Multi-ancestry genome-wide analysis identifies shared genetic effects and common genetic variants for self-reported sleep duration.

Both short (≤6 h per night) and long sleep duration (≥9 h per night) are associated with increased risk of chronic diseases. Despite evidence linking habitual sleep duration and risk of disease, the genetic determinants of sleep duration in the general population are poorly understood, especially outside of European (EUR) populations. Here, we report that a polygenic score of 78 European ancestry sleep duration single-nucleotide polymorphisms (SNPs) is associated with sleep duration in an African (n = 7288; P = 0.003), an East Asian (n = 13 618; P = 6 × 10-4) and a South Asian (n = 7485; P = 0.025) genetic ancestry cohort, but not in a Hispanic/Latino cohort (n = 8726; P = 0.71). Furthermore, in a pan-ancestry (N = 483 235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 73 loci are associated with genome-wide statistical significance. Follow-up of five loci (near HACD2, COG5, PRR12, SH3RF1 and KCNQ5) identified expression-quantitative trait loci for PRR12 and COG5 in brain tissues and pleiotropic associations with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.

Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.

STUDY QUESTION: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? SUMMARY ANSWER: By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. WHAT IS KNOWN ALREADY: AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. STUDY DESIGN, SIZE, DURATION: We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. PARTICIPANTS/MATERIALS, SETTING, METHODS: Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. MAIN RESULTS AND THE ROLE OF CHANCE: We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. WIDER IMPLICATIONS OF THE FINDINGS: Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Chronic Periodontitis Genome-wide Association Study in the Hispanic Community Health Study / Study of Latinos.

Chronic periodontitis (CP) has a genetic component, particularly its severe forms. Evidence from genome-wide association studies (GWASs) has highlighted several potential novel loci. Here, the authors report the first GWAS of CP among a large community-based sample of Hispanics/Latinos. The authors interrogated a quantitative trait of CP (mean interproximal clinical attachment level determined by full-mouth periodontal examinations) among 10,935 adult participants (mean age: 45 y, range: 18 to 76 y) from the Hispanic Community Health Study / Study of Latinos. Genotyping was done with a custom Illumina Omni2.5M array, and imputation to approximately 20 million single-nucleotide polymorphisms was based on the 1000 Genomes Project phase 1 reference panel. Analyses were based on linear mixed models adjusting for sex, age, study design features, ancestry, and kinship and employed a conventional P < 5 × 10-8 statistical significance threshold. The authors identified a genome-wide significant association signal in the 1q42.2 locus ( TSNAX-DISC1 noncoding RNA, lead single-nucleotide polymorphism: rs149133391, minor allele [C] frequency = 0.01, P = 7.9 × 10-9) and 4 more loci with suggestive evidence of association ( P < 5 × 10-6): 1q22 (rs13373934), 5p15.33 (rs186066047), 6p22.3 (rs10456847), and 11p15.1 (rs75715012). We tested these loci for replication in independent samples of European-American ( n = 4,402) and African-American ( n = 908) participants of the Atherosclerosis Risk in Communities study. There was no replication among the European Americans; however, the TSNAX-DISC1 locus replicated in the African-American sample (rs149133391, minor allele frequency = 0.02, P = 9.1 × 10-3), while the 1q22 locus was directionally concordant and nominally significant (rs13373934, P = 4.0 × 10-2). This discovery GWAS of interproximal clinical attachment level-a measure of lifetime periodontal tissue destruction-was conducted in a large, community-based sample of Hispanic/Latinos. It identified a genome-wide significant locus that was independently replicated in an African-American population. Identifying this genetic marker offers direction for interrogation in subsequent genomic and experimental studies of CP.

GWAS Identifies New Loci for Painful Temporomandibular Disorder: Hispanic Community Health Study/Study of Latinos.

Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 106) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10-8) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10-8) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10-8) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10-7) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.

[Routine breast examination and early detection of hypertension and diabetes mellitus by primary care physicians ].

Breast cancer is the leading cause of cancer mortality among women is Israel. On average, 1 in every 12 women develops the disease. While breast self-examination has not proved effective, and routine mass mammography is at present unavailable to the population at large, regular routine breast examination by primary care physicians can effectively screen a large fraction of this country's population. In order to do so, full acceptance of the procedure by women and their physicians is required. This study examines the attitudes and practice of primary care physicians with regard to routine breast examination, and compares them with routine detection of hypertension and diabetes mellitus. A structured questionnaire was distributed to all 97 Kupat Holim (workers' federation sick fund) primary care physicians in the Negev. They included 40 family physicians (FP), board-certified or completing specialization, and 57 general practitioners (GP), not board-certified. There was no difference in response rate between the 2 groups (47%). Nearly all physicians perform routine examinations for detection of hypertension (100% of the FP and 96% of the GP) and diabetes mellitus (91% and 74%, respectively). Of the FP, 96% consider routine breast examination as the task of the primary care physician, versus only 68% of the GP. Accordingly, 92% of the FP stated that they routinely perform the procedure, but only 52% of the GP. Being an FP was positively related with the performance of breast examination, while seeing a large number of patients per clinic session and low job satisfaction were negatively associated with it.

Workload involved in routine breast examination and instruction in breast self-examination in the primary care clinic.

This study evaluates the impact of breast examinations and instruction in breast self-examination as a routine for women aged 30 years and over on the workload in a primary care clinic of the Workers' Sick Fund (Kupat Holim) in Israel. It covers a three-year period from 1977 to 1980. Clinic sessions of four hours duration with an average of 21 patients each were held five times a week. Women who were considered high risk for breast cancer were to be examined twice a year, low risk women once a year. A first breast examination with instruction required on average 10 minutes, a subsequent examination seven minutes. A total of 696 breast examinations were performed, averaging 1.2 breast examinations per clinic session. This resulted in a maximum extra workload of 12 minutes per clinic session of four hours.

Geographical and temporal trends of childhood leukemia in relation to the nuclear plant in the Negev, Israel, 1960-1985.

Gardner et al. (Br Med J 1990; 300: 423-429) reported a high relative risk for childhood leukemia among children, aged 0-24 years at time of diagnosis, born to fathers employed at the Sellafield nuclear plant in the U.K. As a result we looked for spatial and temporal trends of childhood and young adult leukemia in the Negev, where a nuclear plant has been in operation since 1960. We divided the Negev into an Eastern part where plant employees are likely to live, and a Western part where this is quite unlikely. Reported leukemia cases were provided by the Israel Cancer Registry for the age group 0-24, and for the period 1960-1985. We checked this file against data obtained from the hospitals in the area. We added 6 more cases in the Eastern Negev, none in the Western Negev, and none of the reported cases was discarded. There was a total of 192 cases, of which 52% were acute lymphatic leukemia. Jewish and Bedouin children were studied separately. Among Jewish children the average annual incidence rate for the Eastern Negev was 2.76/100,000, the Western Negev 3.51. Over time the leukemia rates were consistently higher in the Western Negev among children aged 0-9 years, which holds especially for acute lymphatic leukemia. There was a sudden increase among girls born during the period 1970-1979 in the northern part of the Western Negev, which was not noticed among boys. No excess cases were found in the small towns around the plant.

Past and present contraceptive behavior of new Soviet immigrant women in Israel.

This exploratory research investigated past and current use of contraceptives among a purposive sample of 117 new immigrant women from the Commonwealth of Independent States (former Soviet Union). The findings confirm the widespread use of induced abortion (IA) as a method of birth control before immigration. Fifty-eight percent of the sample had had at least one IA, and the average was 2.7 IA. The most commonly used types of contraception before immigration were the pill, safe days, withdrawal, and the IUD. Currently used types of contraception were the IUD, safe days, withdrawal, and condoms; however only 45% of the sample were currently using any type of contraception. Of particular interest were the relatively high reported use of the pill before immigration and low current use, and the former low level of condom use and its increase in popularity in Israel. Despite the availability of more effective methods of birth control, safe days and withdrawal remain commonly used. The high cost of the pill was mentioned as a deterrent to its current use. Despite the high prior level of IA, the majority of women in this sample (84%) preferred today to use other birth control methods, and would like the opportunity to receive professional advice. These findings support the need for educational efforts directed toward new immigrant women from CIS.

PIP: In early 1992 in Israel, 117 recent Jewish immigrant women from Belarus, Russia, and the Ukraine completed a questionnaire designed to examine their past and current contraceptive behavior. The mean number of months in Israel was 2.7 months. The mean number of children among the 90 women with children was 1.74 (range 1-5). 58.1% of all 117 women had had at least one induced abortion. The mean number of induced abortions per woman was 2.7 (range 1-12). More than 40% of women who had had at least one induced abortion had at least 3 induced abortions. 104 women were or had been married, or had a steady partner. The most frequently used family planning methods in the past were oral contraceptives (OCs) (33.7%), safe days (24%), withdrawal (15.3%), and IUD (15.3%). Only 4% used condoms in the past. Current family planning methods used included IUD (23%), safe days (23%), withdrawal (18.3%), and condoms (13.5%). Only 2.9% currently used OCs. The mean number of methods currently used was 1.8. Reasons for not using contraception before immigration were: not safe (18%), reduced sexual pleasure (11%), not available (9%), no steady sexual partner (7%), and desire to conceive (5%). After immigration, reasons for not using contraception were too expensive (11%) (especially OCs) and not safe (9%). 84% preferred to use contraception rather than undergo an induced abortion. 62% wanted professional advise on contraception. These findings illustrate the need to provide new immigrant women from the Commonwealth of Independent States with accurate information about the health effects of various family planning methods.