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Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure.

TitleGenetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure.
Publication TypeJournal Article
Year of Publication2018
AuthorsLi, Z, Del-Aguila, JL, Dube, U, Budde, J, Martinez, R, Black, K, Xiao, Q, Cairns, NJ, Dougherty, JD, Lee, J-M, Morris, JC, Bateman, RJ, Karch, CM, Cruchaga, C, Harari, O
Corporate AuthorsDominantly Inherited Alzheimer Network (DIAN)
JournalGenome Med
Volume10
Issue1
Pagination43
Date Published2018 06 08
ISSN1756-994X
KeywordsAdult, Age of Onset, Aged, 80 and over, Alleles, Alzheimer Disease, Apolipoprotein E4, Astrocytes, Cerebral Cortex, Demography, Female, Genetic Variation, Humans, Male, Membrane Glycoproteins, Middle Aged, Nerve Degeneration, Neurons, Receptors, Immunologic, Reproducibility of Results, Sequence Analysis, RNA, Transcriptome
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.

DOI10.1186/s13073-018-0551-4
Alternate JournalGenome Med
PubMed ID29880032
PubMed Central IDPMC5992755
Grant ListP01-AG026276 / AG / NIA NIH HHS / United States
R01 AG044546 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
NIRG-11-200110 / / Alzheimer's Association / International
RF1 AG053303 / AG / NIA NIH HHS / United States
U01 AG046170 / AG / NIA NIH HHS / United States
R01 NS094692 / NS / NINDS NIH HHS / United States
R01 NS085419 / NS / NINDS NIH HHS / United States
R01-NS085419 / NH / NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
U19AG032438 / AG / NIA NIH HHS / United States
P01-AG03991 / AG / NIA NIH HHS / United States
K01AG046374 / NH / NIH HHS / United States
R01NS102272 / / Brain and Behavior Research Foundation / International
RF1AG053303 / AG / NIA NIH HHS / United States
K01 AG046374 / AG / NIA NIH HHS / United States
R21 NS082529 / NS / NINDS NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
R01 MH101454 / MH / NIMH NIH HHS / United States
R01-AG035083 / NH / NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States
P01-AG003991 / NH / NIH HHS / United States
P01 AG003949 / AG / NIA NIH HHS / United States
R01-AG044546 / NH / NIH HHS / United States
U24 NS072026 / NS / NINDS NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG025711 / AG / NIA NIH HHS / United States
R25 DA027995 / DA / NIDA NIH HHS / United States
A2013359S / / BrightFocus Foundation / International
P50-AG05681 / AG / NIA NIH HHS / United States
P01 AG017216 / AG / NIA NIH HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
U01 AG006786 / AG / NIA NIH HHS / United States
U19 AG032438 / AG / NIA NIH HHS / United States
R01 AG035083 / AG / NIA NIH HHS / United States
R01 NS102272 / NS / NINDS NIH HHS / United States