Gender differences in association between expiratory dynamic airway collapse and severity of obstructive sleep apnea.

OBJECTIVES: Repetitive unbalances and tensions generated by inspiratory efforts against an obstructive upper airway during sleep predispose the development of expiratory central airway collapse. In addition, structures of the upper airway between men and women have differences and could be the reasons for differences in obstructive sleep apnea (OSA) prevalence between genders. The present study aimed to evaluate the association between parameters of expiratory dynamic tracheal collapse measured using chest multidetector CT and objectively measured OSA severity between men and women. MATERIALS AND METHODS: A total of 901 participants who underwent chest CT and overnight in-home polysomnography from the Korean Genome and Epidemiology Study were cross-sectionally analyzed (women: 46.2%). The participants were divided into three groups based on OSA severity by apnea-hypopnea index (AHI). Multivariate linear regression analysis was performed to determine the effects of central airway collapse after adjustment for cardiovascular-related covariates. RESULTS: In a multivariate analysis, percentages of expiratory lumen structure reductions involving area, diameter, and perimeter were associated with AHI (all p values < 0.05) and with OSA severity (moderate-to-severe OSA than no OSA: ß = 3.30%, p = 0.03; ß = 2.05%, p = 0.02; ß = 1.97%, p = 0.02, respectively) in women, whereas men had only a greater percentage of expiratory wall thickness reduction in moderate-to-severe OSA than no OSA (ß = 0.72%, p = 0.003). In addition, women with both mild OSA and moderate-to-severe OSA had higher expiratory tracheal collapse than men without OSA, and a moderate effect of sex was observed (p for interaction = 0.007). CONCLUSION: The expiratory dynamic tracheal collapse was independently associated with severity of OSA in women than in men. CLINICAL RELEVANCE STATEMENT: Differences of pharyngeal structures and inherent features of airways by genders may affect the dissimilarities in vulnerability to sleep apnea between men and women. KEY POINTS: • The expiratory dynamic tracheal collapse was independently associated with severity of OSA in women than in men. • Women with over mild OSA had higher expiratory tracheal collapse than men without OSA, and moderate effect of sex was observed. • Structural differences of airway may affect differences in susceptibility of sleep apnea between genders.

Association of long-term hyperglycaemia and insulin resistance with brain atrophy and cognitive decline: A longitudinal cohort study.

AIM: To investigate the longitudinal changes in brain volume and cognitive function associated with diabetes at midlife, and to examine whether long-term hyperglycaemia, insulin resistance or secretory function is associated with brain atrophy and cognitive decline. MATERIALS AND METHODS: We used data from 2377 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. Time-weighted mean glycaemic values were calculated using all measurements over an average duration of 10.6 years from cohort initiation to baseline visits. RESULTS: Type 2 diabetes was associated with greater white matter volume reduction (adjusted volume difference = -1.96 ml, 95% CI: -3.73, -0.18) and executive function decline (adjusted Z score difference = -0.14, 95% CI: -0.23, -0.05) during the follow-up period of 4.2 years. Decline of verbal and visual memory or verbal fluency was not associated with diabetes. Greater executive function decline was associated with higher time-weighted mean HbA1c level over the preceding 10.6 years (P < .001), but not with insulin resistance markers in the diabetes group. Participants with diabetes, whose time-weighted average HbA1c level was maintained above 6.5% over the previous decade, showed greater decline in executive function and global cognition than the normal glucose group. CONCLUSIONS: Long-term hyperglycaemia was a major independent factor associated with rapid cognitive decline in middle-aged adults with diabetes. Maintaining ideal glucose levels in diabetes at midlife might prevent later rapid cognitive decline.

Factors Affecting the Complication Rate of Septoplasty: Analysis of 1,506 Consecutive Cases of Single Surgeon.

Based on the analysis of a single surgeon's consecutive cases, we present the incidence of septoplasty complications and factors that contribute to the increased risk of complications. We retrospectively reviewed the medical records from 1,506 patients diagnosed with deviated nasal septum who underwent septoplasty by a single surgeon from January 2003 until May 2020. The incidence of different complications was investigated. Predisposing factors for specific complications were examined with univariate analysis. The average age of patients was 35 (11-76) years. Out of 1,506 patients, 1,252 were male, and 254 were female. The most frequent complication was insufficient correction (78 cases, 5.2%), and revision septoplasty was performed in 21 cases. We also reported 59 (3.9%), 55 (3.7%), 33 (2.2%), 20 (1.3%), and 18 (1.2%) cases of olfactory dysfunction, hematoma, synechia, abscess, and septal mucosal defect, respectively. Additionally, there were nine (0.6%), six (0.4%), five (0.3%), four (0.3%), and four (0.3%) cases of septal perforation, postoperative bleeding, saddle nose, chondritis, empty nose syndrome, respectively. The proportion of insufficient correction was higher in revision cases than in primary cases. Hematoma formation, abscess formation, and septal mucosal defect occurred more frequently in the bilateral flap elevation group. Olfactory dysfunction was significantly more frequent when the bony batten was inserted, while hematoma, abscess formation, and septal mucosal defect were more frequent when the cartilage batten was used. Septoplasty was associated with the risk of several complications, while complication rates were influenced by choice of surgical techniques and approaches.

Sleep Duration, Sleep Apnea, and Gray Matter Volume.

This study aimed to evaluate the effect of sleep duration on brain structures in the presence versus absence of sleep apnea in middle-aged and older individuals. The study investigated a population-based sample of 2,560 individuals, aged 49-80 years. The presence of sleep apnea and self-reported sleep duration were examined in relation to gray matter volume (GMV) in total and lobar brain regions. We identified ranges of sleep duration associated with maximal GMV using quadratic regression and bootstrap sampling. A significant quadratic association between sleep duration and GMV was observed in total and lobar brain regions of men with sleep apnea. In the fully adjusted model, optimal sleep durations associated with peak GMV between brain regions ranged from 6.7 to 7.0 hours. Shorter and longer sleep durations were associated with lower GMV in total and 4 sub-regions of the brain in men with sleep apnea.

Association of pericardial adipose tissue with left ventricular structure and function: a region-specific effect?

BACKGROUND: The independent role of pericardial adipose tissue (PAT) as an ectopic fat associated with cardiovascular disease (CVD) remains controversial. This study aimed to determine whether PAT is associated with left ventricular (LV) structure and function independent of other markers of general obesity. METHODS: We studied 2471 participants (50.9 % women) without known CVD from the Korean Genome Epidemiology Study, who underwent 2D-echocardiography with tissue Doppler imaging (TDI) and computed tomography measurement for PAT. RESULTS: Study participants with more PAT were more likely to be men and had higher cardiometabolic indices, including blood pressure, glucose, and cholesterol levels (all P < 0.001). Greater pericardial fat levels across quartiles of PAT were associated with increased LV mass index and left atrial volume index (all P < 0.001) and decreased systolic (P = 0.015) and early diastolic (P < 0.001) TDI velocities, except for LV ejection fraction. These associations remained after a multivariable-adjusted model for traditional CV risk factors and persisted even after additional adjustment for general adiposity measures, such as waist circumference and body mass index. PAT was also the only obesity index independently associated with systolic TDI velocity (P < 0.001). CONCLUSIONS: PAT was associated with subclinical LV structural and functional deterioration, and these associations were independent of and stronger than with general and abdominal obesity measures.

Sleep structure and electroencephalographic spectral power of middle-aged or older adults: Normative values by age and sex in the Korean population.

The fine structure of sleep electrocortical activity reflects health and disease. The current study provides normative data for sleep structure and electroencephalography (EEG) spectral power measures derived from overnight polysomnography (PSG) and examines the effect of age and sex among Korean middle-aged and older adults with or without obstructive sleep apnea (OSA). We analysed home PSG data from 1,153 adult participants of an ongoing population-based cohort study, the Korean Genome and Epidemiology Study. Sleep stages were visually scored and spectral power was measured on a single-channel EEG (C4-A1). We computed spectral power for five frequency ranges. The EEG power was reported in relative (%) and log-transformed absolute values (µV2 ). With ageing, the proportion of N1 sleep increased, whereas N3 decreased, which is more noticeable in men than in women. The amount of N3 was relatively low in this cohort. With ageing, relative delta power decreased and alpha and sigma power increased for the whole sleep period, which was more pronounced during REM sleep in non-OSA. For men compared with women, relative theta power was lower during REM and sigma and beta were higher during N1 sleep. The differences of relative powers by age and sex in OSA were comparable to those in non-OSA. In a community-based Korean population, we present normative data of sleep structure and spectral power for middle-aged or older adults of a non-Caucasian ethnicity. The values varied with age and sex and were not influenced by sleep apnea.

Obesity and muscle may have synergic effect more than independent effects on brain volume in community-based elderly.

OBJECTIVE: To evaluate the individual and combined effects of obesity and muscle mass on brain volume in a community-dwelling healthy older population. METHODS: One thousand two hundred nine participants (M:F = 574:635, mean age 63.6 ± 6.9 years) were included. The cross-sectional area of visceral fat (VF), the height-adjusted appendicular skeletal muscle mass (ASM/height2), and the ratio of thigh muscle to visceral fat (TM/VF) represented obesity, muscle mass, and their integrated value, respectively. Linear regression analysis was performed to establish associations between 215 brain compartment volumes and VF, ASM/height2, and TM/VF after adjusting for covariates. RESULTS: On regression analysis, TM/VF had a positive correlation to the volumes of temporal lobe and cerebellum. TM/VF was associated with volumes of 10 subcompartments. TM/VF was positively correlated with the volumes of left entorhinal cortex, right temporal pole and inferior temporal gyrus related to cognition (p < 0.05, respectively), and the volumes of cerebellum and right pallidum related to movement (p < 0.05, respectively). However, VF had a negative correlation to temporal lobe volume and ASM/height2 had no significant correlation to any of the brain lobes. VF and ASM/height2 were correlated with volumes of 5 subcompartments and one subcompartment, respectively, CONCLUSIONS: TM/VF reflects the integrated effect of obesity and muscle mass and is associated with the volume of more brain regions compared to indices of obesity or muscle mass alone. The positive effect of muscle mass and the negative effect of obesity change the volumes of brain regions related to cognition and movement which were not significantly affected by obesity or muscle mass alone. KEY POINTS: • If obesity and muscle mass were considered together, we could find more significant brain volume changes which were not found in obesity or muscle alone. • The ratio of thigh muscle to visceral fat was positively correlated with the volumes of entorhinal cortex, temporal pole, and inferior temporal gyrus related to cognition. • The ratio of thigh muscle to visceral fat was positively correlated with the volumes of cerebellum and pallidum related to movement.

Paravertebral Muscles as Indexes of Sarcopenia and Sarcopenic Obesity: Comparison With Imaging and Muscle Function Indexes and Impact on Cardiovascular and Metabolic Disorders.

OBJECTIVE. The objectives of this study were to propose the use of the cross-sectional area of paravertebral muscle (PMA) and the ratio of the PMA to the cross-sectional area of visceral fat (PVR) as new indexes of sarcopenia or sarcopenic obesity through comparison with existing indexes and to show the clinical associations of PMA and PVR with hypertension and diabetes. SUBJECTS AND METHODS. A total of 1270 participants (608 men and 662 women; mean [± SD] age, 63.57 ± 6.94 years) were recruited from a community-based population of elderly individuals. PMA and PVR were measured on single-slice abdominal CT images. Pearson correlation was used to evaluate the correlation of PMA and PVR with widely used imaging and muscle function indexes of sarcopenia and sarcopenic obesity. Tertile categories of PMA and PVR were evaluated to investigate associations with risks for hypertension and diabetes in men and women, by use of separate multivariable logistic regression models. RESULTS. PMA was correlated with the cross-sectional area of thigh muscle on CT, appendicular skeletal muscle mass (ASM) on dual-energy x-ray absorptiometry, height-adjusted ASM (calculated as ASM divided by the height in meters squared), and body mass index (BMI)-adjusted ASM (calculated as ASM divided by BMI) (p < .01). PMA was also correlated with hand grip strength and gait speeds (p < .01). PVR was correlated with height-adjusted ASM and BMI-adjusted ASM (p < .01). A high PVR significantly decreased the odds ratios for hypertension and diabetes in the unadjusted model and the model adjusted for age, smoking, and drinking status. The ratio of the cross-sectional area of thigh muscle to the cross-sectional area of visceral fat and the BMI-adjusted ASM produced results similar to those of PVR in terms of the odds ratios for hypertension and diabetes. CONCLUSION. Single-slice abdominal CT can supply PMA and visceral fat information together. PMA and PVR were found to be reliable indexes of sarcopenia and sarcopenic obesity. A high PVR was associated with low risks for hypertension and diabetes.

Sarcopenia is associated with decreased gray matter volume in the parietal lobe: a longitudinal cohort study.

BACKGROUND: Substantial evidence supports an association between physical activity and cognitive function. However, the role of muscle mass and function in brain structural changes is not well known. This study investigated whether sarcopenia, defined as low muscle mass and strength, accelerates brain volume atrophy. METHODS: A total of 1284 participants with sarcopenic measurements and baseline and 4-year follow-up brain magnetic resonance images were recruited from the Korean Genome and Epidemiology Study. Muscle mass was represented as appendicular skeletal muscle mass divided by the body mass index. Muscle function was measured by handgrip strength. The low mass and strength groups were defined as being in the lowest quintile of each variable for one's sex. Sarcopenia was defined as being in the lowest quintile for both muscle mass and handgrip strength. RESULTS: Of the 1284 participants, 12·6%, 10·8%, and 5·4% were classified as the low mass, low strength, and sarcopenia groups, respectively. The adjusted mean changes of gray matter (GM) volume during 4-year follow-up period were - 9·6 mL in the control group, whereas - 11·6 mL in the other three groups (P < 0·001). The significantly greater atrophy in parietal GM was observed in the sarcopenia group compared with the control group. In a joint regression model, low muscle mass, but not muscle strength, was an independent factor associated with a decrease of GM volume. CONCLUSIONS: Sarcopenia is associated with parietal GM volume atrophy, in a middle-aged population. Maintaining good levels of muscle mass could be important for brain health in later adulthood.

Postoperative results of ventilation tube insertion: a retrospective multicenter study for suggestion of grading system of otitis media with effusion.

BACKGROUND: In otitis media with effusion (OME), it is important to know when to surgically intervene and when careful monitoring is more appropriate. This study aimed to visualize and classify the clinical manifestations of OME and the correlation between the new grading system and postoperative results after ventilation tube insertion (VTI). METHODS: We classified the collective 1,012 ears from 506 patients into six groups: grade 0 (no effusion), grade I (scant effusion, but abnormal), grade II (effusion less than half of the tympanic cavity), grade III (effusion over half of the tympanic cavity, with air bubbles), grade IV (complete effusion), and grade V (retracted tympanic membrane or hemotympanum without air bubbles). RESULTS: The mean age at VTI was 5.2 (±2.9) years and mean duration between diagnosis and operation was 4.1 (±1.8) months. Between the grades, the nature of the middle ear effusion was also significantly different (p < 0.001). The duration of ventilation tube retention after VTI was significantly different when compared between two groups: grade I-IV and grade V (p = 0.019). Our results showed that the recurrence rate, as well as rate of revision VTI, increased as the grade increased (p < 0.001). CONCLUSIONS: The new grading system of OME using endoscopic otoscope evaluation had a significant correlation with the age at VTI, the nature of middle ear effusion, the recurrence rate of OME, and the rate of revision VTI.

Relationship of obstructive sleep apnoea severity and subclinical systemic atherosclerosis.

Obstructive sleep apnoea (OSA) is a common form of sleep disordered breathing. Untreated OSA might accelerate atherosclerosis, potentially increasing the cardiovascular disease burden in patients. The present study aimed to evaluate the association between objectively measured OSA severity and the presence of subclinical systemic atherosclerosis using noninvasive measurements, including tomographic quantification of the calcium burden.A total of 2157 participants of the Korean Genome and Epidemiology Study, who were free of structural heart disease and underwent both in-home polysomnography and chest computed tomography, were cross-sectionally analysed. Participants were divided into three groups based on the severity of OSA: no OSA (apnoea-hypopnoea index (AHI) <5 events·h-1, n=1096), mild OSA (AHI 5- <15 events·h-1, n=700) and moderate-to-severe OSA (AHI ≥15 events·h-1, n=361). Calcium deposits in the thoracic aorta and coronary arteries were measured by the Agatston score.Participants with moderate-to-severe OSA were 1.6 times (95% CI 1.18-2.15 times; p=0.002) more likely to have ascending thoracic aorta calcification (≥100 units) than those without OSA, after adjustment for cardiovascular risk factors. In addition, the association between moderate-to-severe OSA and ascending thoracic aorta calcification of subjects with higher epicardial fat volume was slightly stronger than that in patients without OSA and in the lowest epicardial fat volume tertile (OR 2.11, 95% CI 1.30-3.43).Severity of OSA in the general population was independently associated with subclinical systemic atherosclerosis. These findings highlight the potential importance of severe OSA, especially in subjects with higher epicardial fat, as a possible predictive factor for systemic atherosclerosis and cardiovascular disease.

Neck Circumference and Cerebral Gray Matter Volume.

BACKGROUND: While obesity is linked with brain atrophy and dementia incidence, associations with regional adiposity are uncertain. Our goal was to determine whether cerebral gray matter volume is related to neck circumference (NC), a measure of regional adiposity having unique relationships with metabolic disorders and cardiovascular disease. METHODS: Magnetic resonance imaging and NC were cross-sectionally assessed from 2011 to 2014 in a population-based sample of 2916 men and women in the Korean Genome and Epidemiology Study. RESULTS: For men, NC was inversely associated with total and regional gray matter in the frontal, temporal, and occipital lobes after adjusting for age and intracranial brain volume. Associations were especially strong in the presence of diabetes. With further adjustment for indices of body composition and other characteristics, total and frontal gray matter in diabetic men were lowered by 6.1 mL (95% confidence interval: 2.5-9.7, P=0.004) and 2.9 mL (95% confidence interval: 1.0-4.9, P=0.017), respectively, per SD increase in NC (2.3 cm). For men without diabetes, and in all women, associations were less apparent. CONCLUSIONS: In men with diabetes, NC was inversely associated with cerebral gray matter volume. The link between neck anthropometry and brain aging in diabetic men warrants further consideration.

Prevalence and Characteristics of Restless Legs Syndrome in Korean Adults: A Study in Two Independent Samples of the General Population.

BACKGROUND: Restless legs syndrome (RLS) is a common sleep disorder, although it has a low prevalence in Asian populations. However, the reported RLS prevalence in -Korean adults is mostly 4.5-12.1%, which is higher than that reported in other Asian populations. This study aimed to diagnose RLS and exclude mimicking conditions in 2 independent samples of Korean adults, and to compare its prevalence to that from previous studies performed in Asian countries. METHODS: Study populations included a (1) nationwide stratified random sample (n = 2,824; age 19-79 years) and (2) community-based cohort (n = 2,685; age 47-79 years). We applied the Cambridge-Hopkins diagnostic questionnaire to diagnose RLS and differentiate it from RLS mimics. Sleep-related symptoms, mood, and medical conditions were compared between the RLS and non-RLS groups. Prior studies of the RLS prevalence in Asia were systematically reviewed and compared to our findings. RESULTS: The adjusted RLS prevalence was 0.4 and 1.3% in populations 1 and 2, respectively. In both populations, subjects with RLS had more depression. The prevalence of RLS mimics was 5.1 and 2.6%, in populations 1 and 2, respectively. The RLS prevalence in Asia was higher when RLS was defined by the presence of essential clinical features and lower when a differential diagnosis was additionally implemented. CONCLUSIONS: The RLS prevalence in Korean adults considering RLS mimics is comparable to that in adults from other Asian countries (< 2%). The reported RLS prevalence varies depending on the diagnostic method employed.

Increased risk for new-onset hypertension in midlife male snorers: The 14-year follow-up study.

While the association between sleep-related breathing disorders such as snoring and hypertension has been well established, it still remains unclear whether the association differs by age and gender. Therefore, in this 14-year follow-up study, we examined the independent association between self-reported snoring and the incidence of hypertension by gender and age groups in a large cohort of Korean adults. A total of 4,954 adults, aged 40-69 years, free of hypertension at baseline were enrolled. Participants were divided into three groups based on a self-reported snoring frequency: never; occasional (snoring <4 nights per week); and habitual snorer (snoring ≥4 nights). At baseline and biennial follow-up visits, blood pressure was measured by trained examiners. Incident hypertension was defined as the first occurrence at any follow-up examination where the participants had blood pressure ≥140/90 mmHg or were being treated with antihypertensive medication. After adjusting for known cardiovascular risk factors, only in men aged ≤45 years was habitual snoring significantly associated with a 1.5 times higher risk for incident hypertension than never snoring. In this age group, habitual snoring was significantly associated with increased risk for the development of hypertension, regardless of the presence of excessive daytime sleepiness. In women, snoring was not significantly associated with hypertension incidence in any age group. The present study suggests that young male snorers may be at high risk for the future development of hypertension, which has important clinical implications for early detection and treatment of snoring to reduce the burden of cardiovascular disease.

Changes in Brain Volume Associated With Vegetable Intake in a General Population.

Objective: Although brain atrophy is a natural process of healthy aging, diet may play a role in delaying the process across age. We sought to investigate how food groups associate brain region-specific volume changes over 4 years in a general population. Methods: We obtained data from the Korean Genome and Epidemiology Study on 848 community-dwelling individuals. The participants completed a dietary examination using a food frequency questionnaire between 2005 and 2006 to determine habitual usual intakes of food consumption and two brain magnetic resonance imaging (MRI) scans between 2011 and 2014 and between 2015 and 2017, respectively. The 106 food items in the questionnaire were regrouped into 18 food groups. A multivariable generalized linear model was used with the adjustment of potential confounding variables. Results: The average age at baseline was 53.5 years. The average follow-up year of brain MRI was 4.13 ± 0.33 years. With considering a corrected p value due to multiple comparisons, vegetable intake indicated a statistically significant inverse association with gray matter volume change (ß = -2.28, p = 0.006), after adjusting for potential confounding variables. Particularly, the temporal region showed a significant inverse association with vegetable intake (ß= -0.63, p = 0.002). Conclusions: In a longitudinal study among 848 cognitively healthy participants from a general population, we found significant inverse associations between vegetable intake and brain gray matter volume change, particularly the change of temporal region.

Serum long-chain n-3 polyunsaturated fatty acids and aortic calcification in middle-aged men: The population-based cross-sectional ERA-JUMP study.

BACKGROUND AND AIM: Few studies have examined the association of long-chain n-3 polyunsaturated fatty acids (LCn-3PUFAs) with the measures of atherosclerosis in the general population. This study aimed to examine the relationship of total LCn-3PUFAs, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) with aortic calcification. METHODS AND RESULTS: In a multiethnic population-based cross-sectional study of 998 asymptomatic men aged 40-49 years (300 US-White, 101 US-Black, 287 Japanese American, and 310 Japanese in Japan), we examined the relationship of serum LCn-3PUFAs to aortic calcification (measured by electron-beam computed tomography and quantified using the Agatston method) using Tobit regression and ordinal logistic regression after adjusting for potential confounders. Overall 56.5% participants had an aortic calcification score (AoCaS) > 0. The means (SD) of total LCn-3PUFAs, EPA, and DHA were 5.8% (3.3%), 1.4% (1.3%), and 3.7% (2.1%), respectively. In multivariable-adjusted Tobit regression, a 1-SD increase in total LCn-3PUFAs, EPA, and DHA was associated with 29% (95% CI = 0.51, 1.00), 9% (95% CI = 0.68, 1.23), and 35% (95% CI = 0.46, 0.91) lower AoCaS, respectively. Results were similar in ordinal logistic regression analysis. There was no significant interaction between race/ethnicity and total LCn-3PUFAs, EPA or DHA on aortic calcification. CONCLUSIONS: This study showed the significant inverse association of LCn-3PUFAs with aortic calcification independent of conventional cardiovascular risk factors among men in the general population. This association appeared to be driven by DHA but not EPA.

Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci.

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.

Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

Identification of five novel genetic loci related to facial morphology by genome-wide association studies.

BACKGROUND: Face morphology is strongly determined by genetic factors. However, only a small number of genes related to face morphology have been identified to date. Here, we performed a two-stage genome-wide association study (GWAS) of 85 face morphological traits in 7569 Koreans (5643 in the discovery set and 1926 in the replication set). RESULTS: In this study, we analyzed 85 facial traits, including facial angles. After discovery GWAS, 128 single nucleotide polymorphisms (SNPs) showing an association of P < 5 × 10- 6 were selected to determine the replication of the associations, and meta-analysis of discovery GWAS and the replication analysis resulted in five genome-wide significant loci. The OSR1-WDR35 [rs7567283, G allele, beta (se) = -0.536 (0.096), P = 2.75 × 10- 8] locus was associated with the facial frontal contour; the HOXD1-MTX2 [rs970797, A allele, beta (se) = 0.015 (0.003), P = 3.97 × 10- 9] and WDR27 [rs3736712, C allele, beta (se) = 0.293 (0.048), P = 8.44 × 10- 10] loci were associated with eye shape; and the SOX9 [rs2193054, C allele, beta (se) (ln-transformed) = -0.007 (0.001), P = 6.17 × 10- 17] and DHX35 [rs2206437, A allele, beta (se) = -0.283 (0.047), P = 1.61 × 10- 9] loci were associated with nose shape. WDR35 and SOX9 were related to known craniofacial malformations, i.e., cranioectodermal dysplasia 2 and campomelic dysplasia, respectively. In addition, we found three independent association signals in the SOX9 locus, and six known loci for nose size and shape were replicated in this study population. Interestingly, four SNPs within these five face morphology-related loci showed discrepancies in allele frequencies among ethnic groups. CONCLUSIONS: We identified five novel face morphology loci that were associated with facial frontal contour, nose shape, and eye shape. Our findings provide useful genetic information for the determination of face morphology.

Common variants in DRD2 are associated with sleep duration: the CARe consortium.

Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.