Identification of risk genes for Alzheimer's disease by gene embedding.

Autor:	Lagisetty Y; Department of Biology and Pharmacology, UTHealth McGovern Medical School, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Bourquard T; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Al-Ramahi I; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.; Center for Alzheimer's and Neurodegenerative Diseases, Baylor College of Medicine, Houston, TX 77030, USA., Mangleburg CG; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Mota S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Soleimani S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Shulman JM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.; Center for Alzheimer's and Neurodegenerative Diseases, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Botas J; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.; Center for Alzheimer's and Neurodegenerative Diseases, Baylor College of Medicine, Houston, TX 77030, USA., Lee K; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Lichtarge O; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Center for Alzheimer's and Neurodegenerative Diseases, Baylor College of Medicine, Houston, TX 77030, USA.; Computational and Integrative Biomedical Research Center, Baylor College of Medicine, Houston, TX 77030, USA.; Lead contact.
Jazyk:	angličtina
Zdroj:	Cell genomics [Cell Genom] 2022 Sep 14; Vol. 2 (9). Date of Electronic Publication: 2022 Jul 26.
DOI:	10.1016/j.xgen.2022.100162
Abstrakt:	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. Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
Databáze:	MEDLINE
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