Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure
Abstract Background Alzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the specific effects that pathological mutations and coding variants associated with AD have on the cellular composition of the brain are often ignored. Methods We develop...
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doaj-dda71abaa386494db5ac296efd6f0e092020-11-25T00:42:28ZengBMCGenome Medicine1756-994X2018-06-0110111910.1186/s13073-018-0551-4Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structureZeran Li0Jorge L. Del-Aguila1Umber Dube2John Budde3Rita Martinez4Kathleen Black5Qingli Xiao6Nigel J. Cairns7The Dominantly Inherited Alzheimer Network (DIAN)Joseph D. Dougherty8Jin-Moo Lee9John C. Morris10Randall J. Bateman11Celeste M. Karch12Carlos Cruchaga13Oscar Harari14Department of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineAbstract Background Alzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the specific effects that pathological mutations and coding variants associated with AD have on the cellular composition of the brain are often ignored. Methods We developed and optimized a cell-type-specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. Results We found that neuronal and astrocyte relative proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1, or PSEN2 presented lower neuron and higher astrocyte relative proportions compared to sporadic AD. Similarly, the APOE ε4 allele also showed decreased neuronal and increased astrocyte relative proportions compared to AD non-carriers. In contrast, carriers of variants in TREM2 risk showed a lower degree of neuronal loss compared to matched AD cases in multiple independent studies. Conclusions These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-sequencing studies for cell composition and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD.http://link.springer.com/article/10.1186/s13073-018-0551-4Digital deconvolutionAlzheimer’s diseaseBrain cellular compositionBulk RNA-sequencingAutosomal dominant ADTREM2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zeran Li Jorge L. Del-Aguila Umber Dube John Budde Rita Martinez Kathleen Black Qingli Xiao Nigel J. Cairns The Dominantly Inherited Alzheimer Network (DIAN) Joseph D. Dougherty Jin-Moo Lee John C. Morris Randall J. Bateman Celeste M. Karch Carlos Cruchaga Oscar Harari |
spellingShingle |
Zeran Li Jorge L. Del-Aguila Umber Dube John Budde Rita Martinez Kathleen Black Qingli Xiao Nigel J. Cairns The Dominantly Inherited Alzheimer Network (DIAN) Joseph D. Dougherty Jin-Moo Lee John C. Morris Randall J. Bateman Celeste M. Karch Carlos Cruchaga Oscar Harari Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure Genome Medicine Digital deconvolution Alzheimer’s disease Brain cellular composition Bulk RNA-sequencing Autosomal dominant AD TREM2 |
author_facet |
Zeran Li Jorge L. Del-Aguila Umber Dube John Budde Rita Martinez Kathleen Black Qingli Xiao Nigel J. Cairns The Dominantly Inherited Alzheimer Network (DIAN) Joseph D. Dougherty Jin-Moo Lee John C. Morris Randall J. Bateman Celeste M. Karch Carlos Cruchaga Oscar Harari |
author_sort |
Zeran Li |
title |
Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure |
title_short |
Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure |
title_full |
Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure |
title_fullStr |
Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure |
title_full_unstemmed |
Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure |
title_sort |
genetic variants associated with alzheimer’s disease confer different cerebral cortex cell-type population structure |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2018-06-01 |
description |
Abstract Background Alzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the specific effects that pathological mutations and coding variants associated with AD have on the cellular composition of the brain are often ignored. Methods We developed and optimized a cell-type-specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. Results We found that neuronal and astrocyte relative proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1, or PSEN2 presented lower neuron and higher astrocyte relative proportions compared to sporadic AD. Similarly, the APOE ε4 allele also showed decreased neuronal and increased astrocyte relative proportions compared to AD non-carriers. In contrast, carriers of variants in TREM2 risk showed a lower degree of neuronal loss compared to matched AD cases in multiple independent studies. Conclusions These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-sequencing studies for cell composition and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD. |
topic |
Digital deconvolution Alzheimer’s disease Brain cellular composition Bulk RNA-sequencing Autosomal dominant AD TREM2 |
url |
http://link.springer.com/article/10.1186/s13073-018-0551-4 |
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