Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers

Mafalda Ramos de Matos; Catarina Ferreira; Sanna-Kaisa Herukka; Hilkka Soininen; André Janeiro; Isabel Santana; Inês Baldeiras; Maria Rosário Almeida; Alberto Lleó; Oriol Dols-Icardo; Daniel Alcolea; Luisa Benussi; Giuliano Binetti; Anna Paterlini; Roberta Ghidoni; Benedetta Nacmias; Olga Meulenbroek; Linda J C van Waalwijk van Doorn; H Bea J Kuiperi; Lucrezia Hausner; Gunhild Waldemar; Anja Hviid Simonsen; Magda Tsolaki; Olymbia Gkatzima; Catarina Resende de Oliveira; Marcel M Verbeek; Jordi Clarimon; Mikko Hiltunen; Alexandre de Mendonça; Madalena Martins

doi:10.3233/JAD-180512

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers

Mafalda Ramos de Matos, Catarina Ferreira, Sanna-Kaisa Herukka, Hilkka Soininen, André Janeiro, Isabel Santana, Inês Baldeiras, Maria Rosário Almeida, Alberto Lleó, Oriol Dols-Icardo, Daniel Alcolea, Luisa Benussi, Giuliano Binetti, Anna Paterlini, Roberta Ghidoni, Benedetta Nacmias, Olga Meulenbroek, Linda J C van Waalwijk van Doorn, H Bea J Kuiperi, Lucrezia HausnerGunhild Waldemar, Anja Hviid Simonsen, Magda Tsolaki, Olymbia Gkatzima, Catarina Resende de Oliveira, Marcel M Verbeek, Jordi Clarimon, Mikko Hiltunen, Alexandre de Mendonça, Madalena Martins

Department of Clinical Medicine

5 Citations (Scopus)

Abstract

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

Original language	English
Journal	Journal of Alzheimer's Disease
Volume	66
Issue number	2
Pages (from-to)	639-652
Number of pages	14
ISSN	1387-2877
DOIs	https://doi.org/10.3233/JAD-180512
Publication status	Published - 2018

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Ramos de Matos, M., Ferreira, C., Herukka, S.-K., Soininen, H., Janeiro, A., Santana, I., Baldeiras, I., Almeida, M. R., Lleó, A., Dols-Icardo, O., Alcolea, D., Benussi, L., Binetti, G., Paterlini, A., Ghidoni, R., Nacmias, B., Meulenbroek, O., van Waalwijk van Doorn, L. J. C., Kuiperi, H. B. J., ... Martins, M. (2018). Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. Journal of Alzheimer's Disease, 66(2), 639-652. https://doi.org/10.3233/JAD-180512

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. / Ramos de Matos, Mafalda; Ferreira, Catarina; Herukka, Sanna-Kaisa et al.
In: Journal of Alzheimer's Disease, Vol. 66, No. 2, 2018, p. 639-652.

Research output: Contribution to journal › Journal article › Research › peer-review

Ramos de Matos, M, Ferreira, C, Herukka, S-K, Soininen, H, Janeiro, A, Santana, I, Baldeiras, I, Almeida, MR, Lleó, A, Dols-Icardo, O, Alcolea, D, Benussi, L, Binetti, G, Paterlini, A, Ghidoni, R, Nacmias, B, Meulenbroek, O, van Waalwijk van Doorn, LJC, Kuiperi, HBJ, Hausner, L, Waldemar, G, Simonsen, AH, Tsolaki, M, Gkatzima, O, Resende de Oliveira, C, Verbeek, MM, Clarimon, J, Hiltunen, M, de Mendonça, A & Martins, M 2018, 'Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers', Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 639-652. https://doi.org/10.3233/JAD-180512

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title = "Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers",

abstract = "Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.",

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year = "2018",

doi = "10.3233/JAD-180512",

language = "English",

volume = "66",

pages = "639--652",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

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T1 - Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers

AU - Ramos de Matos, Mafalda

AU - Ferreira, Catarina

AU - Herukka, Sanna-Kaisa

AU - Soininen, Hilkka

AU - Janeiro, André

AU - Santana, Isabel

AU - Baldeiras, Inês

AU - Almeida, Maria Rosário

AU - Lleó, Alberto

AU - Dols-Icardo, Oriol

AU - Alcolea, Daniel

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Paterlini, Anna

AU - Ghidoni, Roberta

AU - Nacmias, Benedetta

AU - Meulenbroek, Olga

AU - van Waalwijk van Doorn, Linda J C

AU - Kuiperi, H Bea J

AU - Hausner, Lucrezia

AU - Waldemar, Gunhild

AU - Simonsen, Anja Hviid

AU - Tsolaki, Magda

AU - Gkatzima, Olymbia

AU - Resende de Oliveira, Catarina

AU - Verbeek, Marcel M

AU - Clarimon, Jordi

AU - Hiltunen, Mikko

AU - de Mendonça, Alexandre

AU - Martins, Madalena

PY - 2018

Y1 - 2018

N2 - Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

AB - Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

U2 - 10.3233/JAD-180512

DO - 10.3233/JAD-180512

M3 - Journal article

C2 - 30320580

SN - 1387-2877

VL - 66

SP - 639

EP - 652

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

IS - 2

ER -

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers

Abstract

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