Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC-1α) and RORA.
Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR-related orphan receptor-a gene (RORA) and the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC-1α) were significantly associated with the Li response (empirical P-value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P-value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev-erb-alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response.
Inserm U1144, Paris, F-75006, France. pierre.a.geoffroy@gmail.com.|Université Paris Descartes, UMR-S 1144, Paris, F-75006, France. pierre.a.geoffroy@gmail.com.|Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1144, Paris, F-75013, France. pierre.a.geoffroy@gmail.com.|Pôle de Psychiatrie et de Médecine Addictologique, AP-HP, GH Saint-Louis, Lariboisière, F. Widal, 75475 Paris cedex 10, France. pierre.a.geoffroy@gmail.com.|Fondation FondaMental, Créteil, France. pierre.a.geoffroy@gmail.com.
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Geoffroy
Inserm U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S 1144, Paris, F-75006, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1144, Paris, F-75013, France.|Pôle de Psychiatrie et de Médecine Addictologique, AP-HP, GH Saint-Louis, Lariboisière, F. Widal, 75475 Paris cedex 10, France.|Fondation FondaMental, Créteil, France.
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0000-0002-5377-1488
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Etain
Inserm U955, Psychiatrie Translationnelle, Créteil, France.
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Lajnef
Inserm U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S 1144, Paris, F-75006, France.|AP-HP, Pôle de Psychiatrie, groupe hospitalier Henri Mondor, Créteil, France.
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Zerdazi
Inserm U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S 1144, Paris, F-75006, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1144, Paris, F-75013, France.|Pôle de Psychiatrie et de Médecine Addictologique, AP-HP, GH Saint-Louis, Lariboisière, F. Widal, 75475 Paris cedex 10, France.
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Brichant-Petitjean
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University, Munich, Germany.
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Heilbronner
Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
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Hou
Institute of Human Genetics, University of Bonn, Bonn, Germany.
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Degenhardt
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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Rietschel
Human Genetics Branch, NIMH Intramural Research Program, National Institutes of Health, and, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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McMahon
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University, Munich, Germany.|Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.|Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Göttingen, Germany.
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Schulze
Fondation FondaMental, Créteil, France.|Inserm U955, Psychiatrie Translationnelle, Créteil, France.|Université Paris Est, Faculté de Médecine, Créteil, France.
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Jamain
Inserm U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S 1144, Paris, F-75006, France.
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Marie-Claire
Inserm U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S 1144, Paris, F-75006, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1144, Paris, F-75013, France.|Pôle de Psychiatrie et de Médecine Addictologique, AP-HP, GH Saint-Louis, Lariboisière, F. Widal, 75475 Paris cedex 10, France.|Fondation FondaMental, Créteil, France.
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Bellivier
D000328:Adult; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D018020:Lithium Compounds / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics
D006360:Heat-Shock Proteins; D018020:Lithium Compounds; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C539738:RORA protein, human; D014157:Transcription Factors
Bipolar disorder; circadian genes; circadian rhythms; clock genes; lithium carbonate; lithium salts