Association between circadian genes, bipolar disorders and chronotypes.

Area of Science:

• Neurogenetics
• Chronobiology
• Psychiatric Genetics

Background:

• Circadian rhythm abnormalities are implicated in bipolar disorder (BD) pathogenesis.
• Previous genetic studies on circadian genes and BD susceptibility have yielded inconsistent results.
• The behavioral consequences of genetic risk variants for BD remain poorly understood, lacking correlation with phenotypic biomarkers like chronotypes.

Purpose of the Study:

• To identify specific circadian gene variants associated with bipolar disorder (BD).
• To investigate the correlation between identified genetic variants and observable circadian phenotypes in BD patients.
• To elucidate the role of circadian gene variants in BD susceptibility and phenotypic expression.

Main Methods:

• Meta-analysis of allele frequencies for 353 single nucleotide polymorphisms (SNPs) across 21 circadian genes in two independent BD and control samples.
• Utilized a "reverse phenotyping approach" to correlate specific SNPs with circadian phenotypes in a subsample of patients and controls.
• Statistical analysis included logistic regression for association studies and correlation analysis for genotype-phenotype relationships.

Main Results:

• A significant association was found between the TIMELESS gene variant rs774045 and BD susceptibility (OR=1.49, p=0.0008).
• The RORA gene variant rs782931 was also significantly associated with BD susceptibility (OR=1.31, p=0.0006).
• rs774045 correlated with eveningness and a languid circadian type, while rs782931 associated with a rigid circadian type.

Conclusions:

• Variants in the TIMELESS and RORA genes may contribute to susceptibility to bipolar disorder (BD).
• These identified genetic variants are associated with specific circadian phenotypes, including chronotype and rhythm rigidity.
• Individuals carrying these variants may have a reduced capacity to adapt to external environmental cues, potentially influencing BD pathophysiology.