Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.</p

Measurement of the transverse momentum distribution of [Z over γ*] bosons in proton-proton collisions at √s = 7 TeV with the ATLAS detector

A measurement of the [Z over γ*] transverse momentum (p[Z over T]) distribution in proton–proton collisions at √s = 7 TeV is presented using [Z over γ*] →e[superscript +]e[superscript −] and [Z over γ*] →μ[superscript +]μ[superscript −] decays collected with the ATLAS detector in data sets with integrated luminosities of 35 pb[superscript −1] and 40 pb[superscript −1], respectively. The normalized differential cross sections are measured separately for electron and muon decay channels as well as for their combination up to p[Z over T] of 350 GeV for invariant dilepton masses 66 GeV<m[subscript ℓℓ]<116 GeV. The measurement is compared to predictions of perturbative QCD and various event generators. The prediction of resummed QCD combined with fixed order perturbative QCD is found to be in good agreement with the data.United States. Dept. of EnergyNational Science Foundation (U.S.)Brookhaven National LaboratoryEuropean Organization for Nuclear Researc

Correlates of sexual functioning in Italian menopausal women.

Abstract OBJECTIVES: To analyze the sexuality of Italian menopausal women. DESIGN: Cross-sectional study. POPULATION: Menopausal women consecutively observed during the study period in menopause clinics. METHODS: Women were interviewed about their current and premenopausal sexual activity: sexual intercourse frequency and self-rated sexual desire, capacity for orgasm and sexual satisfaction were recorded. Women were defined as having poor sexual functioning if they had one or less sexual intercourses per week or answered 'absent/poor' to the questions about the sexual domains. RESULTS: Oral hormone therapy (HT) use (odds ratio (OR) 0.43 for desire, 0.54 for orgasm and 0.56 for overall sexual satisfaction, all p < 0.001) and transdermal HT (OR 0.38, 0.53 and 0.53, respectively, all p < 0.001) were significantly associated with lower risk of poor sexual functioning. Higher physical and mental component scores (PCS and MCS, range 0-100) of the Short Form-12 are inversely related to poor sexual functioning (OR by point 0.96, 0.95, 0.95 for PCS and 0.96, 0.96 and 0.95, for MCS, respectively, all p < 0.001). Pain during and symptoms after sexual intercourse were significantly related to desire (OR 1.96 and 1.78, respectively), orgasm (OR 2.22 and 2.06, respectively) and sexual satisfaction (OR 2.02 and 1.79, respectively). The partner's health problems were associated with low sexual intercourse frequency (OR 4.18, p < 0.001) and absent/poor overall satisfaction (OR 2.61, p < 0.001). CONCLUSIONS: This study shows that, in menopausal Italian women attending menopause clinics, sexual function is associated with the quality of sexual life in reproductive age, partner's health status, current quality of life, HT and occurrence of pain during and symptoms after sexual intercour

FACTORS ASSOCIATED WITH CLIMATERIC SYMPTOMS IN WOMEN AROUND MENOPAUSE ATTENDING MANOPAUSE CLINICS IN ITALY

Objective: To obtain data on correlates of climacteric symptoms in women around menopause attending menopause clinics in Italy. Methods: Since 1997 a large cross sectional study has been conducted on the characteristics of women around menopause attending a network of first level menopause outpatient\u2019s clinics in Italy. A total of 66,501 (mean age 54.4 years) women are considered in the present paper. Results: The odds ratios of moderate and severe hot flashes/night sweats were lower in more educated women and (for severe symptoms only) in women reporting regular physical activity. Depression, difficulty to sleep, forgetfulness and irritability tended to be less frequent in more educated women and (depression only) in women reporting regular physical activity. Parous women reported more frequently these symptoms. Conclusions: This large study confirms in Southern European population that low education, body mass index and low physical activity are associated with climacteric symptoms. Parous women are at greater risk of psychological symptoms. \ua9 2005 Elsevier Ireland Ltd. All rights reserved

Factors associated with total cholesterol levels in women around menopause attending menopause clinics in Italy

OBJECTIVE: To obtain data on correlates of total cholesterol (TC) levels in women around menopause attending menopause clinics in Italy. METHODS: Since 1997, a large cross-sectional study has been conducted concerning the characteristics of women around the time of the menopause attending a network of first-level menopause out-patient clinics in Italy for general counselling about the menopause or treatment of menopausal symptoms. Women observed consecutively at the participating centers were eligible for the study. Up to March 2000, TC was measured in 23 018 cases, which are considered in this analysis. RESULTS: The adjusted mean level of TC rose with age, from 216 mg/dl in women aged 57 years. Mean TC increased with body mass index (BMI, kg/m2), being 224 mg/dl in women with BMI 26. Considering menopausal status, the crude mean TC level was 216 mg/dl in premenopausal women, 227 mg/dl in women reporting a surgical menopause and 229 mg/dl in women reporting a natural menopause. These differences were still present when the analysis took into account the effect of age and other potential covariates, the adjusted values being 221, 225 and 227, respectively. Similar findings emerged when we considered the distribution of study subjects according to selected levels of TC ( 250 mg/dl vs. 57 years in comparison with women aged 26 vs. < 24, and for women in spontaneous menopause vs. premenopause, were all 1.2 (all statistically significant). CONCLUSIONS: This analysis, based on a large data set, confirms the role of overweight as a determinant of TC in postmenopausal women, and indicates the role of the menopause as a determinant of TC level in women aged 50-60 years

Premature ovarian failure: frequency and risk factors among women attending a network of menopause clinics in Italy

Objective To determine the frequency and causes of preterm ovarian failure (menopause before 40 years of age) and early menopause (menopause between 40 and 45 years). Design Cross sectional study. Setting Menopause clinics in Italy. Population Women attending menopause clinics in Italy. Methods Between 1997 and 1999 we conducted a large cross sectional study on the characteristics of women around menopause attending a network of first-level outpatient menopause clinics in Italy for general counselling about menopause or treatment of menopausal symptoms. Eligible for the study were all women aged 45-75 years consecutively observed for the first time at the participating centres on randomly selected days during the study period. Main outcome measure Factors associated with preterm ovarian failure. Results Out of 15,253 women aged 55 years or more with spontaneous menopause who entered the study, 269 (1.8%) reported preterm ovarian failure, and 1085 (7.1%) reported spontaneous menopause at age 40-45 years. The risk of preterm ovarian failure and of early menopause was higher in women reporting lifelong irregular menstrual cycles: in comparison with women reporting menopause at age greater than or equal to45 years, the OR (irregular vs regular mestrual cycles) of preterm ovarian failure was 1.3 (95% CI 1.0-1.7) and of early menopause of 1.2 (95% CI 1.0-1.5). Parous women reported less frequently preterm ovarian failure (chi(2) trend P < 0.05) and early menopause (OR 0.8, 95% CI 0.7-1.0). No significant association emerged between risk of preterm ovarian failure or menopause at age 40 to <45 and education, age at menarche, oral contraceptive use and smoking habits. Conclusion Nulliparity and lifelong irregular menstrual cycles are associated with an increased risk of preterm ovarian failure

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P &lt; 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.</p

Risk factors for type 2 diabetes in women attending menopause clinics in Italy: a cross-sectional study

OBJECTIVE: To analyze risk factors for type 2 diabetes among women attending menopause clinics in Italy for counselling about the menopause. SUBJECTS: Women attending a network of first-level outpatient menopause clinics in Italy for general counselling about menopause or treatment of menopausal symptoms. METHODS: Cross-sectional study with no exclusion criteria. Type 2 diabetes was defined according to National Diabetes Data Groups Indications and the fasting blood glucose at an oral glucose tolerance test within the previous year. RESULTS: Out of the 44 694 considered in this analysis, 808 had a diagnosis of diabetes type 2 (1.8%). In comparison with women aged or = 57 years. Type 2 diabetes was less frequently reported in more educated women (OR high school/university vs. primary school = 0.44 (95% CI, 0.36-0.55)). Being overweight was associated with an increased risk of type 2 diabetes. In comparison with women reporting a low level of physical activity, the multivariate OR of type 2 diabetes was 0.67 (95% CI, 0.54-0.84) for women reporting regular physical activity. In comparison with premenopausal women, the multivariate OR of type 2 diabetes was 1.38 (95% CI, 1.03-1.84) in women with natural menopause. This finding was present also after allowing for the potential confounding effect of age. The multivariate OR of diabetes for users of hormonal replacement therapy was 0.58 (95% CI, 0.46-0.73). CONCLUSIONS: This large cross-sectional study suggests that postmenopausal women are at higher risk of type 2 diabetes after allowance for the effect of age. Other main determinants of risk of type 2 diabetes in women around menopause were low socioeconomic status and being overweight. Diabetes was found less frequently in those taking hormone replacement therapy

Publisher Correction:Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article