Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

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.

Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables. METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

Using linkage analysis to identify quantitative trait loci for sleep apnea in relationship to body mass index.

To understand the genetics of sleep apnea, we evaluated the relationship between the apnea hypopnea index (AHI) and body mass index (BMI) through linkage analysis to identify genetic loci that may influence AHI and BMI jointly and AHI independent of BMI. Haseman-Elston sibling regression was conducted on AHI, AHI adjusted for BMI and BMI in African-American and European-American pedigrees. A comparison of the magnitude of linkage peaks was used to assess the relationship between AHI and BMI. In EAs, the strongest evidence for linkage to AHI was on 6q23-25 and 10q24-q25, both decreasing after BMI adjustment, suggesting loci with pleiotropic effects. Also, a promising area of linkage to AHI but not BMI was observed on 6p11-q11 near the orexin-2 receptor, suggesting BMI independent pathways. In AAs the strongest evidence of linkage for AHI after adjusting for BMI was on chromosome 8p21.3 with linkage increasing after BMI adjustment and on 8q24.1 with linkage decreasing after BMI adjustment. Novel linkage peaks were also observed in AAs to both BMI and AHI on chromosome 13 near the serotonin-2a receptor. These analyses suggest genetic loci for sleep apnea that operate both independently of BMI and through BMI-related pathways.

Heritability of upper airway dimensions derived using acoustic pharyngometry.

Acoustic pharyngometry represents a simple, quick noninvasive method of measuring upper airway dimensions, which are predictive of sleep apnoea risk. The aim of the present study was to assess the genetic basis of upper airway size as determined using pharyngometry. Participants in the Cleveland Family Study aged >14 yrs underwent three acoustic pharyngometric measurements. Variance component models adjusted for age and sex were used to estimate the heritability of pharyngometry-derived airway measures. A total of 568 out of 655 (87%) subjects provided pharyngometric curves of sufficient quality. Although African-Americans tended to show narrower airways compared with white subjects, heritability patterns were similar in these two groups. The minimum cross-sectional area exhibited a heritability of 0.34 in white subjects and 0.39 in African-Americans, suggesting that 30-40% of the total variance in this measure is explained by shared familial factors. Estimates were unchanged after adjustment for body mass index or neck circumference. In contrast, oropharyngeal length did not show significant heritability in either ethnic group. The minimum cross-sectional area of the oropharynx is a highly heritable trait, suggesting the presence of an underlying genetic basis. These findings demonstrate the potential utility of acoustic pharyngometry in dissecting the genetic basis of sleep apnoea.

Shared genetic basis for obstructive sleep apnea and adiposity measures.

INTRODUCTION: Obesity and obstructive sleep apnea each have a substantial genetic basis and commonly coexist in individuals. The degree to which the genetic underpinnings for these disorders overlap has not been previously quantified. METHODS: A total of 1802 individuals from 310 families in the Cleveland Family Study underwent home sleep studies as well as standardized assessment of body mass index (BMI) and circumferences at the waist, hip and neck. In 713 participants with laboratory sleep studies, fasting blood samples were assayed for leptin, adiponectin and resistin. Variance component models were used to estimate heritability and genetic correlations. RESULTS: The heritability of the apnea hypopnea index (AHI) was 0.37+/-0.04 and 0.33+/-0.07 for home and laboratory sleep studies, respectively. The genetic correlations between AHI and anthropomorphic adiposity measures ranged from 0.57 to 0.61, suggesting that obesity can explain nearly 40% of the genetic variance in sleep apnea. The magnitude of the genetic correlations between apnea severity and adipokine levels was substantially less than those with anthropomorphic measures, ranging from 0.11 to 0.46. After adjusting for BMI, no significant genetic correlation with apnea severity was observed for any of the other adiposity measures. CONCLUSIONS: Substantial but not complete overlap in genetic bases exists between sleep apnea and anthropomorphic indices of adiposity, and this overlap accounts for more than one-third of the genetic variance in apnea severity. These findings suggest that genetic polymorphisms exist that importantly influence sleep apnea susceptibility through both obesity-dependent and -independent pathways.

Linkage of serum leptin levels in families with sleep apnea.

OBJECTIVE: To identify regions on the genome linked to plasma leptin levels. DESIGN: Full genome scan with 402 microsatellite markers, spaced approximately 10 cM apart. Data were analyzed using the Haseman-Elston regression linkage analysis. SUBJECTS: A total of 160 sibling pairs from 59 predominantly African American, obese families recruited to participate in a genetic-epidemiological study of obstructive sleep apnea. MEASUREMENTS: Serum leptin levels adjusted for age, sex, race and body mass index (BMI). RESULTS: Suggestive linkage peaks were observed on chromosomes 2 (P=0.00170; marker D2S1384), 3 (P=0.00007; marker D3S3034), 4 (P=0.00020; marker D4S1652) and 21 (P=0.00053; marker D21s1411). CONCLUSION: The peak on chromosome 3 is near the gene for glycogensynthase kinase 2 beta, an important factor in glucose homeostasis. Linkage was generally stronger after BMI adjustment, suggesting the potential influence of a number of metabolic pathways on leptin levels other than those that directly determine obesity levels. The evidence of linkage for leptin levels is consistent with prior linkage analyses for cholesterol, hypertension and other metabolic phenotypes.

Predictors of loud snoring in persons with spinal cord injury.

BACKGROUND: Predictors of loud snoring were examined in a cohort of 197 persons with chronic spinal cord injury (SCI) recruited by advertisement and from a Veterans Affairs Medical Center SCI Service. METHODS: Data were collected on age, marital status, antispasticity medications, duration of injury, level and completeness of injury, stature, and weight. Body mass index (BMI) was calculated for all participants. A health questionnaire was used to collect data on snoring and respiratory history. Habitual snorers were defined as those who reported loud snoring more than 1 night per week. RESULTS: The mean age (+/- SD) was 51.2 +/- 14.8 years, and 84 of 197 (42.6%) were habitual snorers. The most obese research subjects, regardless of antispasticity medication use, were more likely to report snoring, but the risk of snoring was greatest among subjects who were obese and used antispasticity medication. Subjects who used antispasticity medication and had a BMI above the median (> or = 25.3 kg/m2) had a 7-fold risk of reporting snoring compared with subjects below the median who did not use antispasticity medication (P = .001). The greatest risk occurred in those who used diazepam alone or baclofen and diazepam together and had a BMI at or above the median. Subjects who used these medications and had a BMI below the median did not have a significantly increased risk. Neurological motor completeness, level of injury, age, and years since injury were not significant predictors of snoring. CONCLUSION: Because snoring is a marker for obstructive sleep apnea (OSA), the data suggest that in obese individuals with SCI, the use of antispasticity medications may be a risk factor for OSA.

Diesel exhaust exposure and lung cancer: adjustment for the effect of smoking in a retrospective cohort study.

BACKGROUND: The extent that cigarette smoking may confound the relationship between diesel exhaust exposure and lung cancer was assessed in a retrospective cohort study of 55,395 U.S. railroad workers followed from 1959 to 1976. METHODS: The relative risk (RR) of lung cancer due to diesel exhaust was indirectly adjusted using job-specific smoking data from a case-control study of railroad workers who died between 1981-1982 and from a survey of 514 living workers from an active railroad in 1982. Adjustment factors were developed based on the distribution of job-specific smoking rates. RESULTS: The unadjusted RR for lung cancer was 1.58 (95% CI = 1.14-2. 20) for workers aged 40-44 in 1959, who experienced the longest possible duration of exposure, and the smoking adjusted RR was 1.44 (1.01-2.05). CONCLUSIONS: After considering differences in smoking rates between workers exposed and unexposed to diesel exhaust in a relatively large blue-collar cohort, there were still elevated risks of lung cancer in workers in jobs with diesel exhaust exposure.

Attitudes toward colon cancer gene testing: factors predicting test uptake.

OBJECTIVES: Genetic discoveries in hereditary nonpolyposis colorectal cancer (HNPCC) have made possible genetic testing to determine susceptibility to this form of colorectal cancer (CRC). This study measured the uptake of genetic testing for HNPCC among first-degree relatives of CRC patients and conducted a preliminary analysis of the predictors of test uptake. MATERIALS AND METHODS: We compared 77 test acceptors and 181 decliners on demographic, medical history, and psychological characteristics, controlling for distance from the testing center. The psychological factors studied were risk perception for CRC, frequency of cancer thoughts, and perceived ability to cope with unfavorable genetic information. RESULTS: In the final regression model, after accounting for all variables, the significant predictors of test uptake were increased risk perception, greater perceived confidence in ability to cope with unfavorable genetic information, more frequent cancer thoughts, and having had at least one colonoscopy. The association between risk perception and uptake was dependent on frequency of cancer thoughts. Among those who thought about getting CRC more often, the probability of testing increased as perceived risk increased to approximately 50% likelihood of getting CRC and then leveled off. In contrast, among those who never or rarely thought about getting CRC, risk perception was unrelated to testing decision. CONCLUSIONS: Our findings are consistent with the associations reported between psychological factors and other cancer screening behaviors.