Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration ( p < 5 × 10 −8 ; 43 loci at p < 6 × 10 −9 ). Replication is observed for PAX8 , VRK2 , and FBXL12/UBL5/PIN1 loci in the CHARGE study ( n = 47,180; p < 6.3 × 10 −4 ), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis ( n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.
102Sleep is an essential homeostatically-regulated state of decreased activity and alertness 103 conserved across animal species, and both short and long sleep duration associate with 104 chronic disease and all-cause mortality 1,2 . Defining genetic contributions to sleep 105 duration could point to regulatory mechanisms and clarify causal disease relationships. 106Through genome-wide association analyses in 446,118 participants of European 107 ancestry from the UK Biobank, we discover 78 loci for self-reported sleep duration that 108 further impact accelerometer-derived measures of sleep duration, daytime inactivity 109 duration, sleep efficiency and number of sleep bouts in a subgroup (n=85,499) with up 110 to 7-day accelerometry. Associations are enriched for genes expressed in several brain 111 regions, and for pathways including striatum and subpallium development, 112 mechanosensory response, dopamine binding, synaptic neurotransmission, 113 catecholamine production, synaptic plasticity, and unsaturated fatty acid 114 metabolism. Genetic correlation analysis indicates shared biological links between sleep 115 duration and psychiatric, cognitive, anthropometric and metabolic traits and Mendelian 116 randomization highlights a causal link of longer sleep with schizophrenia. 117 118 Research in model organisms (reviewed in 3,4 ) has delineated aspects of the neural-119 circuitry of sleep-wake regulation 5 and molecular components including specific 120 neurotransmitter and neuropeptide systems, intracellular signaling molecules, ion 121 channels, circadian clock genes and metabolic and immune factors 4 , but their specific 122 roles and relevance to human sleep regulation are largely unknown. Prospective 123 epidemiologic studies suggest that both short (<6,7 hours per night) and long (>8,9 124 hours per night) habitual self-reported sleep duration associate with cognitive and 125 psychiatric, metabolic, cardiovascular, and immunological dysfunction as well as all-126 cause mortality compared to sleeping 7-8 hours per night 6-12 . Furthermore, chronic 127 sleep deprivation in modern society may lead to increased errors and accidents 13 . Yet, 128 whether short or long habitual sleep duration causally contributes to disease initiation or 129 progression remains to be established. 130 131 Habitual self-reported sleep duration is a complex trait with an established genetic 132 component (twin-and family-based heritability (h 2 ) estimates =9-45% 14-20 ). Candidate 133 gene sequencing in pedigrees and functional validation of rare, missense variants 134 established BHLHE41 (previously DEC2), a repressor of CLOCK/ARNTL activity, as a 135 causal gene 21,22 , supporting the role of the circadian clock in sleep regulation. Previous 136 genome-wide association studies (GWAS) in up to 128,286 individuals identified 137 association of common variants at or near the PAX8 and VRK2 genes 20,23,24 . 138 139Here, we extend GWAS of self-reported sleep duration in UK Biobank to discover 78 140 loci, test for consistency of eff...
Average arterial oxyhemoglobin saturation during sleep (AvSpO 2 S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth wholegenome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, 1,2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO 2 S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p ¼ 7.9 3 10 À7 ). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO 2 S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO 2 S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO 2 S.Arterial oxyhemoglobin saturation (SpO 2 ) reflects the adequacy of ventilation and oxygen transport, fundamental physiological properties that are tightly regulated at molecular and cellular levels to ensure delivery of oxygen to vital tissues. Reductions in oxyhemoglobin saturation lead to increased rates of mortality and cognitive decline. 3 Given its clinical relevance, oxygen saturation is commonly monitored in patients with pulmonary, cardiac, and sleep
Short sleep duration has been linked to negative health effects, but is a complex phenotype with many contributing factors, including genetic. We evaluated 27 common single nucleotide polymorphisms (SNPs) in candidate genes previously reported to be associated with other sleep variables for association with self-reported habitual sleep duration in the UK Biobank in 111 975 individuals of European ancestry. Genetic variation in DAT1 (rs464049) was significantly associated with sleep duration after correction for multiple testing (p = 4.00 × 10 −5 ), whereas SNPs correlated to a previously studied variable number tandem repeat (VNTR) in DAT1 were not significant in this population. We also replicated a previously reported association in DRD2. Independent replication of these associations and a second signal in DRD2 (rs11214607) was observed in an additional 261 870 participants of European ancestry from the UK Biobank. Meta-analysis confirmed genome-wide significant association of DAT1 rs464049 (G, beta [standard error, SE] = −0.96 [0.18] minutes/allele, p = 5.71 × 10 −10 ) and studywide significant association of DRD2 (rs17601612, C, beta [SE] = −0.66 [0.18] minutes/allele, p = 1.77 × 10 −5 ; rs11214607, C, beta [SE] = 1.08 (0.24) minutes/allele, p = 1.39 × 10 −6 ). Overall, SNPs in two dopamine-related genes were significantly associated with sleep duration, highlighting the important link of the dopamine system with adult sleep duration in humans.
In humans, the gallbladder normally lies, at least partially, within the gallbladder fossa, a depression located on the visceral surface of the liver, between the right anatomical lobe of the liver and the quadrate liver lobe. During routine cadaveric dissections, we noted that livers from cadavers without gallbladders appeared to have less distinct gallbladder fossae than did livers where gallbladders were present. The purpose of the present study was to test the hypothesis that the volume of the gallbladder fossa is greater in livers when a gallbladder is present than in livers without gallbladders. To test this hypothesis, livers with their associated gallbladder were removed from cadavers and the visceral surface of each sample was observed to determine whether or not a gallbladder was present. After photographing all livers and removing gallbladders, if present, the volume of the irregularly‐shaped gallbladder fossa was determined from a mold of the fossa. To make this mold, an insulating foam sealant (Dow, Midland, MI, USA) was instilled into the area of the fossa. After foam expansion was complete, the material was trimmed flush with the surrounding liver parenchyma. This mold then was removed from the fossa and allowed to air‐dry. The volume of the gallbladder fossa was calculated by dividing the weight of the mold by the density of the foam material. Additionally, the dimensions of each fossa were estimated using an electronic digital caliper (VWR, Radnor, PA, USA) to measure the largest distance for the depth, length, and width of each mold. Statistical analyses were performed using R. Comparison of group means utilized Welch’s t‐test and the Pearson product‐moment correlation coefficient was used for correlation analyses. Livers were obtained from 34 cadavers (19 females, 15 males) with a mean age of 84.1 ± 10.8 yrs (range of 60–105 yrs). There were 8 cadavers without gallbladders (6 females, 2 males, mean age of 83.9 ± 6.6 yrs), and 26 cadavers with gallbladders (13 females, 13 males, mean age of 84.2 ± 11.9 yrs). The mean volume of gallbladder fossae from livers with gallbladders (31.01 ± 17.82 ml) was significantly greater than fossae in livers without gallbladders (8.75 ± 4.72 ml) (p=2.3 e‐06). All three measurements taken of the fossae molds (depth, length, and width) were significantly larger in the “with gallbladder livers” (p<0.05), with the largest percent difference being between the depth of the fossae – mean depth of the fossae mold from livers with a gallbladder was 20.69 ± 6.17 mm versus fossae without gallbladders having a mean depth of 7.60 ± 2.57 mm (p=1.77e‐09). When comparing the volume of fossae to the depth, length, and width of the molds, the correlation was strongest between the volume and the depth of the fossae (r=0.838, p=6.1e‐10). In conclusion, the mean volume of the gallbladder fossa was significantly greater for livers in which a gallbladder was present than in livers lacking gallbladders, with the greatest relative change in the fossae dimensions, after gallbladder remova...
The gallbladder normally lies within a fossa on the visceral surface of the liver. The primary purpose of this study was to determine whether the volume of this fossa was reduced after cholecystectomy. Livers were obtained from embalmed cadavers of 19 females and 15 males with a mean age of 84.1 ± 10.8 yrs. The presence of a gallbladder was assessed, the volume of the irregularly-shaped gallbladder fossa determined from a mold of the fossa, and the dimensions of each fossa were estimated. The mean volume of gallbladder fossae from livers with gallbladders (n = 26; 13 females and 13 males) was 31.01 ± 17.82 ml, which was significantly greater than fossae in livers without gallbladders (n = 8, 6 females, 2 males) which was 8.75 ± 4.72 ml (P<0.0001). This difference still was significant after correcting fossa volume for overall liver weight and length of the femur. Livers with gallbladders had significantly larger dimensions (depth, length, and width) of their fossae molds than did livers without gallbladders (P<0.05). The largest percentage difference between the two groups in these dimensions was in the fossae depth, and there was a significant, positive correlation between all three of these dimensions and the overall volume of the fossae. Even looking only at female livers which tend to be smaller, gallbladder fossa volume was reduced in livers without a gallbladder. Thus, the present study demonstrated that the mean gallbladder fossa volume was significantly decreased in livers lacking gallbladders, even after correcting for the liver weight and size of the individual. While the mechanisms behind these changes in fossa volume currently are unknown, alterations in mechanical pressure relayed to adjacent liver cells after gallbladder removal may play a role in these fossa volume differences.
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