sanna-Kaisa Laitinen, Marjo Remes, Anne M. Koivisto, Anne M. Mattila, Kari M. Lehtimäki, Terho Verhey, Frans R. J. Visser, Pieter Jelle Soininen, Hilkka Hiltunen, Mikko PLoS One Research Article 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 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 Aβ(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-ε4, CLU and MS4A4A influence both AD risk and CSF Aβ(1–42). Public Library of Science 2013-04-03 /pmc/articles/PMC3616106/ /pubmed/23573206 http://dx.doi.org/10.1371/journal.pone.0059676 Text en © 2013 Elias-Sonnenschein et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Elias-Sonnenschein, Lyzel S. Helisalmi, Seppo Natunen, Teemu Hall, Anette Paajanen, Teemu Herukka, Sanna-Kaisa Laitinen, Marjo Remes, Anne M. Koivisto, Anne M. Mattila, Kari M. Lehtimäki, Terho Verhey, Frans R. J. Visser, Pieter Jelle Soininen, Hilkka Hiltunen, Mikko Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort |
title | Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort |
title_full | Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort |
title_fullStr | Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort |
title_full_unstemmed | Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort |
title_short | Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort |
title_sort | genetic loci associated with alzheimer’s disease and cerebrospinal fluid biomarkers in a finnish case-control cohort |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616106/ https://www.ncbi.nlm.nih.gov/pubmed/23573206 http://dx.doi.org/10.1371/journal.pone.0059676 |
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