Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.
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ABSTRACT:
SUBMITTER: Dashti HS
PROVIDER: S-EPMC6405943 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.
Dashti Hassan S HS Jones Samuel E SE Wood Andrew R AR Lane Jacqueline M JM van Hees Vincent T VT Wang Heming H Rhodes Jessica A JA Song Yanwei Y Patel Krunal K Anderson Simon G SG Beaumont Robin N RN Bechtold David A DA Bowden Jack J Cade Brian E BE Garaulet Marta M Kyle Simon D SD Little Max A MA Loudon Andrew S AS Luik Annemarie I AI Scheer Frank A J L FAJL Spiegelhalder Kai K Tyrrell Jessica J Gottlieb Daniel J DJ Tiemeier Henning H Ray David W DW Purcell Shaun M SM Frayling Timothy M TM Redline Susan S Lawlor Deborah A DA Rutter Martin K MK Weedon Michael N MN Saxena Richa R
Nature communications 20190307 1
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<sup>-8</sup>; 43 loci at p < 6 × 10<sup>-9</sup>). Replication is observed for PAX8, VRK2, and FBXL12/UBL5/PIN1 loci in the CHARGE study (n = 47,180; p < 6.3 × 10<sup>-4</sup>), and 55 signals show ...[more]
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Project description: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.
| S-EPMC4975467 | biostudies-literature
Project description:Self-reported short or long sleep duration has been associated with adverse cardiometabolic health outcomes in laboratory and epidemiologic studies, but interpretation of such data has been limited by methodologic issues.Adult respondents of the 2007-2008 US National Health and Nutrition Examination Survey (NHANES) were examined in a cross-sectional analysis (N=5649). Self-reported sleep duration was categorized as very short (<5 h), short (5-6 h), normal (7-8 h), or long (?9 h). Obesity, diabetes mellitus (DM), hypertension, and hyperlipidemia were objectively assessed by self-reported history. Statistical analyses included univariate comparisons across sleep duration categories for all variables. Binary logistic regression analyses and cardiometabolic factor as outcome, with sleep duration category as predictor, were assessed with and without covariates. Observed relationships were further assessed for dependence on race/ethnicity.In adjusted analyses, very short sleep was associated with self-reported hypertension (odds ratio [OR], 2.02, [95% confidence interval {CI},1.45-2.81]; P<0.0001), self-reported hyperlipidemia (OR, 1.96 [95% CI, 1.43-2.69]; P<0.0001), objective hyperlipidemia (OR, 1.41 [95% CI, 1.04-1.91]; P=0.03), self-reported DM (OR, 1.76 [95% CI, 1.13-2.74]; P=0.01), and objective obesity (OR, 1.53 [95% CI, 1.03-1.43]; P=0.005). Regarding short sleep (5-6 h), in adjusted analyses, elevated risk was seen for self-reported hypertension (OR, 1.22 [95% CI, 1.02-1.45]; P=0.03) self-reported obesity (OR, 1.21 [95% CI, 1.03-1.43]; P=0.02), and objective obesity (OR, 1.17 [95% CI, 1.00-1.38]; P<0.05). Regarding long sleep (?9 h), no elevated risk was found for any outcomes. Interactions with race/ethnicity were significant for all outcomes; race/ethnicity differences in patterns of risk varied by outcome studied. In particular, the relationship between very short sleep and obesity was strongest among blacks and the relationship between short sleep and hypertension is strongest among non-Hispanic whites, blacks, and non-Mexican Hispanics/Latinos.Short sleep duration is associated with self-reported and objectively determined adverse cardiometabolic outcomes, even after adjustment for many covariates. Also, these patterns of risk depend on race/ethnicity.
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Project description:Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~?15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p?=?1.5?×?10-4) and sedentary behaviours (18 vs. 15%, p?=?9.7?×?10-4). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: -0.91, SE?=?0.18, p?=?8.2?×?10-7), and odds of hypertension (Odds ratio/SD: 0.84, SE?=?0.03, p?=?4.9?×?10-8). Our results advocate the value of physical activity for reducing blood pressure.
| S-EPMC6288145 | biostudies-literature
Project description:Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~ 15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p = 1.5 × 10-4) and sedentary behaviours (18 vs. 15%, p = 9.7 × 10-4). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: -0.91, SE = 0.18, p = 8.2 × 10-7), and odds of hypertension (Odds ratio/SD: 0.84, SE = 0.03, p = 4.9 × 10-8). Our results advocate the value of physical activity for reducing blood pressure.
| S-EPMC6288145 | biostudies-literature
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Project description:Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
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Project description:Study objectivesThe current study sought to determine whether sleep duration and change in sleep duration are associated with all-cause mortality in a community sample of middle-aged and older adults while accounting for several confounding factors including prevalent sleep-disordered breathing (SDB).MethodsHabitual sleep duration was assessed using self-report (< 7, 7-8, ? 9 h/night) at the baseline and at the follow-up visits of the Sleep Heart Health Study. Techniques of survival analysis were used to relate habitual sleep duration and change in sleep duration to all-cause mortality after adjusting for covariates such as age, sex, race, body mass index, smoking history, prevalent hypertension, diabetes, cardiovascular disease, antidepressant medication use, and SDB severity.ResultsCompared to a sleep duration of 7-8 h/night, habitually long sleep duration (? 9 h/night), but not short sleep duration (< 7 h/night), was associated with all-cause mortality with an adjusted hazards ratio of 1.25 (95% confidence interval [CI]: 1.05, 1.47). Participants who progressed from short or normal sleep duration to long sleep duration had increased risk for all-cause mortality with adjusted hazard ratios of 1.75 (95% CI: 1.08, 2.78) and 1.63 (95% CI: 1.26, 2.13), respectively. Finally, a change from long to short sleep duration was also associated with all-cause mortality.ConclusionLong sleep duration or a shift from long to short sleep duration are independently associated with all-cause mortality.
| S-EPMC5070744 | biostudies-literature
Project description:BackgroundChronic inadequate sleep and frequent daytime napping may inflict deleterious health effects including weight gain, cardiometabolic and psychiatric diseases, and cancer. It is plausible that these relations may be partly influenced by the consumption of suboptimal diets.ObjectivesThe study aimed to identify potential causal links of genetically proxied longer habitual sleep duration and more frequent daytime napping on 61 dietary variables derived from an FFQ. In addition, the study aimed to assess potential bidirectional causal links between habitual sleep duration or daytime napping and macronutrient composition.MethodsGenetic variants robustly associated with habitual sleep duration and daytime napping from published genome-wide association analyses were used. Outcomes included 61 dietary variables estimated from FFQs in the UK Biobank (n = 361,194). For bidirectional associations with macronutrient composition, genetic variants associated with percentage of energy from carbohydrate, fat, and protein were used. Two-sample Mendelian randomization (MR) effects were estimated with inverse-variance weighted (IVW) analysis.ResultsIn 2-sample MR, genetically proxied longer sleep duration was associated with a 0.068 (95% CI: 0.034, 0.103) category increase in salad/raw vegetable intake [P false discovery rate (FDR) = 0.006] per hour of sleep and with "no major dietary changes in the past 5 years" (P FDR = 0.043). No associations were evident for daytime napping on dietary variables (all P FDR > 0.05). In addition, there were no bidirectional associations between habitual sleep duration or daytime napping with the relative intake of carbohydrate, fat, and protein (all P IVW > 0.05).ConclusionsIn this MR study, there was modest evidence for associations between habitual sleep duration with dietary intake and no evidence for associations between daytime napping frequency with dietary intake. These preliminary findings suggest that changes to habitual sleep duration or daytime napping frequency may have limited impact on long-term changes in dietary intake.
| S-EPMC8171253 | biostudies-literature
Project description: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 study-wide 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.
| S-EPMC6335867 | biostudies-literature