title: Associations between period 3 gene polymorphisms and sleep- /chronotype-related variables in patients with late-life insomnia.
abstract: A variable number tandem repeat polymorphism (VNTR) in the period 3 (PER3) gene has been associated with heritable sleep and circadian variables, including self-rated chronotypes, polysomnographic (PSG) variables, insomnia and circadian sleep-wake disorders. This report describes novel molecular and clinical analyses of PER3 VNTR polymorphisms to better define their functional consequences. As the PER3 VNTR is located in the exonic (protein coding) region of PER3, we initially investigated whether both alleles (variants) are transcribed into messenger RNA in human fibroblasts. The VNTR showed bi-allelic gene expression. We next investigated genetic associations in relation to clinical variables in 274 older adult Caucasian individuals. Independent variables included genotypes for the PER3 VNTR as well as a representative set of single nucleotide polymorphisms (SNPs) that tag common variants at the PER3 locus (linkage disequilibrium (LD) between genetic variants < 0.5). In order to comprehensively evaluate variables analyzed individually in prior analyses, dependent measures included PSG total sleep time and sleep latency, self-rated chronotype, estimated with the Composite Scale (CS), and lifestyle regularity, estimated using the social rhythm metric (SRM). Initially, genetic polymorphisms were individually analyzed in relation to each outcome variable using analysis of variance (ANOVA). Nominally significant associations were further tested using regression analyses that incorporated individual ANOVA-associated DNA variants as potential predictors and each of the selected sleep/circadian variables as outcomes. The covariates included age, gender, body mass index and an index of medical co-morbidity. Significant genetic associations with the VNTR were not detected with the sleep or circadian variables. Nominally significant associations were detected between SNP rs1012477 and CS scores (p = 0.003) and between rs10462021 and SRM (p = 0.047); rs11579477 and average delta power (p = 0.043) (analyses uncorrected for multiple comparisons). In conclusion, alleles of the VNTR are expressed at the transcript level and may have a functional effect in cells expressing the PER3 gene. PER3 polymorphisms had a modest impact on selected sleep/circadian variables in our sample, suggesting that PER3 is associated with sleep and circadian function beyond VNTR polymorphisms. Further replicate analyses in larger, independent samples are recommended.
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Hader A
authors.initials: HA
authors.lastname: Mansour
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Wood
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Kodavali V
authors.initials: KV
authors.lastname: Chowdari
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Tumuluru
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Mikhil
authors.initials: M
authors.lastname: Bamne
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Monk
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Martica H
authors.initials: MH
authors.lastname: Hall
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Buysse
authors.affiliation: a Department of Psychiatry , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.|b Department of Human Genetics, Graduate School of Public Health , University of Pittsburgh , Pittsburgh , PA , USA.
authors.forename: Vishwajit L
authors.initials: VL
authors.lastname: Nimgaonkar
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004247:DNA / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005840:Gentian Violet; D006801:Humans; D008297:Male; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012890:Sleep; D007319:Sleep Initiation and Maintenance Disorders / Q000235:genetics*
chemical_list: C512644:PER3 protein, human; D056950:Period Circadian Proteins; D004247:DNA; D005840:Gentian Violet
keywords: Association; PER3; circadian; genetic; insomnia; period3; sleep