Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC-1α) and RORA

Genes Brain Behav. 2016 Sep;15(7):660-8. doi: 10.1111/gbb.12306. Epub 2016 Aug 2.

Abstract

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.

Keywords: Bipolar disorder; circadian genes; circadian rhythms; clock genes; lithium carbonate; lithium salts.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / genetics*
  • Bipolar Disorder / metabolism
  • Circadian Rhythm / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heat-Shock Proteins / genetics
  • Humans
  • Lithium Compounds / therapeutic use*
  • Male
  • Middle Aged
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics*
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Polymorphism, Single Nucleotide
  • Transcription Factors / genetics

Substances

  • Heat-Shock Proteins
  • Lithium Compounds
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RORA protein, human
  • Transcription Factors