Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers
Por:
de Matos, MR, Ferreira, C, Herukka, SK, Soininen, H, Janeiro, A, Santana, I, Baldeiras, I, Almeida, MR, Lleo, A, Dols-Icardo, O, Alcolea, D, Benussi, L, Binetti, G, Paterlini, A, Ghidoni, R, Nacmias, B, Meulenbroek, O, van Doorn, LJCV, Kuiperi, HBJ, Hausner, L, Waldemar, G, Simonsen, AH, Tsolaki, M, Gkatzima, O, de Oliveira, CR, Verbeek, MM, Clarimon, J, Hiltunen, M, de Mendonca, A, Martins, M
Publicada:
1 ene 2018
Resumen:
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 (A beta(1-42)), 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 A beta(1-42) is decreased due to the accumulation of A beta(1-42) 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 A beta(1-42), 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.
Filiaciones:
de Matos, MR:
Univ Lisbon, Fac Med, Inst Med Mol, Lisbon, Portugal
Ferreira, C:
Univ Lisbon, Fac Med, Inst Med Mol, Lisbon, Portugal
Herukka, SK:
Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland
Kuopio Univ Hosp, Dept Neurol, Kuopio, Finland
Soininen, H:
Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland
Kuopio Univ Hosp, Dept Neurol, Kuopio, Finland
Janeiro, A:
Univ Lisbon, Fac Med, Inst Med Mol, Lisbon, Portugal
Santana, I:
Univ Coimbra, Neurochem Lab, Ctr Neurosci & Cell Biol, Neurogenet Lab,CNC,CHUC, Coimbra, Portugal
Univ Coimbra, Fac Med, CNC IBILI, Coimbra, Portugal
Baldeiras, I:
Univ Coimbra, Neurochem Lab, Ctr Neurosci & Cell Biol, Neurogenet Lab,CNC,CHUC, Coimbra, Portugal
Univ Coimbra, Fac Med, CNC IBILI, Coimbra, Portugal
Almeida, MR:
Univ Coimbra, Neurochem Lab, Ctr Neurosci & Cell Biol, Neurogenet Lab,CNC,CHUC, Coimbra, Portugal
Univ Coimbra, Fac Med, CNC IBILI, Coimbra, Portugal
Lleo, A:
Autonomous Univ Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Memory Unit, Barcelona, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Dols-Icardo, O:
Autonomous Univ Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Memory Unit, Barcelona, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Alcolea, D:
Autonomous Univ Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Memory Unit, Barcelona, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Benussi, L:
IRCCS Cento S Giovanni Dio Fatebenefratelli, Mol Markers Lab, Brescia, Italy
Binetti, G:
IRCCS Cento S Giovanni Dio Fatebenefratelli, Mol Markers Lab, Brescia, Italy
IRCCS Cento S Giovanni Dio Fatebenefratelli, MAC Memory Clin, Brescia, Italy
Paterlini, A:
IRCCS Cento S Giovanni Dio Fatebenefratelli, Mol Markers Lab, Brescia, Italy
Ghidoni, R:
IRCCS Cento S Giovanni Dio Fatebenefratelli, Mol Markers Lab, Brescia, Italy
Nacmias, B:
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
Meulenbroek, O:
Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Radboud Alzheimer Ctr,Dept Geriatr, Nijmegen, Netherlands
van Doorn, LJCV:
Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol,Radboud Alzheimer Ctr,Dept Lab Med, Nijmegen, Netherlands
Kuiperi, HBJ:
Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol,Radboud Alzheimer Ctr,Dept Lab Med, Nijmegen, Netherlands
Hausner, L:
Heidelberg Univ, Med Fac Mannheim, Dept Geriatr Psychiat CIMH, Mannheim, Germany
Waldemar, G:
Univ Copenhagen, Dept Neurol, Danish Dementia Res Ctr, Rigshosp, Copenhagen, Denmark
Simonsen, AH:
Univ Copenhagen, Dept Neurol, Danish Dementia Res Ctr, Rigshosp, Copenhagen, Denmark
Tsolaki, M:
Aristotle Univ Thessaloniki, Dept Neurol 1, Macedonia, Greece
Greek Alzheimer Assoc, Thessaloniki, Greece
Gkatzima, O:
Greek Assoc Alzheimers Dis & Related Disorders Al, Thessaloniki, Greece
de Oliveira, CR:
Univ Coimbra, Neurochem Lab, Ctr Neurosci & Cell Biol, Neurogenet Lab,CNC,CHUC, Coimbra, Portugal
Univ Coimbra, Fac Med, CNC IBILI, Coimbra, Portugal
Verbeek, MM:
Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol,Radboud Alzheimer Ctr,Dept Lab Med, Nijmegen, Netherlands
Clarimon, J:
Autonomous Univ Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Memory Unit, Barcelona, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hiltunen, M:
Univ Eastern Finland, Inst Biomed, Kuopio, Finland
de Mendonca, A:
Univ Lisbon, Fac Med, Inst Med Mol, Lisbon, Portugal
Martins, M:
Univ Lisbon, Fac Med, Inst Med Mol, Lisbon, Portugal
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