title: Systems Genetics Analysis to Identify the Genetic Modulation of a Glaucoma-Associated Gene.
abstract: Loss of retinal ganglion cells (RGCs) is one of the hallmarks of retinal neurodegenerative diseases, glaucoma being one of the most common. Recently, γ-synuclein (SNCG) was shown to be highly expressed in the somas and axons of RGCs. In various mouse models of glaucoma, downregulation of Sncg gene expression correlates with RGC loss. To investigate the regulation of Sncg in RGCs, we used a systems genetics approach to identify a gene that modulates the expression of Sncg, followed by confirmatory studies in both healthy and diseased retinas. We found that chromosome 1 harbors an eQTL that modulates the expression of Sncg in the mouse retina and identified Pfdn2 as the candidate upstream modulator of Sncg expression. Downregulation of Pfdn2 in enriched RGCs causes a concomitant reduction in Sncg. In this chapter, we describe our strategy and methods for identifying and confirming a genetic modulation of a glaucoma-associated gene. A similar method can be applied to other genes expressed in other tissues.
authors.affiliation: Department of Anatomy and Neurobiology, Hamilton Eye Institute, The University of Tennessee Health Science Center, 930 Madison Ave., Suite 710, Memphis, TN, 38163, USA.
authors.forename: Sumana R
authors.initials: SR
authors.lastname: Chintalapudi
authors.affiliation: Department of Ophthalmology, Hamilton Eye Institute, The University of Tennessee Health Science Center, 930 Madison Ave., Suite 710, Memphis, TN, 38163, USA. mjanlonski@uthsc.edu.|Department of Anatomy and Neurobiology, Hamilton Eye Institute, The University of Tennessee Health Science Center, 930 Madison Ave., Suite 710, Memphis, TN, 38163, USA. mjanlonski@uthsc.edu.|Department of Pharmaceutical Sciences, Hamilton Eye Institute, The University of Tennessee Health Science Center, 930 Madison Ave., Suite 710, Memphis, TN, 38163, USA. mjanlonski@uthsc.edu.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Jablonski
mesh_terms: D000818:Animals; D015415:Biomarkers; D001947:Breeding; D002874:Chromosome Mapping; D016208:Databases, Factual; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D005901:Glaucoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015203:Reproducibility of Results; D012160:Retina / Q000166:cytology / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: Eye; Flow cytometry; PFDN2; Primary retinal ganglion cells; Retinal neurodegenerative diseases SNCG; Systems genetics; Use case; eQTL; siRNA transfection