Dysregulated Fc gamma receptor–mediated phagocytosis pathway in Alzheimer's disease: network-based gene expression analysis

TY - JOUR

T1 - Dysregulated Fc gamma receptor–mediated phagocytosis pathway in Alzheimer's disease

T2 - network-based gene expression analysis

AU - AddNeuroMed consortium and the Alzheimer's Disease Neuroimaging Initiative

AU - Park, Young Ho

AU - Hodges, Angela

AU - Risacher, Shannon L.

AU - Lin, Kuang

AU - Jang, Jae Won

AU - Ahn, Soyeon

AU - Kim, Sang Yun

AU - Lovestone, Simon

AU - Simmons, Andrew

AU - Weiner, Michael W.

AU - Saykin, Andrew J.

AU - Nho, Kwangsik

PY - 2020/4

Y1 - 2020/4

N2 - Transcriptomics has become an important tool for identification of biological pathways dysregulated in Alzheimer's disease (AD). We performed a network-based gene expression analysis of blood-based microarray gene expression profiles using 2 independent cohorts, Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 661) and AddNeuroMed (N = 674). Weighted gene coexpression network analysis identified 17 modules from ADNI and 13 from AddNeuroMed. Four of the modules derived in ADNI were significantly related to AD; 5 modules in AddNeuroMed were significant. Gene-set enrichment analysis of the AD-related modules identified and replicated 3 biological pathways including the Fc gamma receptor–mediated phagocytosis pathway. Module-based association analysis showed the AD-related module, which has the 3 pathways, to be associated with cognitive function and neuroimaging biomarkers. Gene-based association analysis identified PRKCD in the Fc gamma receptor–mediated phagocytosis pathway as being significantly associated with cognitive function and cerebrospinal fluid biomarkers. The identification of the Fc gamma receptor–mediated phagocytosis pathway implicates the peripheral innate immune system in the pathophysiology of AD. PRKCD is known to be related to neurodegeneration induced by amyloid-β.

AB - Transcriptomics has become an important tool for identification of biological pathways dysregulated in Alzheimer's disease (AD). We performed a network-based gene expression analysis of blood-based microarray gene expression profiles using 2 independent cohorts, Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 661) and AddNeuroMed (N = 674). Weighted gene coexpression network analysis identified 17 modules from ADNI and 13 from AddNeuroMed. Four of the modules derived in ADNI were significantly related to AD; 5 modules in AddNeuroMed were significant. Gene-set enrichment analysis of the AD-related modules identified and replicated 3 biological pathways including the Fc gamma receptor–mediated phagocytosis pathway. Module-based association analysis showed the AD-related module, which has the 3 pathways, to be associated with cognitive function and neuroimaging biomarkers. Gene-based association analysis identified PRKCD in the Fc gamma receptor–mediated phagocytosis pathway as being significantly associated with cognitive function and cerebrospinal fluid biomarkers. The identification of the Fc gamma receptor–mediated phagocytosis pathway implicates the peripheral innate immune system in the pathophysiology of AD. PRKCD is known to be related to neurodegeneration induced by amyloid-β.

KW - Alzheimer's disease

KW - Coexpression

KW - Network

KW - Phagocytosis

KW - PRKCD

KW - Transcriptome

U2 - 10.1016/j.neurobiolaging.2019.12.001

DO - 10.1016/j.neurobiolaging.2019.12.001

M3 - Article

AN - SCOPUS:85077384675

SN - 0197-4580

VL - 88

SP - 24

EP - 32

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -