Dataset Information

Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder.

ABSTRACT:

Study objectives

To screen the PER3 promoter for polymorphisms and investigate the phenotypic associations of these polymorphisms with diurnal preference, delayed sleep phase disorder/syndrome (DSPD/DSPS), and their effects on reporter gene expression.

Design

Interspecific comparison was used to define the approximate extent of the PER3 promoter as the region between the transcriptional start site and nucleotide position -874. This region was screened in DNA pools using PCR and direct sequencing, which was also used to screen DNA from individual participants. The different promoter alleles were cloned into a luciferase expression vector and a deletion library created. Promoter activation was measured by chemiluminescence.

Setting

N/A.

Patients or participants

DNA samples were obtained from volunteers with defined diurnal preference (3 x 80, selected from a pool of 1,590), and DSPD patients (n=23).

Interventions

N/A.

Measurements and results

We verified three single nucleotide polymorphisms (G -320T, C -319A, G -294A), and found a novel variable number tandem repeat (VNTR) polymorphism (-318 1/2 VNTR). The -320T and -319A alleles occurred more frequently in DSPD compared to morning (P = 0.042 for each) or evening types (P = 0.006 and 0.033). The allele combination TA2G was more prevalent in DSPD compared to morning (P 0.033) or evening types (P = 0.002). Luciferase expression driven by the TA2G combination was greater than for the more common GC2A (P < 0.05) and the rarer TA1G (P < 0.001) combinations. Deletion reporter constructs identified two enhancer regions (-703 to -605, and -283 to -80).

Conclusions

Polymorphisms in the PER3 promoter could affect its expression, leading to potential differences in the observed functions of PER3.

SUBMITTER: Archer SN

PROVIDER: S-EPMC2864885 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Publications

Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder.

Archer Simon N SN Carpen Jayshan D JD Gibson Mark M Lim Gim Hui GH Johnston Jonathan D JD Skene Debra J DJ von Schantz Malcolm M

Sleep 20100501 5

<h4>Study objectives</h4>To screen the PER3 promoter for polymorphisms and investigate the phenotypic associations of these polymorphisms with diurnal preference, delayed sleep phase disorder/syndrome (DSPD/DSPS), and their effects on reporter gene expression.<h4>Design</h4>Interspecific comparison was used to define the approximate extent of the PER3 promoter as the region between the transcriptional start site and nucleotide position -874. This region was screened in DNA pools using PCR and di ...[more]

PMID: 20469812

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Project description:ImportanceMorning diurnal preference is associated with reduced risk of major depressive disorder (MDD); however, causality in this association is uncertain.ObjectiveTo examine the association of genetically proxied morning diurnal preference with depression risk using mendelian randomization.Design, setting, and participantsThis 2-sample mendelian randomization study used summary-level genetic associations with diurnal preference and MDD. Up to 340 genetic loci associated with diurnal preference in a meta-analysis of the UK Biobank and 23andMe cohorts were considered as genetic proxies for diurnal preference. The effect size of these variants was scaled using genetic associations with accelerometer-based measurement of sleep midpoint. Genetic associations with MDD were obtained from a meta-analysis of genome-wide association studies data from the Psychiatric Genomics Consortium and UK Biobank. The inverse-variance weighted method was used to estimate the association of genetically proxied morning diurnal preference, corresponding to a 1-hour earlier sleep midpoint, with MDD risk.ExposuresMorning diurnal preference scaled to a 1-hour earlier, objectively measured sleep midpoint.Main outcomes and measuresRisk of MDD, including self-reported and clinically diagnosed cases, as ascertained in meta-analyses of genome-wide association studies.ResultsA total of 697 828 individuals (all of European ancestry) were in the UK Biobank and 23andMe cohorts; 85 502 in the UK Biobank had measurements of the sleep midpoint. A further 170 756 individuals with MDD and 329 443 control participants (all of European ancestry) were in the Psychiatric Genomics Consortium and UK Biobank data. Genetically proxied earlier diurnal preference was associated with a 23% lower risk of depression (odds ratio [OR] per 1-hour earlier sleep midpoint, 0.77 [95% CI, 0.63-0.94]; P = .01). This association was similar when restricting analysis to individuals with MDD as stringently defined by the Psychiatric Genomics Consortium (OR, 0.73 [95% CI, 0.54-1.00]; P = .05) but not statistically significant when defined by hospital-based billing codes in the UK Biobank (OR, 0.64 [95% CI, 0.39-1.06]; P = .08). Sensitivity analyses examining potential bias due to pleiotropy or reverse causality showed similar findings (eg, intercept [SE], 0.00 [0.001]; P = .66 by Egger intercept test).Conclusions and relevanceThe results of this mendelian randomization study support a protective association of earlier diurnal preference with risk of MDD and provide estimates contextualized to an objective sleep timing measure. Further investigation in the form of randomized clinical trials may be warranted.

Dataset Information

Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder.

Study objectives

Design

Setting

Patients or participants

Interventions

Measurements and results

Conclusions

Publications

Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder.

Similar Datasets

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