Limits...
A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.

McCarthy MJ, Nievergelt CM, Kelsoe JR, Welsh DK - PLoS ONE (2012)

Bottom Line: However, no significant clock gene findings have emerged from genome-wide association studies (GWAS).Then we compared the results to a set of lithium-responsive genes.Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.

View Article: PubMed Central - PubMed

Affiliation: Veterans Affairs San Diego Healthcare System, San Diego, California, United Sates of America. mmccarthy@ucsd.edu

ABSTRACT
Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian "clock genes" associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential "core" clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.

Show MeSH

Related in: MedlinePlus

Organization of the extended clock network.The core clock oscillator is a set of ∼18 genes that encode for transcriptional regulators (middle). These proteins are organized in complex feedback loops with positive (green) and negative (red) limbs that generate the ∼24 hr rhythms in gene expression responsible for maintaining circadian rhythms. Upstream clock modulators influence the period and/or amplitude of rhythms by altering protein stability, cellular distribution, or phosphorylation of proteins within the core clock (top). Core clock transcriptional regulators generate expression rhythms in numerous downstream clock controlled genes that are not the “gears of the clock” involved in generating rhythms, but may be important effectors or “hands of the clock” (bottom).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3285204&req=5

pone-0032091-g001: Organization of the extended clock network.The core clock oscillator is a set of ∼18 genes that encode for transcriptional regulators (middle). These proteins are organized in complex feedback loops with positive (green) and negative (red) limbs that generate the ∼24 hr rhythms in gene expression responsible for maintaining circadian rhythms. Upstream clock modulators influence the period and/or amplitude of rhythms by altering protein stability, cellular distribution, or phosphorylation of proteins within the core clock (top). Core clock transcriptional regulators generate expression rhythms in numerous downstream clock controlled genes that are not the “gears of the clock” involved in generating rhythms, but may be important effectors or “hands of the clock” (bottom).

Mentions: To explore these three possibilities, we conducted a quantitative bioinformatic survey of GWAS results that employed an online repository of genetic data, allowing us to examine multiple GWAS data sets for various psychiatric phenotypes simultaneously. Using this approach, we examined the associations of clock genes with BD and three additional psychiatric conditions for which there is substantial evidence of shared clinical features, genetic overlap and/or enrichment in families of affected BD probands: MDD, SCH and ADHD [24], [37]–[42]. Since circadian rhythm abnormalities are best described in BD, we refer to this group of disorders as the “BD spectrum” of illnesses in order to establish an operational definition, but acknowledge the arbitrariness and limitations of this BD-centered scheme. We also surveyed genes whose expression is reportedly lithium-sensitive in mouse brain [5]. Clock genes were examined at three separate levels: first, 18 “core clock” genes for which an extensive literature supports a critical function in maintaining circadian rhythms; second, an extended set of 342 clock modulator genes that regulate rhythm period and amplitude, but are not involved in the central circadian oscillator; and third, clock outputs, also called clock controlled genes (Figure 1). We found that among the core clock genes there is a statistical over-representation of association with BD-spectrum illnesses in GWAS and lithium sensitive genes. CCGs that were rhythmic in multiple tissues were more likely than weakly rhythmic or non-rhythmic genes to show associations with BD-spectrum illnesses and/or to be lithium-sensitive. In contrast, clock modulator genes were illness associated and lithium responsive only at chance rates.


A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.

McCarthy MJ, Nievergelt CM, Kelsoe JR, Welsh DK - PLoS ONE (2012)

Organization of the extended clock network.The core clock oscillator is a set of ∼18 genes that encode for transcriptional regulators (middle). These proteins are organized in complex feedback loops with positive (green) and negative (red) limbs that generate the ∼24 hr rhythms in gene expression responsible for maintaining circadian rhythms. Upstream clock modulators influence the period and/or amplitude of rhythms by altering protein stability, cellular distribution, or phosphorylation of proteins within the core clock (top). Core clock transcriptional regulators generate expression rhythms in numerous downstream clock controlled genes that are not the “gears of the clock” involved in generating rhythms, but may be important effectors or “hands of the clock” (bottom).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285204&req=5

pone-0032091-g001: Organization of the extended clock network.The core clock oscillator is a set of ∼18 genes that encode for transcriptional regulators (middle). These proteins are organized in complex feedback loops with positive (green) and negative (red) limbs that generate the ∼24 hr rhythms in gene expression responsible for maintaining circadian rhythms. Upstream clock modulators influence the period and/or amplitude of rhythms by altering protein stability, cellular distribution, or phosphorylation of proteins within the core clock (top). Core clock transcriptional regulators generate expression rhythms in numerous downstream clock controlled genes that are not the “gears of the clock” involved in generating rhythms, but may be important effectors or “hands of the clock” (bottom).
Mentions: To explore these three possibilities, we conducted a quantitative bioinformatic survey of GWAS results that employed an online repository of genetic data, allowing us to examine multiple GWAS data sets for various psychiatric phenotypes simultaneously. Using this approach, we examined the associations of clock genes with BD and three additional psychiatric conditions for which there is substantial evidence of shared clinical features, genetic overlap and/or enrichment in families of affected BD probands: MDD, SCH and ADHD [24], [37]–[42]. Since circadian rhythm abnormalities are best described in BD, we refer to this group of disorders as the “BD spectrum” of illnesses in order to establish an operational definition, but acknowledge the arbitrariness and limitations of this BD-centered scheme. We also surveyed genes whose expression is reportedly lithium-sensitive in mouse brain [5]. Clock genes were examined at three separate levels: first, 18 “core clock” genes for which an extensive literature supports a critical function in maintaining circadian rhythms; second, an extended set of 342 clock modulator genes that regulate rhythm period and amplitude, but are not involved in the central circadian oscillator; and third, clock outputs, also called clock controlled genes (Figure 1). We found that among the core clock genes there is a statistical over-representation of association with BD-spectrum illnesses in GWAS and lithium sensitive genes. CCGs that were rhythmic in multiple tissues were more likely than weakly rhythmic or non-rhythmic genes to show associations with BD-spectrum illnesses and/or to be lithium-sensitive. In contrast, clock modulator genes were illness associated and lithium responsive only at chance rates.

Bottom Line: However, no significant clock gene findings have emerged from genome-wide association studies (GWAS).Then we compared the results to a set of lithium-responsive genes.Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.

View Article: PubMed Central - PubMed

Affiliation: Veterans Affairs San Diego Healthcare System, San Diego, California, United Sates of America. mmccarthy@ucsd.edu

ABSTRACT
Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian "clock genes" associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential "core" clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.

Show MeSH
Related in: MedlinePlus