Genetics of neurodegeneration : Alzheimer, Lewy body and motor neuron diseases in the Finnish population

Forskningsoutput: AvhandlingDoktorsavhandlingSamling av artiklar

Sammanfattning

This thesis project aimed to study the genetic background of common neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS) in the Finnish population. In the first study, we analysed the role of the amyloid precursor protein (APP) and apolipoprotein E (APOE) genes in AD neuropathology. Mutations in the APP gene cause early-onset familial AD and there is some evidence that APP gene variants would play a role in late-onset AD, too. We genotyped more than 50 common variations in the APP gene and sequenced the APP promoter area to detect rare variations in the area, both known and new. In the Finnish elderly population we did not find any of the APP variations to clearly associate with neuropathologically diagnosed AD or with any of the neuropathological features of AD such as cortical β-amyloid, cerebrovascular β-amyloid or neurofibrillary tangles. In addition, the APOEε4 results were updated, using the whole Vantaa85+ cohort. APOE ε4 is currently the strongest known risk factor for late-onset AD. We found a very strong association of APOE ε4 to all neuropathological features of AD. In the second study, we investigated how the common variants in the α-synuclein (SNCA) gene affect different brain pathologies. -synuclein is the main component of the Lewy bodies, which are the pathological hallmarks of PD and DLB, and which are sometimes found also in AD. We genotyped 11 SNPs from the SNCA gene region. We found no association with the cortical β-amyloid and only a faint one with Lewy related pathology. However, we found an association with neurofibrillary tangles. The SNP (rs2572324) associated with a p=0.004 after the Bonferroni correction. The two-locus analysis suggest an independent effect of APOE ε4 (OR=8.67) and rs2572324 (OR=3.36). In the subjects with both risk factors the effect was almost multiplicatively increased (OR=23.3). 35 subjects out of 38 with both risk factors had severe tau-pathology. These results demonstrated the first evidence for a role of genetic variation in SNCA in tau pathology. Moreover, β-amyloid pathology was not associated with the SNCA variants, demonstrating a dissection of genetic effect on the two principal pathological features of AD. In the third study, we performed a whole-genome genotyping using Finnish ALS samples. The Vantaa85+ study subjects were used as controls. This was the first ALS genome-wide association study to find a genome-wide significant association. The location associated with familial ALS was on the chromosome 9p21, which had been noticed before, but the area had been much larger. The area has also been associated with frontotemporal dementia (FTD). Now we managed to define the area with a 42 SNP haplotype. This considerably reduced the area of interest (down to 232 kb) and increased the possibility to find the mutation behind the disease. This haplotype was found in around 40% of the Finnish familial ALS cases and likely explains the high rate of ALS as well as FTD in Finnish population. In the fourth study, we performed a genome-wide association study of DLB in the Vantaa85+ cohort and found two novel areas to be associated with DLB: The c2p21 location with 9 SNP haplotype (p=5.2x10-7) and the c6p21 location with 6 SNP haplotype (p=1.3x10-7). The c6p21 was significant at the genome-wide level. The c2orf21 haplotype has two genes on its area, c2orf72 and SPTBN1. SPTBN1 is the candidate gene since it encodes beta-spectrin, a component of Lewy bodies, while c2orf72 is barely expressed in the brain. The c6p21 associated haplotype block is located in the HLA region and includes HLA-DPB1 and -DPA1 genes. These studies show that the Finnish population is well-suited to study the genetics of neurodegeneration. Our results showed that neuropathologically defined parameters and diagnoses are strongly associated with genetic risk factors, even with relatively low numbers of samples. Hence, phenotypic precision (pathology) is an important element of the statistical power of a study.
Originalspråkengelska
UtgivningsortHelsinki
Förlag
Tryckta ISBN978-951-51-1458-7
Elektroniska ISBN978-951-51-1459-4
StatusPublicerad - 2015
MoE-publikationstypG5 Doktorsavhandling (artikel)

Vetenskapsgrenar

  • 3112 Neurovetenskaper
  • 3124 Neurologi och psykiatri

Citera det här

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title = "Genetics of neurodegeneration : Alzheimer, Lewy body and motor neuron diseases in the Finnish population",
abstract = "This thesis project aimed to study the genetic background of common neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS) in the Finnish population. In the first study, we analysed the role of the amyloid precursor protein (APP) and apolipoprotein E (APOE) genes in AD neuropathology. Mutations in the APP gene cause early-onset familial AD and there is some evidence that APP gene variants would play a role in late-onset AD, too. We genotyped more than 50 common variations in the APP gene and sequenced the APP promoter area to detect rare variations in the area, both known and new. In the Finnish elderly population we did not find any of the APP variations to clearly associate with neuropathologically diagnosed AD or with any of the neuropathological features of AD such as cortical β-amyloid, cerebrovascular β-amyloid or neurofibrillary tangles. In addition, the APOEε4 results were updated, using the whole Vantaa85+ cohort. APOE ε4 is currently the strongest known risk factor for late-onset AD. We found a very strong association of APOE ε4 to all neuropathological features of AD. In the second study, we investigated how the common variants in the α-synuclein (SNCA) gene affect different brain pathologies. -synuclein is the main component of the Lewy bodies, which are the pathological hallmarks of PD and DLB, and which are sometimes found also in AD. We genotyped 11 SNPs from the SNCA gene region. We found no association with the cortical β-amyloid and only a faint one with Lewy related pathology. However, we found an association with neurofibrillary tangles. The SNP (rs2572324) associated with a p=0.004 after the Bonferroni correction. The two-locus analysis suggest an independent effect of APOE ε4 (OR=8.67) and rs2572324 (OR=3.36). In the subjects with both risk factors the effect was almost multiplicatively increased (OR=23.3). 35 subjects out of 38 with both risk factors had severe tau-pathology. These results demonstrated the first evidence for a role of genetic variation in SNCA in tau pathology. Moreover, β-amyloid pathology was not associated with the SNCA variants, demonstrating a dissection of genetic effect on the two principal pathological features of AD. In the third study, we performed a whole-genome genotyping using Finnish ALS samples. The Vantaa85+ study subjects were used as controls. This was the first ALS genome-wide association study to find a genome-wide significant association. The location associated with familial ALS was on the chromosome 9p21, which had been noticed before, but the area had been much larger. The area has also been associated with frontotemporal dementia (FTD). Now we managed to define the area with a 42 SNP haplotype. This considerably reduced the area of interest (down to 232 kb) and increased the possibility to find the mutation behind the disease. This haplotype was found in around 40{\%} of the Finnish familial ALS cases and likely explains the high rate of ALS as well as FTD in Finnish population. In the fourth study, we performed a genome-wide association study of DLB in the Vantaa85+ cohort and found two novel areas to be associated with DLB: The c2p21 location with 9 SNP haplotype (p=5.2x10-7) and the c6p21 location with 6 SNP haplotype (p=1.3x10-7). The c6p21 was significant at the genome-wide level. The c2orf21 haplotype has two genes on its area, c2orf72 and SPTBN1. SPTBN1 is the candidate gene since it encodes beta-spectrin, a component of Lewy bodies, while c2orf72 is barely expressed in the brain. The c6p21 associated haplotype block is located in the HLA region and includes HLA-DPB1 and -DPA1 genes. These studies show that the Finnish population is well-suited to study the genetics of neurodegeneration. Our results showed that neuropathologically defined parameters and diagnoses are strongly associated with genetic risk factors, even with relatively low numbers of samples. Hence, phenotypic precision (pathology) is an important element of the statistical power of a study.",
keywords = "Aged, Aged, 80 and over, Alzheimer Disease, +genetics, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Amyotrophic Lateral Sclerosis, +epidemiology, Apolipoproteins E, Brain, +pathology, Cerebral Amyloid Angiopathy, Cerebral Cortex, Genetic Predisposition to Disease, Genome-Wide Association Study, Genetic Association Studies, Chromosomes, Human, Pair 9, Lewy Bodies, Lewy Body Disease, Neocortex, Nerve Degeneration, Neurodegenerative Diseases, Neurofibrillary Tangles, Neurons, alpha-Synuclein, Polymorphism, Single Nucleotide, Superoxide Dismutase, tau Proteins, +metabolism, 3112 Neurosciences, 3124 Neurology and psychiatry",
author = "Terhi Peuralinna",
note = "M1 - 50 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:",
year = "2015",
language = "English",
isbn = "978-951-51-1458-7",
series = "Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis",
publisher = "University of Helsinki",
number = "67/2015",
address = "Finland",

}

Genetics of neurodegeneration : Alzheimer, Lewy body and motor neuron diseases in the Finnish population. / Peuralinna, Terhi.

Helsinki : University of Helsinki, 2015. 50 s.

Forskningsoutput: AvhandlingDoktorsavhandlingSamling av artiklar

TY - THES

T1 - Genetics of neurodegeneration : Alzheimer, Lewy body and motor neuron diseases in the Finnish population

AU - Peuralinna, Terhi

N1 - M1 - 50 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:

PY - 2015

Y1 - 2015

N2 - This thesis project aimed to study the genetic background of common neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS) in the Finnish population. In the first study, we analysed the role of the amyloid precursor protein (APP) and apolipoprotein E (APOE) genes in AD neuropathology. Mutations in the APP gene cause early-onset familial AD and there is some evidence that APP gene variants would play a role in late-onset AD, too. We genotyped more than 50 common variations in the APP gene and sequenced the APP promoter area to detect rare variations in the area, both known and new. In the Finnish elderly population we did not find any of the APP variations to clearly associate with neuropathologically diagnosed AD or with any of the neuropathological features of AD such as cortical β-amyloid, cerebrovascular β-amyloid or neurofibrillary tangles. In addition, the APOEε4 results were updated, using the whole Vantaa85+ cohort. APOE ε4 is currently the strongest known risk factor for late-onset AD. We found a very strong association of APOE ε4 to all neuropathological features of AD. In the second study, we investigated how the common variants in the α-synuclein (SNCA) gene affect different brain pathologies. -synuclein is the main component of the Lewy bodies, which are the pathological hallmarks of PD and DLB, and which are sometimes found also in AD. We genotyped 11 SNPs from the SNCA gene region. We found no association with the cortical β-amyloid and only a faint one with Lewy related pathology. However, we found an association with neurofibrillary tangles. The SNP (rs2572324) associated with a p=0.004 after the Bonferroni correction. The two-locus analysis suggest an independent effect of APOE ε4 (OR=8.67) and rs2572324 (OR=3.36). In the subjects with both risk factors the effect was almost multiplicatively increased (OR=23.3). 35 subjects out of 38 with both risk factors had severe tau-pathology. These results demonstrated the first evidence for a role of genetic variation in SNCA in tau pathology. Moreover, β-amyloid pathology was not associated with the SNCA variants, demonstrating a dissection of genetic effect on the two principal pathological features of AD. In the third study, we performed a whole-genome genotyping using Finnish ALS samples. The Vantaa85+ study subjects were used as controls. This was the first ALS genome-wide association study to find a genome-wide significant association. The location associated with familial ALS was on the chromosome 9p21, which had been noticed before, but the area had been much larger. The area has also been associated with frontotemporal dementia (FTD). Now we managed to define the area with a 42 SNP haplotype. This considerably reduced the area of interest (down to 232 kb) and increased the possibility to find the mutation behind the disease. This haplotype was found in around 40% of the Finnish familial ALS cases and likely explains the high rate of ALS as well as FTD in Finnish population. In the fourth study, we performed a genome-wide association study of DLB in the Vantaa85+ cohort and found two novel areas to be associated with DLB: The c2p21 location with 9 SNP haplotype (p=5.2x10-7) and the c6p21 location with 6 SNP haplotype (p=1.3x10-7). The c6p21 was significant at the genome-wide level. The c2orf21 haplotype has two genes on its area, c2orf72 and SPTBN1. SPTBN1 is the candidate gene since it encodes beta-spectrin, a component of Lewy bodies, while c2orf72 is barely expressed in the brain. The c6p21 associated haplotype block is located in the HLA region and includes HLA-DPB1 and -DPA1 genes. These studies show that the Finnish population is well-suited to study the genetics of neurodegeneration. Our results showed that neuropathologically defined parameters and diagnoses are strongly associated with genetic risk factors, even with relatively low numbers of samples. Hence, phenotypic precision (pathology) is an important element of the statistical power of a study.

AB - This thesis project aimed to study the genetic background of common neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS) in the Finnish population. In the first study, we analysed the role of the amyloid precursor protein (APP) and apolipoprotein E (APOE) genes in AD neuropathology. Mutations in the APP gene cause early-onset familial AD and there is some evidence that APP gene variants would play a role in late-onset AD, too. We genotyped more than 50 common variations in the APP gene and sequenced the APP promoter area to detect rare variations in the area, both known and new. In the Finnish elderly population we did not find any of the APP variations to clearly associate with neuropathologically diagnosed AD or with any of the neuropathological features of AD such as cortical β-amyloid, cerebrovascular β-amyloid or neurofibrillary tangles. In addition, the APOEε4 results were updated, using the whole Vantaa85+ cohort. APOE ε4 is currently the strongest known risk factor for late-onset AD. We found a very strong association of APOE ε4 to all neuropathological features of AD. In the second study, we investigated how the common variants in the α-synuclein (SNCA) gene affect different brain pathologies. -synuclein is the main component of the Lewy bodies, which are the pathological hallmarks of PD and DLB, and which are sometimes found also in AD. We genotyped 11 SNPs from the SNCA gene region. We found no association with the cortical β-amyloid and only a faint one with Lewy related pathology. However, we found an association with neurofibrillary tangles. The SNP (rs2572324) associated with a p=0.004 after the Bonferroni correction. The two-locus analysis suggest an independent effect of APOE ε4 (OR=8.67) and rs2572324 (OR=3.36). In the subjects with both risk factors the effect was almost multiplicatively increased (OR=23.3). 35 subjects out of 38 with both risk factors had severe tau-pathology. These results demonstrated the first evidence for a role of genetic variation in SNCA in tau pathology. Moreover, β-amyloid pathology was not associated with the SNCA variants, demonstrating a dissection of genetic effect on the two principal pathological features of AD. In the third study, we performed a whole-genome genotyping using Finnish ALS samples. The Vantaa85+ study subjects were used as controls. This was the first ALS genome-wide association study to find a genome-wide significant association. The location associated with familial ALS was on the chromosome 9p21, which had been noticed before, but the area had been much larger. The area has also been associated with frontotemporal dementia (FTD). Now we managed to define the area with a 42 SNP haplotype. This considerably reduced the area of interest (down to 232 kb) and increased the possibility to find the mutation behind the disease. This haplotype was found in around 40% of the Finnish familial ALS cases and likely explains the high rate of ALS as well as FTD in Finnish population. In the fourth study, we performed a genome-wide association study of DLB in the Vantaa85+ cohort and found two novel areas to be associated with DLB: The c2p21 location with 9 SNP haplotype (p=5.2x10-7) and the c6p21 location with 6 SNP haplotype (p=1.3x10-7). The c6p21 was significant at the genome-wide level. The c2orf21 haplotype has two genes on its area, c2orf72 and SPTBN1. SPTBN1 is the candidate gene since it encodes beta-spectrin, a component of Lewy bodies, while c2orf72 is barely expressed in the brain. The c6p21 associated haplotype block is located in the HLA region and includes HLA-DPB1 and -DPA1 genes. These studies show that the Finnish population is well-suited to study the genetics of neurodegeneration. Our results showed that neuropathologically defined parameters and diagnoses are strongly associated with genetic risk factors, even with relatively low numbers of samples. Hence, phenotypic precision (pathology) is an important element of the statistical power of a study.

KW - Aged

KW - Aged, 80 and over

KW - Alzheimer Disease

KW - +genetics

KW - Amyloid beta-Peptides

KW - Amyloid beta-Protein Precursor

KW - Amyotrophic Lateral Sclerosis

KW - +epidemiology

KW - Apolipoproteins E

KW - Brain

KW - +pathology

KW - Cerebral Amyloid Angiopathy

KW - Cerebral Cortex

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genetic Association Studies

KW - Chromosomes, Human, Pair 9

KW - Lewy Bodies

KW - Lewy Body Disease

KW - Neocortex

KW - Nerve Degeneration

KW - Neurodegenerative Diseases

KW - Neurofibrillary Tangles

KW - Neurons

KW - alpha-Synuclein

KW - Polymorphism, Single Nucleotide

KW - Superoxide Dismutase

KW - tau Proteins

KW - +metabolism

KW - 3112 Neurosciences

KW - 3124 Neurology and psychiatry

M3 - Doctoral Thesis

SN - 978-951-51-1458-7

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - University of Helsinki

CY - Helsinki

ER -

Peuralinna T. Genetics of neurodegeneration : Alzheimer, Lewy body and motor neuron diseases in the Finnish population. Helsinki: University of Helsinki, 2015. 50 s. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis ; 67/2015).