Yun Joong Kim1,2,3, Junbeom Jeon4, Jaemoon Shin4, Nan Young Kim3, Jeong Hoon Hong1, Jae-Min Oh1, SangKyoon Hong3, Yeo Jin Kim5, Young-Eun Kim2, Suk Yun Kang6, Hyeo-Il Ma2, Unjoo Lee7, Jeehee Yoon4. 1. ILSONG Institute of Life Science, Hallym University, Anyang, Korea. 2. Department of Neurology, Hallym University Sacred Heart hospital, Hallym University College of Medicine, Hallym University, Anyang, Korea. 3. Hallym Institute of Translational Genomics & Bioinformatics, Hallym University Medical Center, Anyang, Korea. 4. Department of Computer Engineering, Hallym University, Chuncheon, Korea. 5. Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Hallym University, Chuncheon, Korea. 6. Department of Neurology, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hallym University, Dongtan, Korea. 7. Department of Electronic Engineering, Hallym University, Chuncheon, Korea.
Abstract
BACKGROUND AND OBJECTIVES: Many hereditary movement disorders with complex phenotypes without a locus symbol prefix for familial PD present as parkinsonism; however, the dysregulation of genes associated with these phenotypes in the SNpc of PD patients has not been systematically studied. METHODS: Gene set enrichment analyses were performed using 10 previously published genome-wide expression datasets obtained by laser-captured microdissection of pigmented neurons in the SNpc. A custom-curated gene set for hereditary parkinsonism consisting of causative genes (n = 78) related to disorders with a parkinsonism phenotype, but not necessarily idiopathic or monogenic PD, was constructed from the Online Mendelian Inheritance in Man database. RESULTS: In 9 of the 10 gene expression data sets, gene set enrichment analysis showed that the disease-causing genes for hereditary parkinsonism were downregulated in the SNpc in PD patients compared to controls (nominal P values <0.05 in five studies). Among the 63 leading edge subset genes representing downregulated genes in PD, 79.4% were genes without a locus symbol prefix for familial PD. A meta-gene set enrichment analysis performed with a random-effect model showed an association between the gene set for hereditary parkinsonism and PD with a negative normalized enrichment score value (-1.40; 95% CI: -1.52∼-1.28; P < 6.2E-05). CONCLUSION: Disease-causing genes with a parkinsonism phenotype are downregulated in the SNpc in PD. Our study highlights the importance of genes associated with hereditary movement disorders with parkinsonism in understanding the pathogenesis of PD.
BACKGROUND AND OBJECTIVES: Many hereditary movement disorders with complex phenotypes without a locus symbol prefix for familial PD present as parkinsonism; however, the dysregulation of genes associated with these phenotypes in the SNpc of PDpatients has not been systematically studied. METHODS: Gene set enrichment analyses were performed using 10 previously published genome-wide expression datasets obtained by laser-captured microdissection of pigmented neurons in the SNpc. A custom-curated gene set for hereditary parkinsonism consisting of causative genes (n = 78) related to disorders with a parkinsonism phenotype, but not necessarily idiopathic or monogenic PD, was constructed from the Online Mendelian Inheritance in Man database. RESULTS: In 9 of the 10 gene expression data sets, gene set enrichment analysis showed that the disease-causing genes for hereditary parkinsonism were downregulated in the SNpc in PDpatients compared to controls (nominal P values <0.05 in five studies). Among the 63 leading edge subset genes representing downregulated genes in PD, 79.4% were genes without a locus symbol prefix for familial PD. A meta-gene set enrichment analysis performed with a random-effect model showed an association between the gene set for hereditary parkinsonism and PD with a negative normalized enrichment score value (-1.40; 95% CI: -1.52∼-1.28; P < 6.2E-05). CONCLUSION: Disease-causing genes with a parkinsonism phenotype are downregulated in the SNpc in PD. Our study highlights the importance of genes associated with hereditary movement disorders with parkinsonism in understanding the pathogenesis of PD.