Identification of Risk Genes for Alzheimer's Disease by Gene Embedding

Overview

Journal Cell Genom

Date 2022 Oct 21

PMID 36268052

Authors

Yashwanth Lagisetty

Thomas Bourquard

Ismael Al-Ramahi

Carl Grant Mangleburg

Samantha Mota

Shirin Soleimani

Joshua M Shulman

Juan Botas

Kwanghyuk Lee

Olivier Lichtarge

Affiliations

Soon will be listed here.

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 AD brains and modulated neurological phenotypes in mice. Four that were differentially overexpressed and modified neurodegeneration 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.

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References

Leggio G, Torrisi S, Mastrogiacomo R, Mauro D, Chisari M, Devroye C . The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans. Mol Psychiatry. 2019; 26(4):1272-1285. DOI: 10.1038/s41380-019-0511-4. View

Onur T, Laitman A, Zhao H, Keyho R, Kim H, Wang J . Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis. Elife. 2021; 10. PMC: 8149125. DOI: 10.7554/eLife.64564. View

Pavel M, Imarisio S, Menzies F, Jimenez-Sanchez M, Siddiqi F, Wu X . CCT complex restricts neuropathogenic protein aggregation via autophagy. Nat Commun. 2016; 7:13821. PMC: 5155164. DOI: 10.1038/ncomms13821. View

Lisewski A, Quiros J, Ng C, Adikesavan A, Miura K, Putluri N . Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell. 2014; 158(4):916-928. PMC: 4167585. DOI: 10.1016/j.cell.2014.07.011. View

Chumakov I, Nabirotchkin S, Cholet N, Milet A, Boucard A, Toulorge D . Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy. Sci Rep. 2015; 5:7608. PMC: 5378993. DOI: 10.1038/srep07608. View

Zhou W, Zhao Z, Nielsen J, Fritsche L, LeFaive J, Gagliano Taliun S . Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts. Nat Genet. 2020; 52(6):634-639. PMC: 7871731. DOI: 10.1038/s41588-020-0621-6. View

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

Johnson E, Dammer E, Duong D, Ping L, Zhou M, Yin L . Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020; 26(5):769-780. PMC: 7405761. DOI: 10.1038/s41591-020-0815-6. View

Yang F, Diao X, Wang F, Wang Q, Sun J, Zhou Y . Identification of Key Regulatory Genes and Pathways in Prefrontal Cortex of Alzheimer's Disease. Interdiscip Sci. 2020; 12(1):90-98. DOI: 10.1007/s12539-019-00353-8. View

10.

De Ferrari G, Inestrosa N . Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000; 33(1):1-12. DOI: 10.1016/s0165-0173(00)00021-7. View

11.

Kern D, Cepeda M, Lovestone S, Seabrook G . Aiding the discovery of new treatments for dementia by uncovering unknown benefits of existing medications. Alzheimers Dement (N Y). 2019; 5:862-870. PMC: 6909196. DOI: 10.1016/j.trci.2019.07.012. View

12.

Martin M, Gao X, Lee J, Nelson G, Detels R, Goedert J . Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet. 2002; 31(4):429-34. DOI: 10.1038/ng934. View

13.

Hebert L, Weuve J, Scherr P, Evans D . Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013; 80(19):1778-83. PMC: 3719424. DOI: 10.1212/WNL.0b013e31828726f5. View

14.

Bis J, Jian X, Kunkle B, Chen Y, Hamilton-Nelson K, Bush W . Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. Mol Psychiatry. 2018; 25(8):1859-1875. PMC: 6375806. DOI: 10.1038/s41380-018-0112-7. View

15.

de Leeuw C, Mooij J, Heskes T, Posthuma D . MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015; 11(4):e1004219. PMC: 4401657. DOI: 10.1371/journal.pcbi.1004219. View

16.

Yamakawa H, Cheng J, Penney J, Gao F, Rueda R, Wang J . The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons. Cell Rep. 2017; 20(6):1319-1334. DOI: 10.1016/j.celrep.2017.07.044. View

17.

Greene C, Krishnan A, Wong A, Ricciotti E, Zelaya R, Himmelstein D . Understanding multicellular function and disease with human tissue-specific networks. Nat Genet. 2015; 47(6):569-76. PMC: 4828725. DOI: 10.1038/ng.3259. View

18.

Bult C, Blake J, Smith C, Kadin J, Richardson J . Mouse Genome Database (MGD) 2019. Nucleic Acids Res. 2018; 47(D1):D801-D806. PMC: 6323923. DOI: 10.1093/nar/gky1056. View

19.

Uberti D, Lanni C, Racchi M, Govoni S, Memo M . Conformationally altered p53: a putative peripheral marker for Alzheimer's disease. Neurodegener Dis. 2008; 5(3-4):209-11. DOI: 10.1159/000113704. View

20.

Cordell H . Detecting gene-gene interactions that underlie human diseases. Nat Rev Genet. 2009; 10(6):392-404. PMC: 2872761. DOI: 10.1038/nrg2579. View