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Genome Med. 2018 Jun 8;10(1):43. doi: 10.1186/s13073-018-0551-4.

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

Author information

1
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
2
Medical Scientist Training Program, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA.
3
Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA.
4
Department of Pathology & Immunology, Washington University in St. Louis, School of Medicine, 510 S. Kingshighway, MC 8131, Saint Louis, MO, 63110, USA.
5
Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA.
6
Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA.
7
Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.
8
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.
9
Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.
10
Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.
11
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA. harario@wustl.edu.

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.

KEYWORDS:

Alzheimer’s disease; Autosomal dominant AD; Brain cellular composition; Bulk RNA-sequencing; Digital deconvolution; TREM2

PMID:
29880032
PMCID:
PMC5992755
DOI:
10.1186/s13073-018-0551-4
[Indexed for MEDLINE]
Free PMC Article

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