Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.

Summary:Purpose: Defining prognostic factors for neocortical epilepsy surgery is important for the identification of ideal candidates and for predicting the prognosis of individual patients. We use multivariate analysis to identify favorable prognostic factors for neocortical epilepsy surgery.Methods: One hundred ninety-three neocortical epilepsy patients, including 91 without focal lesions on MRI, were included. Sixty-one had frontal lobe epilepsy (FLE), 80 had neocortical temporal lobe epilepsy (nTLE), 21 had parietal lobe epilepsy (PLE), and 22 had occipital lobe epilepsy (OLE). The primary outcome variable was patient status ≥2 years after surgery (i.e., seizure free or not). Clinical characteristics and the recent presurgical diagnostic modalities were considered as probable prognostic factors. Univariate and standard multiple logistic regression analyses were used to identify favorable prognostic factors. Results:The seizure-free rate was 57.5%. By univariate analysis, a focal lesion on MRI, localized ictal onset on surface EEG, epilepsies other than FLE, localized hypometabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET), and pathologies other than cortical dysplasia were significantly associated with a seizure-free outcome (p < 0.05). Multivariate analysis revealed that a focal lesion on MRI (p = 0.003), correct localization by FDG-PET (p = 0.007), and localized ictal onset on EEG (p = 0.01) were independent predictors of a good outcome.Conclusions: The presence of a focal lesion on MRI, correct localized hypometabolism on FDG-PET, or localized ictal rhythms on EEG were identified as predictors of a seizure-free outcome. Our results suggest that these findings allow the selection of better candidates for neocortical epilepsy surgery.

Background and PurposeaaInsomnia is a common complaint in adults. However, large epidemiologic studies of insomnia involving Asian populations are rarely reported. We performed an epidemiologic study of insomnia in a large Korean adult population.MethodsaaA total of 5,000 subjects (2,470 men and 2,530 women) were interviewed by telephone. A representative sample of subjects aged 20 to 69 years was constituted according to a stratified, multistage random sampling method. Insomnia was defined as either any difficulty getting to sleep or getting back to sleep after waking in the night.ResultsaaMore than one fifth (n=1,141, 22.8%) of the 5,000 subjects complained of insomnia, with the prevalence being significantly higher in women (25.3%) than in men (20.2%, p<0.001). Logistic regression revealed that the prevalence of insomnia increased significantly with age (p<0.001), being higher in those aged 60-69 years than in those aged 20-29 years (OR=2.368, 95% CI=1.762-3.182, p<0.001), and was lower in those with a monthly income of >4.5 million Korean won than in those with an income of <1.5 million Korean won (OR=0.689, 95% CI= 0. 523-0.906, p<0.01).

Background and PurposeEndothelial impairment is a linking mechanism between obstructive sleep apnea (OSA) and cardiovascular diseases. Profiles of endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) reflect the degree of endothelial impairment. The aims of this study were to measure the levels of EMPs and progenitor cells in OSA, determine the correlations between these factors and OSA severity and the degree of atherosclerosis, and document any changes in these factors after therapy.MethodsSubjects with (n=82) and without (n=22) OSA were recruited prospectively. We measured the number of colony-forming units (CFU) in cell culture as the endothelial progenitor cell index, and the number of EMPs using flow cytometry with CD31 [platelet endothelial cell adhesion molecule (PECAM)], CD42 (platelet glycoprotein), annexin V, and CD62E (E-selectin) antibodies at baseline and after 4-6 weeks of continuous positive airway pressure (CPAP) therapy. Carotid intima-media thickness (IMT) was regarded as a marker of atherosclerosis.ResultsThe levels of PECAM+CD42- (p<0.001), PECAM+annexin V+ (p<0.001), and E-selectin+ microparticles (p=0.001) were higher in OSA subjects than in non-OSA subjects. The number of CFU did not differ between the two groups. OSA severity independently predicted the levels of PECAM+CD42- (p=0.02) and PECAM+annexin V+ (p=0.004). Carotid IMT was correlated with OSA severity (p<0.001), PECAM+CD42- (p=0.03), and PECAM+annexin V+ (p=0.01). Neither OSA severity nor carotid IMT was correlated with either the number of CFU or E-selectin+. CPAP therapy decreased the occurrence of E-selectin+ (p<0.001) in 21 of the OSA subjects, but had no effect on the other microparticles of the number of CFU.ConclusionsOSA led to the overproduction of EMPs, which moderately correlated with OSA severity and the degree of atherosclerosis, and partly responded to therapy. The endothelial impairment might contribute to future cardiovascular events.