Year: 2022
Type: article
Abstract: Most disease-gene association methods do not account for gene-gene interactions, even though these play a crucial role in complex, polygenic diseases like Alzheimer’s disease (AD). To discover new genes whose interactions may contribute to pathology, we introduce GeneEMBED. This approach compares the functional perturbations induced in gene interaction network neighborhoods by coding variants from disease versus healthy subjects. In two independent AD cohorts of 5,169 exomes and 969 genomes, GeneEMBED identified novel candidates. These genes were differentially expressed in post mortem AD brains and modulated neurological phenotypes in mice. Four that were differentially overexpressed and modified neurodegeneration in vivo are PLEC, UTRN, TP53, and POLD1. Notably, TP53 and POLD1 are involved in DNA break repair and inhibited by approved drugs. While these data show proof of concept in AD, GeneEMBED is a general approach that should be broadly applicable to identify genes relevant to risk mechanisms and therapy of other complex diseases.
Source: Cell Genomics
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $8,900
Funders: Michael J. Fox Foundation for Parkinson's Research, Mayo Clinic, Illinois Department of Public Health, Mayo Foundation for Medical Education and Research, Icahn School of Medicine at Mount Sinai, Arizona Department of Health Services, CurePSP, Rush University, Translational Genomics Research Institute, Veterans Administration Medical Center, Arizona Biomedical Research Commission, National Institutes of Health, Alzheimer's Disease Research Center, University of Pittsburgh, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: G1052080286, Epidemiologic Study of Neural Reserve and Neurobiology of Aging, G1258278173, G1606131442, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample, G2079542735, G2161113364, G2181322794, G2345704987, G2355179167, Gene discovery in PSP by transcriptome, neuropathology and sequence analysis, G2642611343, G2743177214, G2762323504, G2765380810, G2886312875, G2893686963, G3021174146, Plasma AB as a Surrogate Genetic Marker for LOAD, G3036763132, Exploring the Role of the Brain Transcriptome in Cognitive Decline, G3228411741, G3250808129, G3251040009, G3255618601, G3521153818, G3540482749, G356044358, Identifying, validating and targeting AD susceptibility networks in monocytes, ADSP Follow-up in Multi-Ethnic Cohorts via Endophenotypes, Omics & Model Systems, Pathway discovery, validation and compound identification for Alzheimer's disease, Alzheimers Disease Patient Registry, G3918109904, Einstein Aging Study, G4056054268, G4193400840, G4298864339, G4356727394, Functional Determinants in G-Protein-Coupled Receptors, G4440353152, Replication and Extension of ADSP Discoveries in African-Americans, A knowledge map to find Alzheimer's disease drugs, Exploring the Role of the Brain Epigenome: Cognitive Decline and Life Experiences, G4727311221, G4741916379, G4791902628, Risk Factors, Pathology, and Clinical Expressions of AD, Rush Alzheimer's Disease Core Center, G5030236256, G5248879280, Alzheimer's Disease Genetics Consortium, G5325683966, G5427725083, G5484535055, G5550361198, G5558075022, G5627134285, G5752060496, G578809140, G5952929075, G6030318873, Multi-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targets, Consortium for Alzheimers Sequence Analysis (CASA), Sequence-based Discovery of AD Risk & Protective Alleles, Cognitive Decline and Dementia: Life Experiences and the Brain Histone Epigenome, Florida Alzheimer's Disease Research, G6530347775, G6648385527, G6814118465, G682054764, G6875889451, Genome wide association study of gene expression levels in Alzheimer's disease, Arizona Alzheimer's Disease Core Center, Discovery of Novel Proteomic Targets for Treatment of Alzheimer's Disease, G7161884846, Tau and Neurodegeneration II: A therapeutic target, G7431531211, G7457767463, A Systems Approach to Targeting Innate Immunity in AD, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders, G7747731141, G7836467104, G7924111682, Sequence-based Discovery of AD Risk & Protective Alleles, G8148368415, G8237925204, G8289575266, G8324823946, G8346902290, Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer's Disease (AD), G8470537573, AD Gene Discovery: Exome Chip, New Endophenotypes & Functional Studies in CHARGE, G8516215044, Functional Dissection of Alzheimer's Disease Networks in Drosophila: from Association to Causal Modulators of Age-Dependent Neurodegeration, Identification and characterization of AD risk networks using multi-dimensional "omics" data, G8629123209, Deconstructing and modeling the single cell architecture of the Alzheimer brain, G8793648130, G9000005508, G9000107134, G9000113025, G9000159448, G9000185113, G9000283702, G9000355711, Genome Center for Alzheimer's Disease (GCAD), Decoding the impact of sex differences on Alzheimer's disease risk, Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila Models, Cognitive Computing of Alzheimer's Disease Genes and Risk, G947960016, Mayo Alzheimer's Disease Research Center, G961669115
OpenAlex ID: W4288045192