Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates RTFDC1 at the CASS4 locus.

Autor:	Burton EA; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; CAMB Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Argenziano M; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Cook K; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Ridler M; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Lu S; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Su C; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Manduchi E; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Littleton SH; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; CAMB Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Leonard ME; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Hodge KM; Emory University, Atlanta, GA, USA., Wang LS; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Schellenberg GD; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Johnson ME; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Pahl MC; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Pippin JA; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Wells AD; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Anderson SA; Department of Child and Adolescent Psychiatry and Behavioral Services, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Brown CD; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Grant SFA; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Division Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Chesi A; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 22. Date of Electronic Publication: 2024 Aug 22.
DOI:	10.1101/2024.08.22.609230
Abstrakt:	Late-onset Alzheimer's disease (LOAD) research has principally focused on neurons over the years due to their known role in the production of amyloid beta plaques and neurofibrillary tangles. In contrast, recent genomic studies of LOAD have implicated microglia as culprits of the prolonged inflammation exacerbating the neurodegeneration observed in patient brains. Indeed, recent LOAD genome-wide association studies (GWAS) have reported multiple loci near genes related to microglial function, including TREM2 , ABI3 , and CR1 . However, GWAS alone cannot pinpoint underlying causal variants or effector genes at such loci, as most signals reside in non-coding regions of the genome and could presumably confer their influence frequently via long-range regulatory interactions. We elected to carry out a combination of ATAC-seq and high-resolution promoter-focused Capture-C in two human microglial cell models (iPSC-derived microglia and HMC3) in order to physically map interactions between LOAD GWAS-implicated candidate causal variants and their corresponding putative effector genes. Notably, we observed consistent evidence that rs6024870 at the GWAS CASS4 locus contacted the promoter of nearby gene, RTFDC1 . We subsequently observed a directionallly consistent decrease in RTFDC1 expression with the the protective minor A allele of rs6024870 via both luciferase assays in HMC3 cells and expression studies in primary human microglia. Through CRISPR-Cas9-mediated deletion of the putative regulatory region harboring rs6024870 in HMC3 cells, we observed increased pro-inflammatory cytokine secretion and decreased DNA double strand break repair related, at least in part, to RTFDC1 expression levels. Our variant-to-function approach therefore reveals that the rs6024870-harboring regulatory element at the LOAD ' CASS4' GWAS locus influences both microglial inflammatory capacity and DNA damage resolution, along with cumulative evidence implicating RTFDC1 as a novel candidate effector gene. Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
Databáze:	MEDLINE
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