Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Cedric Howald
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Maria Gutierrez-Arcelus
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland
Emilie Falconnet
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland
Christelle Borel
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland
Dieter Kunz
Institute of Physiology, Charité-Universitätsmedizin Berlin, Working Group Sleep Research & Clinical Chronobiology, Berlin, Germany
Achim Kramer
Charité–Universitätsmedizin, Laboratory of Chronobiology, Berlin, Germany
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
Emmanouil T Dermitzakis
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland
Stylianos E Antonarakis
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland
The importance of natural gene expression variation for human behavior is undisputed, but its impact on circadian physiology remains mostly unexplored. Using umbilical cord fibroblasts, we have determined by genome-wide association how common genetic variation impacts upon cellular circadian function. Gene set enrichment points to differences in protein catabolism as one major source of clock variation in humans. The two most significant alleles regulated expression of COPS7B, a subunit of the COP9 signalosome. We further show that the signalosome complex is imported into the nucleus in timed fashion to stabilize the essential circadian protein BMAL1, a novel mechanism to oppose its proteasome-mediated degradation. Thus, circadian clock properties depend in part upon a genetically-encoded competition between stabilizing and destabilizing forces, and genetic alterations in these mechanisms provide one explanation for human chronotype.
