Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man.

Scott EM, Carter AM, Grant PJ. Int J Obes. 2008 Apr;32(4):658-62.

A study assessed the association between SNPs in the clock gene and metabolic syndrome. The 537 subjects from the United Kingdom were recruited via the Leeds Family Health Authority register. The cohort provided blood samples that were used for genotyping and analysis of several measures of metabolic syndrome (as defined by the International Diabetes Federation), including fasting insulin, glucose, cholesterol and triglyceride concentrations.

The authors found haplotypes of clock SNPs (rs4864548-rs3736544-rs1801260) that are associated with metabolic syndrome. The CGC haplotype was found to be protective against metabolic syndrome, whereas the CAT haplotype was overrepresented in subjects with the disorder. Looking at individual markers of metabolic syndrome, the CGC haplotype was associated with lower waist and hip circumference, lower BMI and reduced plasma leptin concentrations.

The SNPs on clock

clock rs4864548-rs3736544-rs1801260

NCBI Variation Viewer rs4864548-rs3736544-rs1801260

A Period 2 genetic variant interacts with plasma SFA to modify plasma lipid concentrations in adults with metabolic syndrome.

Garcia-Rios A, Perez-Martinez P, Delgado-Lista J, Phillips CM, Gjelstad IM, Wright JW, Karlström B, Kiec-Wilk B, van Hees AM, Helal O, Polus A, Defoort C, Riserus U, Blaak EE, Lovegrove JA, Drevon CA, Roche HM, Lopez-Miranda J. J Nutr. 2012 Jul;142(7):1213-8

To assess genetic determinants of metabolic syndrome, this study investigated the association between common SNPs in per2 and plasma lipid metabolism in participants from the European LIPGENE study. The subjects were volunteers with metabolic syndrome recruited from eight European countries via general practitioner databases and advertisements. Subjects had their blood taken for lipid biomarker measurements and for SNP genotyping.

In patients with a high plasma saturated fatty acid (SFA) concentration, the minor allele for rs2304672 in the per2 gene was associated with increased concentrations of fasting plasma triglycerides, triglyceride-rich lipoprotein, apoC-II, apoC-III, and apoB-48 compared to those with the major CC allele. Conversely, carriers of the minor rs2304672 allele with low SFA concentrations had lower plasma concentrations of fasting triglycerides, cholesterol, triglyceride-rich lipoprotein, apoC-II, apoC-III, apoB, and apoB-48 compared to those with the major allele, thus demonstrating an interaction between per2 and lipid metabolism.

rs2304672 in per2

per2 rs2304672

NCBI Variation Viewer rs2304672

Gene-gene interaction between serotonin transporter (SLC6A4) and CLOCK modulates the risk of metabolic syndrome in rotating shiftworkers.

Sookoian S, Gianotti TF, Burgueño A, Pirola CJ. Chronobiol Int. 2010 Jul;27(6):1202-18.

A cross-sectional study of 856 Argentinian factory workers was performed to determine whether mutations in the serotonin-transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4), combined with the presence of clock gene SNPs, had an effect on several markers of metabolic syndrome.

They found that the homozygous rs1554483G–rs4864548A clock haplotype and 5-HTTLPR mutations together were associated with higher systolic and diastolic blood pressure as well as increased plasma triglyceride concentrations in rotating shift workers. Conversely, in day workers with both mutations, these outcomes were decreased. A similar epistatic finding was found with the heterozygous rs1554483G–rs4864548A clock haplotype and diastolic blood pressure.

rs1554483G–rs4864548A in clock

clock rs1554483G–rs4864548A

NCBI Variation Viewer  rs1554483G–rs4864548A

Positional Cloning of the Mouse Circadian Clock Gene

King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, Steeves TD, Vitaterna MH, Kornhauser JM, Lowrey PL, Turek FW, Takahashi JS. Cell. 1997;89(4):641-53.

Genetic mapping and sequencing in mice confirmed the identification of the mammalian gene, clock, involved in the circadian system. A comparison of the nucleotide sequence of the wildtype gene with the previously described Clock mutant revealed a single nucleotide change, an A-T transversion in intron 19. This SNP results in the deletion of exon 19 in the clock gene and a 51 amino acid deletion in the CLOCK protein.

The authors also found widespread expression of clock within several murine tissues and conserved clock gene sequences in other organisms, demonstrating the important function of this gene within the circadian system.

Mutagenesis and Mapping of a Mouse Gene, Clock, Essential for Circadian Behaviour

Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS. Science. 1994;264(5159):719-25.

Using the mutagenic agent, N-ethyl-N-nitrosourea, a mutated lineage of mice was generated with an inheritable phenotype of altered circadian rhythmicity. Wildtype mice maintained normal circadian rhythms in constant darkness with a period of 23.3 – 24 hours, whereas mice heterozygous for the mutation showed a lengthening of the circadian period to approximately 24.4 hours in constant darkness. Homozygous mutant offspring showed the greatest change in circadian phenotype, with an endogenous period of 26-29 hours in the initial weeks under constant dark conditions, after which the animals became arrhythmic.

This genetic mutation was mapped to the midportion of mouse chromosome 5, identifying the novel circadian gene, clock, a key factor regulating the circadian clock system.

SIRT1 gene, schizophrenia and bipolar disorder in the Japanese population: an association study.

Kishi T, Fukuo Y, Kitajima T, Okochi T, Yamanouchi Y, Kinoshita Y, Kawashima K, Inada T, Kunugi H, Kato T, Yoshikawa T, Ujike H, Ozaki N, Iwata N. Genes Brain Behav. 2011 Apr; 10 (3) : 257-63.

Expanding on the previous literature implicating the circadian system in the pathopsychology of bipolar disorder, a genetic association study of 1158 Japanese schizophrenia patients, 730 patients with bipolar I disorder, 278 patients with bipolar II disorderand 2127 controls found a potential association between a sirt1 SNP (rs4746720) and schizophrenia (diagnosis based on psychiatrist assessed DSM-IV criteria). However, after the authors corrected for multiple comparisons via the Bonferroni correction, this association was no longer significant, implying that it may have been a false positive. 

Additionally, a haplotype analysis was performed, in which the authors discovered an association between several haplotypes and psychiatric illness. The T-T-T-T haplotype for the rs12778366rs2273773rs4746720rs10997875 sirt1 SNPs was associated with risk of schizophrenia and the T-T-C-T haplotype was protective against schizophrenia when compared to controls. Both of these associations were still significant after adjusting for multiple comparisons.

rs4746720 in sirt1

sirt1 rs4746720

NCBI Variation Viewer rs4746720

Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder–data from an association study of suicide attempts with clock genes.

Pawlak J, Dmitrzak-Weglarz M, Maciukiewicz M, Wilkosc M, Leszczynska-Rodziewicz A, Zaremba D, Kapelski P, Hauser J. Psychiatry Res. 2015 Apr 30;226(2-3):517-20.

In order to explain the circadian rhythm present in suicide attempts, the authors investigated the relationships between SNPs in circadian genes and suicidal behaviour. A study of 863 bipolar patients from Poland determined that several SNPs on the clock (rs3805148 and rs534654) and timeless (rs11171856 and rs2291739) genes are associated with age of first attempt, violent suicide attempts, multiple suicide attempts, and a family history of suicide as determined by the Structured Clinical Interview for DSM-IV Axis I Disorders.

The SNPs in clock

clock rs3805148-rs534654

NCBI Variation Viewer rs3805148-rs534654

The SNPs in timeless

timeless rs11171856-rs2291739

NCBI Variation Viewer rs11171856-rs2291739

Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder

Lai YC, Kao CF, Lu ML, Chen HC, Chen PY, Chen CH, Shen WW, Wu JY, Lu RB, Kuo PH. PLoS One. 2015 Mar 19;10(3):e0121245.

To investigate the relationship between circadian genetics and disease, the authors performed two studies consisting of 2698 members of the Chinese Han population. It was determined that several SNPs in reverb-α, ror-α and ror-β are associated with bipolar disorder, as determined by the Composite International Diagnostic Interview. After multiple comparison corrections, only rs4774388 in ror-α and rs1327836 in ror-β were still significantly associated with the disorder.

rs4774388 in ror-α

ror-a rs4774388

NCBI Variation Viewer rs4774388

rs1327836 in ror-β

ror-b rs1327836

NCBI Variation Viewer rs1327836

Circadian polymorphisms associated with affective disorders

Kripke DF, Nievergelt CM, Joo E, Shekhtman T, Kelsoe JR. J Circadian Rhythms. 2009 Jan 23;7:2.

To determine the meditatory effect of circadian rhythms in mood disorders, the authors performed a study involving 444 Canadian and American families. 198 SNPs were assessed for relationships with bipolar disorder and chronotype preferences (as measured by a questionnaire for major depression, bipolar disorder, and psychosis and the Basic Language Morningness Scale respectively).

The results indicated that a C/T SNP in the rev-erb-α gene (rs2314339) is associated with bipolar disorder. Additionally, the per3 SNP rs228697 was found to be associated with eveningness and a csnk1e SNP with morning preference.

rs2314339 in rev-erb-α

reverba rs2314339

NCBI Variation Viewer rs2314339

rs228697 in per3

per3 rs228697

NCBI Variation Viewer rs228697

PER2 variation is associated with depression vulnerability

Lavebratt C, Sjöholm LK, Partonen T, Schalling M, Forsell Y. Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):570-81.

This study sampled 1847 people recruited from the Swedish national registry to determine the role of genetics in depression. The authors found significant associations between several individual SNPs in per2 (rs6431590, rs3739064, rs10462023, rs2304672), npas2 (rs1374324), ror-α (rs2028122) and depression. The authors found that these SNPs were overrepresented (rs6431590, rs3739064, rs2304672) or underrepresented (rs10462023, rs1374324, rs2028122) in individuals with depression than in those who were mentally resilient. Additionally, an additive protective correlation was found in a set of per2 SNPs (rs934945–rs6431590–rs3739064; haplotype CTA). When individuals with depression were compared to a control population the authors found that those with depression were more likely to have the rs2290036 SNP in bmal1 and less likely to have the ror-α SNP rs2028122.

The authors also assessed whether the previous associations were still significant after controlling for negative life events or financial strain in the previous year. The results showed that rs10462023 in per2 and rs1374324 in npas2 were still more likely to be found in people with depression than in mentally resilient individuals. Additionally, those with the rs2028122 SNP in ror-α were overrepresented in the depression cases compared to all other subjects, but only when controlling for financial strain.

SNPs in per2

per2 rs934945–rs6431590–rs3739064-rs10462023-rs2304672

NCBI Variation Viewer rs934945rs6431590rs3739064-rs10462023-rs2304672

rs2028122 in rora

ror-a rs2028122

NCBI Variation Viewer rs2028122

rs1374324 in npas2

npas2 rs1374324

NCBI Variation Viewer rs1374324

rs2290036 in bmal1

bmal1 rs2290036

NCBI Variation Viewer rs2290036