Novel Genetic Determinants of Dental Maturation in Children.

Dental occlusion requires harmonious development of teeth, jaws, and other elements of the craniofacial complex, which are regulated by environmental and genetic factors. We performed the first genome-wide association study (GWAS) on dental development (DD) using the Demirjian radiographic method. Radiographic assessments from participants of the Generation R Study (primary study population, N1 = 2,793; mean age of 9.8 y) were correlated with ~30 million genetic variants while adjusting for age, sex, and genomic principal components (proxy for population stratification). Variants associated with DD at genome-wide significant level (P < 5 × 10-8) mapped to 16q12.2 (IRX5) (lead variant rs3922616, B = 0.16; P = 2.2 × 10-8). We used Fisher's combined probability tests weighted by sample size to perform a meta-analysis (N = 14,805) combining radiographic DD at a mean age of 9.8 y from Generation R with data from a previous GWAS (N2 = 12,012) on number of teeth (NT) in infants used as proxy of DD at a mean age of 9.8 y (including the ALSPAC and NFBC1966). This GWAS meta-analysis revealed 3 novel loci mapping to 7p15.3 (IGF2BP3: P = 3.2 × 10-8), 14q13.3 (PAX9: P = 1.9 × 10-8), and 16q12.2 (IRX5: P = 1.2 × 10-9) and validated 8 previously reported NT loci. A polygenic allele score constructed from these 11 loci was associated with radiographic DD in an independent Generation R set of children (N = 703; B = 0.05, P = 0.004). Furthermore, profiling of the identified genes across an atlas of murine and human stem cells observed expression in the cells involved in the formation of bone and/or dental tissues (>0.3 frequency per kilobase of transcript per million mapped reads), likely reflecting functional specialization. Our findings provide biological insight into the polygenic architecture of the pediatric dental maturation process.

BMI in childhood and adolescence is associated with impaired reproductive function-a population-based cohort study from birth to age 50 years.

STUDY QUESTION: What is the association between childhood and adolescent BMI and reproductive capacity in women? SUMMARY ANSWER: Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS). WHAT IS KNOWN ALREADY: Girls with obesity (BMI (kg/m2)>95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited. STUDY DESIGN, SIZE, DURATION: A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth register. Decreased fecundability was defined at age 31 years as time to achieve pregnancy over 12 months. Logistic regression analyses were conducted with adjustments for marital status, education level and smoking at age 31 years. Women with PCOS were excluded from stratification-based sensitivity analyses. Obesity at a specific age group was defined by having at least one BMI value above the 95th percentile during the related period. MAIN RESULTS AND THE ROLE OF CHANCE: BMI at the age of AR (5-7 years) was not associated with fertility outcomes after adjustments, but girls with AR <5.1 years had a higher risk of remaining childless compared to girls with AR over 5.1 years (adjusted odds ratio (OR): 1.45 (1.10-1.92)). At ages 7-10 and 11-15 years, obesity was associated with decreased fecundability (adjusted OR 2.05 (1.26-3.35) and 2.04 (1.21-3.44), respectively) and a lower number of children. At age 11-15 years, both overweight and obesity were associated with a higher risk of childlessness (adjusted OR 1.56 (1.06-2.27), 1.77 (1.02-3.07), respectively), even after excluding women with PCOS. Underweight at age 11-15 years was associated with an increased risk for infertility treatment (adjusted OR 1.55 (1.02-2.36)) and a tendency for an increased risk for infertility assessment (adjusted OR 1.43 (0.97-2.10)) after excluding women with PCOS. LIMITATIONS, REASON FOR CAUTION: Despite a high participation rate throughout the follow-up, some growth data for children over the different age groups were missing. Infertility outcomes were self-reported. A potential over-diagnosis of obesity may have reduced the significance of the association between childhood obesity and fertility outcomes, and the diagnosis of PCOS was self-reported. WIDER IMPLICATIONS OF THE FINDINGS: This study supports previous results showing that girls with obesity in late childhood and in adolescence displayed reduced fertility and an increased risk of remaining childless in adulthood, independently of marital history and PCOS in adulthood. These findings corroborate the body of evidence for a causal relation between early adiposity and the reproductive functions in women. We recommend reinforcing the prevention of obesity in school-age girls to reduce the risk of impaired reproductive functions. STUDY FUNDING/COMPETING INTEREST(S): NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. The Finnish Medical Foundation, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, Biocenter Oulu, University Hospital Oulu and University of Oulu (75617), Jalmari ja Rauha Ahokkaan säätiö, The Finnish Medical Foundation, Medical Research Center Oulu, National Institute for Health Research (UK). M. R. J., S. S. and R. N. received funding by the Academy of Finland (#268336) and the European Union's Horizon 2020 research and innovation program (under Grant agreement no. 633595 for the DynaHEALTH action and GA 733206 for LifeCycle). The funders had no role in study design, in the collection, analysis and interpretation of the data, in the writing of the article and in the decision to submit it for publication. The authors have no conflict of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Farm Environment During Pregnancy and Childhood and Polysensitization at the Age of 31: Prospective Birth Cohort Study in Finland.

BACKGROUND AND OBJECTIVE: The farm environment, especially contact with farm animals in early childhood, may prevent allergic sensitization during adulthood. However, prospective associations between exposure to the farm environment and polysensitization have not been studied. Polysensitization is a risk factor for asthma and asthma-related morbidity. Objective: To investigate whether exposure to a farming environment in early childhood, especially exposure to animals, is associated with sensitization to specific allergens and polysensitization at the age of 31. METHODS: In a prospective birth cohort study, 5509 individuals born in northern Finland in 1966 underwent skin prick testing against birch, timothy, cat, and house dust mite at the age of 31. Prenatal exposure to the farming environment was documented at birth, whereas information on childhood exposure to pets was only collected retrospectively at the age of 31. Data were analyzed using logistic regression. RESULTS: Being born to a family with farm animals was associated with a reduced risk of sensitization to birch, timothy, and cat (adjusted odds ratio [aOR], 0.55 [95%CI, 0.43-0.70]; aOR, 0.62 [95%CI, 0.48-0.79]; aOR, 0.60 [95%CI, 0.47-0.75]) and polysensitization at the age of 31 (aOR, 0.62 [95%CI, 0.48-0.80]). The number of animal species present during childhood was dose-dependently associated with a reduced risk of sensitization to birch, timothy, and cat, as well as of polysensitization. No association was found with sensitization to house dust mite. CONCLUSIONS: Growing up on a farm and contact with higher numbers of animal species in childhood are associated with less frequent sensitization to birch, timothy, and cat allergens and polysensitization in adulthood, but not with sensitization to house dust mite.

Farm Environment During Pregnancy and Childhood and Polysensitization at the Age of 31: Prospective Birth Cohort Study in Finland

BACKGROUND: The farm environment, especially contact with farm animals in early childhood, may prevent allergic sensitization during adulthood. However, prospective associations between exposure to the farm environment and polysensitization have not been studied. Polysensitization is a risk factor for asthma and asthma-related morbidity. OBJECTIVE: To investigate whether exposure to a farming environment in early childhood, especially exposure to animals, is associated with sensitization to specific allergens and polysensitization at the age of 31. METHODS: In a prospective birth cohort study, 5509 individuals born in northern Finland in 1966 underwent skin prick testing against birch, timothy, cat, and house dust mite at the age of 31. Prenatal exposure to the farming environment was documented at birth, whereas information on childhood exposure to pets was only collected retrospectively at the age of 31. Data were analyzed using logistic regression. RESULTS: Being born to a family with farm animals was associated with a reduced risk of sensitization to birch, timothy, and cat (adjusted odds ratio [aOR], 0.55 [95%CI, 0.43-0.70]; aOR, 0.62 [95%CI, 0.48-0.79]; aOR, 0.60 [95%CI, 0.47-0.75]) and polysensitization at the age of 31 (aOR, 0.62 [95%CI, 0.48-0.80]). The number of animal species present during childhood was dose-dependently associated with a reduced risk of sensitization to birch, timothy, and cat, as well as of polysensitization. No association was found with sensitization to house dust mite. CONCLUSIONS: Growing up on a farm and contact with higher numbers of animal species in childhood are associated with less frequent sensitization to birch, timothy, and cat allergens and polysensitization in adulthood, but not with sensitization to house dust mite

ANTECEDENTES: El ambiente de granja, especialmente el contacto con animales de granja en la primera infancia, puede prevenir la sensibilización alérgica durante la edad adulta. Sin embargo, no se han estudiado las posibles asociaciones entre la exposición al entorno agrícola y la polisensibilización. La polisensibilización es un factor de riesgo para el asma y su morbilidad. OBJETIVO: Investigar si el entorno agrícola en la primera infancia, especialmente la exposición a animales, está asociado con la sensibilización a alérgenos específicos y la polisensibilización a la edad de 31 años. MÉTODOS: En un estudio prospectivo de cohorte de nacimiento, 5.509 sujetos nacidos en el norte de Finlandia en 1966 se sometieron a pruebas cutáneas a la edad de 31 años con abedul, hierba timotea, gato y ácaros del polvo doméstico. La exposición prenatal al ambiente agrícola se documentó al nacer, mientras que la información sobre la exposición infantil a las mascotas solo se recopiló retrospectivamente a la edad de 31 años. Se utilizó La regresión logística en los análisis estadísticos. RESULTADOS: Nacer en una familia con animales de granja se asoció con un menor riesgo de sensibilización frente a abedul, hierba timotea o gato (odds ratio ajustado, aOR = 0,55 [intervalo de confianza del 95% 0,43-0,70]; aOR = 0,62 [0,48-0,79] ; aOR = 0,60 [0,47-0,75]) y polisensibilización a la edad de 31 años (aOR = 0,62 [0,48-0,80]). La sensibilización frente a abedul, hierba timotea y gato, así como la polisensibilización, se asociaron de forma dependiente e inversa a la dosis con el número de especies animales presentes durante la infancia. No se encontró asociación con la sensibilización frente a los ácaros del polvo doméstico. CONCLUSIONES: Crecer en una granja y el contacto con un mayor número de especies animales en la infancia se asocia con una menor sensibilización frente al abedul, la hierba timotea, alérgenos de gato y polisensibilización en la edad adulta, pero no con sensibilización frente a los ácaros del polvo doméstico

Mortality by diseases and medical conditions in the offspring of parents with severe mental illness.

PURPOSE: The lifespan of people with severe mental illness (SMI) is shorter compared to the general population. There might be common familial pathway leading to a high co-occurrence of somatic disorders and SMI. To study this we explored the long-term mortality for natural causes in the offspring of people with SMI. METHODS: Participants were members of the Northern Finland Birth Cohort 1966 (NFBC1966; N = 11,325). The data on cause of deaths of the members were obtained from the Population Register Center until year 2015. The data on hospital-treated psychiatric disorders of parents were obtained from nationwide Care Register for Health Care. Cumulative incidences by age were calculated in the NFBC1966 members having a parent with SMI and those who did not have. We were able to take into account multiple confounders. RESULTS: Of the total sample of 11,325 offspring, 853 (7.4%) died during the follow-up period, 74 (8.7%) from the study cohort and 779 (91.3%) from the comparison group. These numbers included 160 stillborn children. There were 557 cases of deaths from diseases and medical conditions and 296 deaths from external causes. The adjusted risk ratio for offspring of mothers with SMI was 1.08 (0.72-1.64), and for offspring of fathers with SMI 0.58 (0.36-0.93). CONCLUSIONS: This was the first long-term follow-up study (up to age 49) of all-cause mortality in offspring of parents with SMI. Our findings were contrary to expectations. Offspring of parents with SMI had no increased risk for dying. In fact, the risk for dying in the group of offspring of fathers with SMI was lower than in the comparison group. This study does not support the assumption of common familial pathway leading to a high co-occurrence of somatic disorders and SMI.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

Vitamin D status and correlates of low vitamin D in schizophrenia, other psychoses and non-psychotic depression - The Northern Finland Birth Cohort 1966 study.

There is limited knowledge available on the association of vitamin D with psychiatric disorders in young adults. We aimed to investigate vitamin D levels and associating factors in schizophrenia, other psychoses and non-psychotic depression. We studied 4,987 participants from the Northern Finland Birth Cohort 1966 (31 years) with available serum 25-hydroxyvitamin D [25(OH)D] measurements. The final sample was divided into four groups: schizophrenia (n = 40), other psychoses (n = 24), non-psychotic depression (n = 264) and control (n = 4659). To account for the influence of environmental and technical covariates, we generated a vitamin D score variable with correction for season, sex, batch effect and latitude. We further examined how vitamin D levels correlate with anthropometric, lifestyle, socioeconomic and psychiatric measures. Neither serum 25(OH)D concentration nor vitamin D score differed between schizophrenia, other psychoses, non-psychotic depression and control group. The prevalence of vitamin D deficiency was 3.2%, insufficiency 25.5%, and sufficiency 71.3%. Low vitamin D score correlated with regular smoking in the group with schizophrenia. No difference was observed in other psychiatric conditions. We did not find any difference in vitamin D status between schizophrenia, psychoses, non-psychotic depression and control groups, but future studies are warranted to elucidate the role of vitamin D in psychiatric conditions.

Age at adiposity rebound in childhood is associated with PCOS diagnosis and obesity in adulthood-longitudinal analysis of BMI data from birth to age 46 in cases of PCOS.

BACKGROUND: Adiposity rebound (AR), the second BMI rise in childhood at around the age of 6 years, is associated with obesity and metabolic alteration in later life. Given that polycystic ovary syndrome (PCOS) has a strong metabolic component, early life growth patterns could reveal a risk of PCOS. Thus, we aimed to investigate the associations between age at AR and PCOS diagnosis and BMI later in life. MATERIALS AND METHODS: This study is part of a prospective, population-based longitudinal study, where women with PCOS diagnosis by age 46 (n = 280) were compared with asymptomatic women (CTRLs, n = 1573). Weight and height data from birth to age 13 years, at age at menarche, and at ages 31 and 46 years were analyzed RESULTS: Women with PCOS had lower birth weight (3357 ± 477 vs. 3 445 ± 505 g, p < 0.001), earlier age at AR (5.2 ± 1.0 vs. 5.6 ± 0.90 years, p < 0.001) and higher BMI from AR onwards compared with controls. Early timing of AR was associated with PCOS diagnosis independently of BMI (OR 1.62, 95% Cl 1.37-1.92). Women with PCOS and early AR had higher BMI at 31 and 46 years when compared to controls with early AR. The age at AR did not associate with T levels at ages 31 or 46 years. CONCLUSIONS: Early AR was associated with PCOS diagnosis and high BMI in adulthood. Adolescent girls with early AR and persisting obesity should be screened for PCOS symptoms, such as persistent irregular cycles and hirsutism.

Pre-pregnancy overweight or obesity and gestational diabetes as predictors of body composition in offspring twenty years later: evidence from two birth cohort studies.

BACKGROUND: Global prevalence of overweight/obesity and gestational diabetes (GDM) is increasing. In pregnant women both conditions affect offspring's later health. Overweight/obesity is a risk factor of GDM; to what extent maternal overweight/obesity explains long-term effects of GDM in offspring is unknown. OBJECTIVE: To evaluate effects of maternal pre-pregnancy overweight/obesity (body mass index (BMI) ⩾25 kg m-2) and GDM, occurring together or separately, on body composition among adult offspring. METHODS: Participants include 891 individuals aged 24.1 years (s.d. 1.4) from two longitudinal cohort studies (ESTER and AYLS). Adult offspring of normoglycemic mothers with overweight/obesity (ONOO, n=153), offspring of mothers with GDM (OGDM; n=191) and controls (n=547) underwent anthropometric measurements and bioimpedance analysis. Gestational diabetes mellitus was diagnosed by oral glucose tolerance test. Data were analyzed by linear regression models adjusted for confounders. RESULTS: Compared with controls, ONOO-participants showed higher BMI (men 1.64 kg m-2 (95% confidence interval 0.57, 2.72); women 1.41 kg m-2 (0.20, 2.63)) and fat percentage (men 2.70% (0.99, 4.41); women 2.98% (0.87, 5.09)) with larger waist circumferences (men 3.34 cm (0.68, 5.99); women 3.09 cm (0.35, 5.83)). Likewise, OGDM-participants showed higher fat percentage (men 1.97% (0.32, 3.61); women 2.32% (0.24, 4.41)). Body mass index was non-significantly different between OGDM-participants and controls (men 0.88 kg m-2 (-0.17, 1.92); women 0.82 kg m-2 (-0.39, 2.04)). Also waist circumferences were larger (men 2.63 cm (-0.01, 5.28); women 3.39 cm (0.60, 6.18)); this difference was statistically significant in OGDM-women only. Differences in body composition measures were stronger among offspring of women with both GDM and overweight/obesity. For instance, fat mass was higher among OGDM-participants of overweight mothers (men 4.24 kg (1.36, 7.11) vs controls; women 5.22 kg (1.33, 9.11)) than OGDM participants of normal weight mothers (men 1.50 kg (-2.11, 5.11) higher vs controls; women 1.57 kg (-3.27, 6.42)). CONCLUSIONS: Maternal pre-pregnancy overweight and GDM are associated with unhealthy body size and composition in offspring over 20 years later. Effects of maternal pre-pregnancy overweight appear more pronounced.

Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels. DESIGN AND METHODS: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. In each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls. RESULTS: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (⩾98 cm) had significantly lower high density lipoprotein (HDL) levels, Apo A1 and albumin values compared with the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, associated adversely with insulin levels and HOMA IR in cases but not in the controls. CONCLUSIONS: Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long-term health of women with PCOS.

Hyperemesis gravidarum and cardiometabolic risk factors in adolescents: a follow-up of the Northern Finland Birth Cohort 1986.

OBJECTIVE: To investigate the long-term consequences of prenatal exposure to maternal hyperemesis gravidarum upon offspring cardiometabolic risk factors. DESIGN: This study is part of the prospective follow-up of the Northern Finland Birth Cohort 1986. SETTING: Between 1 July 1985 and 30 June 1986 all pregnant women in two provinces of Finland were recruited at first antenatal visit (99% of eligible participated). POPULATION: A total of 8953 women with liveborn singleton offspring who consented to having their children followed-up were included. METHODS: Hyperemesis gravidarum (HG) was defined as hospitalisation during pregnancy for HG based on the International Classification of Disease (ICD) code. Women who were not hospitalised for HG during pregnancy were used as a reference group. Data on pregnancy and birth outcomes were obtained via medical records and questionnaires; 6462 adolescents, aged 16 years, underwent anthropometric measurements (HG n = 42, reference n = 6420) and 5648 adolescents had a fasting blood sample taken (HG n = 36, reference n = 5612). MAIN OUTCOME MEASURES: Body mass index (BMI), blood pressure, fasting glucose, and lipid levels in offspring. RESULTS: Multivariate regression analyses showed no differences in offspring BMI (kg/m2 ; adjusted percentage difference HG versus reference, 2.2; 95% CI -0.1, 4.6), systolic blood pressure (adjusted difference 2.1 mmHg; 95% CI -1.5, 5.6), and fasting blood glucose (mmol/l; adjusted percentage difference, 2.3; 95% CI -0.6, 5.4), between adolescents born to mothers with and without HG. CONCLUSIONS: We found no evidence that prenatal exposure to HG has negative consequences for cardiometabolic health of offspring at the age of 16 years. TWEETABLE ABSTRACT: Hyperemesis gravidarum does not affect cardiometabolic health in adolescent offspring.

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.

Body mass index trajectories from 2 to 18 years - exploring differences between European cohorts.

BACKGROUND: In recent decades, there has been an increase in the prevalence of childhood overweight in most high-income countries. Within northern Europe, prevalence tends to be higher in the UK compared with the Scandinavian countries. We aimed to study differences in body mass index (BMI) trajectories between large cohorts of children from UK and Scandinavian populations. METHODS: We compared BMI trajectories in participants from the English Avon Longitudinal Study of Parents and Children born in 1991-1993 (ALSPAC) (N = 6517), the Northern Finland Birth Cohorts born in 1966 (NFBC1966) (N = 3321) and 1986 (NFBC1986) (N = 4764), and the Danish Aarhus Birth Cohort born in 1990-1992 (ABC) (N = 1920). We used multilevel models to estimate BMI trajectories from 2 to 18 years. We explored whether cohort differences were explained by maternal BMI, height, education or smoking during pregnancy and whether differences were attributable to changes in the degree of skew in the BMI distribution. RESULTS: Differences in mean BMI between the cohorts were small but emerged early and persisted in most cases across childhood. Girls in ALSPAC had a higher BMI than all other cohorts throughout childhood, e.g. compared with the NFBC1986 BMI was 2.2-3.5% higher. For boys, the difference emerging over time (comparing the two NFBC's) exceeded the differences across populations (comparing NFBC1986, ABC and ALSPAC). BMI distribution demonstrated increasing right skew with age. CONCLUSION: Population-level differences between cohorts were small, tended to emerge very early, persisted across childhood, and demonstrated an increase in the right-hand tail of the BMI distribution.

Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus-a prospective, population-based cohort study.

STUDY QUESTION: What are the respective roles of polycystic ovary syndrome (PCOS), long-term weight gain and obesity for the development of prediabetes or Type 2 diabetes mellitus (T2DM) by age 46 years? SUMMARY ANSWER: The risk of T2DM in women with PCOS is mainly due to overweight and obesity, although these two factors have a synergistic effect on the development of T2DM. WHAT IS KNOWN ALREADY: PCOS is associated with an increased risk of prediabetes and T2DM. However, the respective roles of PCOS per se and BMI for the development of T2DM have remained unclear. STUDY DESIGN, SIZE, DURATION: In a prospective, general population-based follow-up birth cohort 1966 (n = 5889), postal questionnaires were sent at ages 14 (95% answered), 31 (80% answered) and 46 years (72% answered). Questions about oligoamenorrhoea and hirsutism were asked at age 31 years, and a question about PCOS diagnosis at 46 years. Clinical examination and blood sampling were performed at 31 years in 3127 women, and at 46 years in 3280 women. A 2-h oral glucose tolerance test (OGTT) was performed at 46 years of age in 2780 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women reporting both oligoamenorrhoea and hirsutism at age 31 years and/or diagnosis of PCOS by 46 years were considered as women with PCOS (n = 279). Women without any symptoms at 31 years and without PCOS diagnosis by 46 years were considered as controls (n = 1577). The level of glucose metabolism was classified according to the results of the OGTT and previous information of glucose metabolism status from the national drug and hospital discharge registers. MAIN RESULTS AND THE ROLE OF CHANCE: PCOS per se significantly increased the risk of T2DM in overweight/obese (BMI ≥ 25.0 kg/m2) women with PCOS when compared to overweight/obese controls (odds ratio: 2.45, 95% CI: 1.28-4.67). Normal weight women with PCOS did not present with an increased risk of prediabetes or T2DM. The increase in weight between ages 14, 31 and 46 years was significantly greater in women with PCOS developing T2DM than in women with PCOS and normal glucose tolerance, with the most significant increase occurring in early adulthood (between 14 and 31 years: median with [25%; 75% quartiles]: 27.25 kg [20.43; 34.78] versus 13.80 kg [8.55; 20.20], P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The diagnosis of PCOS was based on self-reporting, and the questionnaire at 46 years did not distinguish between polycystic ovaries only in ultrasonography and the syndrome. Ovarian ultrasonography was not available to aid the diagnosis of PCOS. WIDER IMPLICATIONS OF THE FINDINGS: These results emphasize weight management already during adolescence and early adulthood to prevent the development of T2DM in women with PCOS, as the period between 14 and 31 years seems to be a crucial time-window during which the women with PCOS who are destined to develop T2DM by 46 years of age experience a dramatic weight gain. Furthermore, our results support the view that, particularly in times of limited sources of healthcare systems, OGTT screening should be targeted to overweight/obese women with PCOS rather than to all women with PCOS. STUDY FUNDING/COMPETING INTERESTS: Finnish Medical Foundation; North Ostrobothnia Regional Fund; Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE); Sigrid Juselius Foundation; Biocenter Oulu; University Hospital Oulu and University of Oulu (75617); Medical Research Center Oulu; National Institute for Health Research (UK); National Heart, Lung, and Blood Institute (grant 5R01HL087679-02) through the STAMPEED program (1RL1MH083268-01); National Institute of Health/National Institute of Mental Health (5R01MH63706:02); ENGAGE project and grant agreement HEALTH-F4-2007-201413; EU FP7 EurHEALTHAgeing-277849 European Commission and Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and Medical Research Center, Centenary Early Career Award. The authors have no conflicts of interests. TRIAL REGISTRATION NUMBER: N/A.

Association between occupational psychosocial factors and waist circumference is modified by diet among men.

BACKGROUND/OBJECTIVES: Occupational psychosocial stress has been identified as a risk factor for obesity, whereas dietary habits have a key role in weight control. We examined whether dietary habits modify the association between occupational psychosocial factors and waist circumference. SUBJECTS/METHODS: Data comprised 31-year-old men (n=2222) and women (n=2053) in the Northern Finland Birth Cohort 1966. Waist circumference was measured and data on occupational psychosocial factors (demands, control and social support) and other characteristics were obtained through questionnaires. Healthy and unhealthy diet indices were constructed according to the current dietary guidelines. Associations were examined using analysis of variance adjusted for body mass index at age 14, basic education level, leisure-time physical activity, alcohol consumption, smoking, stress-related eating behaviour and parity. RESULTS: Among men, high job demands and high job control were associated with greater waist circumferences, and there were interactions between unhealthy diet and job demands (P=0.043) and job control (P=0.036) in relation to waist circumference. The waist of men with high demands or high control and low consumption of unhealthy foods (red/processed meat, hamburgers and pizzas, fried potatoes, sugar-sweetened soft drinks and white bread) was smaller than that of men with high demands or high control and high consumption of such foods. No associations were found among women. CONCLUSIONS: A diet based on the current dietary guidelines seems to cancel out the adverse effects of occupational psychosocial factors on waist circumference among young men. Longitudinal studies are needed to assess the risks for obesity-related diseases arising from psychosocial work environments and dietary habits.

Irregular menstruation and hyperandrogenaemia in adolescence are associated with polycystic ovary syndrome and infertility in later life: Northern Finland Birth Cohort 1986 study.

STUDY QUESTION: Do teenage girls with a history of menstrual irregularity and/or elevated androgen levels in adolescence exhibit an increased risk of polycystic ovary syndrome (PCOS) and/or infertility later on in adulthood? SUMMARY ANSWER: Our results suggest that menstrual irregularity and/or elevated androgen levels at 16 years are still associated with symptoms of PCOS at 26 years as well as infertility problems at 26 years but not with decreased pregnancy or delivery rates at 26 years. WHAT IS KNOWN ALREADY: Hyperandrogenaemia is associated with menstrual irregularity, hirsutism, acne and potentially higher risk for PCOS, but there are few follow-up studies investigating whether adolescent hyperandrogenaemia and/or menstrual irregularity are an early sign of PCOS. STUDY DESIGN, SIZE, DURATION: A prospective population-based cohort study was conducted using two postal questionnaires targeting girls in the Northern Finland Birth Cohort 1986 (NFBC1986, n = 4567). The NFBC1986 comprises all expected births from the year 1986 in the two northernmost provinces of Finland. Collection of the database was performed at the age of 16 and 26. The 16-year and 26-year questionnaires included one question about the regularity and length of the menstrual cycle. The 26-year questionnaire also included questions about symptoms of PCOS, reproduction and infertility problems. PARTICIPANTS, SETTING, METHODS: The response rates for the questionnaires were 80% (n = 3669) at 16 years and 50% (n = 2270) at 26 years. At 15-16 years, of 2448 girls, 709 (29%) girls reported menstrual irregularity (symptomatic girls) and 1739 (71%) had regular periods (non-symptomatic girls). After combining data from the two questionnaires a total of 2033 girls were included in the analyses. The χ(2) and Student's t-test was used to compare reproductive outcome and prevalence of clinical hyperandrogenaemia, PCOS and infertility at 26 years between the study groups. Univariate and multivariate logistic regression models were employed to estimate the association of menstrual irregularity at 16 years with clinical hyperandrogenaemia, PCOS and infertility at 26 years. MAIN RESULTS AND THE ROLE OF CHANCE: At follow-up, the proportion of symptomatic girls who had conceived at least once (68.0 versus 67.9%) and had delivered at least one child (25.7 versus 28.1%) was similar to the non-symptomatic women and the groups had similar miscarriage rates (11.6 versus 12.1%). Logistic regression analyses indicated that menstrual irregularity at 16 years was associated with an increased risk of menstrual irregularity [adjusted odds ratio (OR) 1.37, 95% confidence interval (CI) 1.00-1.88, P = 0.050], PCOS (adjusted OR 2.91, 95% CI 1.74-4.84, P < 0.001) and infertility problems (adjusted OR 2.07, 95% CI 1.16-3.76, P = 0.013) at 26 years. At 26 years, women with PCOS (P = 0.013), hirsutism (P = 0.001) and acne (P < 0.001) exhibited significantly higher values of free androgen index (FAI) at 16 years than control women. There was a significant linear trend in the higher FAI quartiles at 16 years towards higher prevalence of PCOS (P = 0.005), hirsutism (P < 0.001) and acne (P < 0.001) at 26 years. Only 10.5% of the girls with menstrual irregularity at 16 years had PCOS at 26 years. LIMITATIONS, REASONS FOR CAUTION: The diagnosis of menstrual irregularity was based on a self-reported questionnaire, thus introducing a risk of information bias in reporting the symptoms. Moreover, ovarian ultrasonography was not available to aid the diagnosis of PCOS and there was no clinical evaluation of hyperandrogenism. The relatively low rate of participation to the questionnaire at 26 years may also have biased the results. WIDER IMPLICATIONS OF THE FINDINGS: Our findings confirm that menstrual irregularity and/or elevated androgen levels are already present in adolescence in women with PCOS and infertility in later life, which strengthens the importance of early identification of menstrual irregularity. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland, the Sigrid Juselius Foundation, University Hospital Oulu and University of Oulu, the European Commission and the Medical Research Council, UK, Welcome Trust (089549/Z/09/Z). None of the authors have any conflict of interest.

Anti-Müllerian hormone: correlation with testosterone and oligo- or amenorrhoea in female adolescence in a population-based cohort study.

STUDY QUESTIONS: Can serum anti-Müllerian hormone (AMH) levels measured in female adolescents predict polycystic ovary syndrome (PCOS)-associated features in adolescence and early adulthood? SUMMARY ANSWER: AMH levels associated well with PCOS-associated features (such as testosterone levels and oligoamenorrhoea) in adolescence, but was not an ideal marker to predict PCOS-associated features in early adulthood. WHAT IS KNOWN ALREADY: Several studies have reported that there is a strong correlation between antral follicle count and serum AMH levels and that women with PCOS/PCO have significantly higher serum AMH levels than women with normal ovaries. Other studies have reported an association between AMH serum levels and hyperandrogenism in adolescence, but none has prospectively assessed AMH as a risk predictor for developing features of PCOS during adulthood. STUDY DESIGN, SIZE, DURATION: A subset of 400 girls was selected from the prospective population-based Northern Finland Birth Cohort 1986 (n = 4567 at age 16 and n = 4503 at age 26). The population has been followed from 1986 to the present. PARTICIPANTS/MATERIAL, SETTING, METHODS: At age 16, 400 girls (100 from each testosterone quartile: 50 with oligo- or amenorrhoea and 50 with a normal menstrual cycle) were selected at random from the cohort for AMH measurement. Metabolic parameters were also assessed at age 16 in all participants. Postal questionnaires enquired about oligo- or amenorrhoea, hirsutism, contraceptive use and reproductive health at ages 16 and 26. MAIN RESULTS AND ROLE OF CHANCE: There was a significant correlation between AMH and testosterone at age 16 (r = 0.36, P < 0.001). AMH levels at age 16 were significantly higher among girls with oligo- or amenorrhoea compared with girls with normal menstrual cycles (35.9 pmol/l [95% CI: 33.2;38.6] versus 27.7 pmol/l [95% CI: 25.0;30.4], P < 0.001). AMH at age 16 was higher in girls who developed hirsutism at age 26 compared with the non-hirsute group (31.4 pmol/l [95% CI 27.1;36.5] versus 25.8 pmol/l [95% CI 23.3;28.6], P = 0.036). AMH at age 16 was also higher in women with PCOS at age 26 compared with the non-PCOS subjects (38.1 pmol/l [95% CI 29.1;48.4] versus 30.2 pmol/l [95% CI 27.9;32.4], P = 0.044). The sensitivity and specificity of the AMH (cut-off 22.5 pmol/l) for predicting PCOS at age 26 was 85.7 and 37.5%, respectively. The addition of testosterone did not significantly improve the accuracy of the test. There was no significant correlation between AMH levels and metabolic indices at age 16. IMPLICATIONS, REASONS FOR CAUTION: AMH is related to oligo- or amenorrhoea in adolescence, but it is not a good marker for metabolic factors. The relatively low rate of participation in the questionnaire at age 26 may also have affected the results. AMH was measured in a subset of the whole cohort. AMH measurement is lacking international standardization and therefore the concentrations and cut-off points are method dependent. WIDER IMPLICATIONS FOR THE FINDINGS: Using a high enough cut-off value of AMH to predict which adolescents are likely to develop PCOS in adulthood could help to manage the condition from an early age due to a good sensitivity. However, because of its low specificity, it is not an ideal diagnostic marker, and its routine use in clinical practice cannot, at present, be recommended. STUDY FUNDINGS AND COMPETING INTERESTS: The study was funded by a grant from Wellcome Trust (089549/Z/09/Z) to H.L., S.F. and M.-R.J. Study funding was also received from Oulu University Hospital Research Funds, Sigrid Juselius Foundation and the Academy of Finland. None of the authors have any competing interest to declare.

Serum sex hormone-binding globulin and testosterone in relation to cardiovascular disease risk factors in young men: a population-based study.

OBJECTIVE: Reduced sex hormone-binding globulin (SHBG) concentration predicts insulin resistance and type 2 diabetes, but its association with cardiovascular disease (CVD) risk is unclear. We examined the association between SHBG and cardiovascular risk factors, independently of total testosterone (TT), in young men. DESIGN: Observational, cross-sectional study. SETTING: General community. PARTICIPANTS: The study included 2716 men aged 31 years in the Northern Finland Birth Cohort in 1996 with clinical examination data and fasting blood samples. OUTCOME VARIABLES: Blood pressure (BP), lipids and C-reactive protein (CRP) as biological CVD risk markers. RESULTS: SHBG concentration was significantly and inversely related to systolic and diastolic BP, triglycerides and CRP, but positively to HDL cholesterol after adjusting for insulin, BMI, waist circumference, smoking, education and physical activity (all P<0.05). These linearly graded associations persisted with additional adjustment for TT. SHBG was significantly associated with total cholesterol only with adjustment for covariates and TT (P<0.05). The direction and magnitude of associations between TT and risk factors were variable, but further adjustment for insulin, adiposity and SHBG showed positive associations between TT and BP, total and LDL-cholesterol and triglycerides and an inverse association with CRP (all P<0.05), but its relation with HDL-cholesterol was no longer significant. CONCLUSIONS: In this cohort of young adult men, higher SHBG concentration was associated with a more favourable CVD risk profile, independently of TT. SHBG concentration modified the associations of TT with CVD risk factors.