title: Preservation Analysis of Macrophage Gene Coexpression Between Human and Mouse Identifies PARK2 as a Genetically Controlled Master Regulator of Oxidative Phosphorylation in Humans.
abstract: Macrophages are key players involved in numerous pathophysiological pathways and an in-depth characterization of their gene regulatory networks can help in better understanding how their dysfunction may impact on human diseases. We here conducted a cross-species network analysis of macrophage gene expression data between human and mouse to identify conserved networks across both species, and assessed whether such networks could reveal new disease-associated regulatory mechanisms. From a sample of 684 individuals processed for genome-wide macrophage gene expression profiling, we identified 27 groups of coexpressed genes (modules). Six modules were found preserved (P < 10-4) in macrophages from 86 mice of the Hybrid Mouse Diversity Panel. One of these modules was significantly [false discovery rate (FDR) = 8.9 × 10-11] enriched for genes belonging to the oxidative phosphorylation (OXPHOS) pathway. This pathway was also found significantly (FDR < 10-4) enriched in susceptibility genes for Alzheimer, Parkinson, and Huntington diseases. We further conducted an expression quantitative trait loci analysis to identify SNP that could regulate macrophage OXPHOS gene expression in humans. This analysis identified the PARK2 rs192804963 as a trans-acting variant influencing (minimal P-value = 4.3 × 10-8) the expression of most OXPHOS genes in humans. Further experimental work demonstrated that PARK2 knockdown expression was associated with increased OXPHOS gene expression in THP1 human macrophages. This work provided strong new evidence that PARK2 participates to the regulatory networks associated with oxidative phosphorylation and suggested that PARK2 genetic variations could act as a trans regulator of OXPHOS gene macrophage expression in humans.
authors: Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1166, F-75013 Paris, France Institute for Cardiometabolism and Nutrition, F-75013 Paris, France.
authors: Veronica
authors: V
authors: Codoni
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
authors: Yuna
authors: Y
authors: Blum
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095 Department of Biomedical Engineering, Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908.
authors: Mete
authors: M
authors: Civelek
authors: Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1166, F-75013 Paris, France Institute for Cardiometabolism and Nutrition, F-75013 Paris, France.
authors: Carole
authors: C
authors: Proust
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029 Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors: Oscar
authors: O
authors: Franzén
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029 Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 141 52, Sweden.
authors: Johan L M
authors: JL
authors: Björkegren
authors: Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1166, F-75013 Paris, France Institute for Cardiometabolism and Nutrition, F-75013 Paris, France.
authors: Wilfried
authors: W
authors: Le Goff
authors: Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1166, F-75013 Paris, France Institute for Cardiometabolism and Nutrition, F-75013 Paris, France.
authors: Francois
authors: F
authors: Cambien
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
authors: Aldons J
authors: AJ
authors: Lusis
authors: Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1166, F-75013 Paris, France Institute for Cardiometabolism and Nutrition, F-75013 Paris, France david.tregouet@upmc.fr.
authors: David-Alexandre
authors: DA
authors: Trégouët
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010085:Oxidative Phosphorylation; D040641:Quantitative Trait Loci; D013045:Species Specificity; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D057188:Workflow
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: cross-species comparison; eQTL analysis; gene expression network analysis; macrophages; trans genetic effects