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Maternal hypothyroidism has been associated with adverse pregnancy outcomes. A large nationwide register-based cohort with data on medication purchases was established to study the associations between maternal hypothyroidism, levothyroxine (LT4) use, and pregnancy and perinatal complications.The data included all singleton births between 2004 and 2013 (N = 571,785) in Finland. Hypothyroid mothers (n = 16,364) were identified in the Finnish Medical Birth Register. Of these women, 95.8% used LT4 medication, and 37.5% had consistent LT4 use during pregnancy. Hypothyroid mothers were compared to mothers without thyroid disease (N = 550,860) using logistic regression. The main outcome measures were pregnancy and perinatal complications.Maternal hypothyroidism was associated with several pregnancy and perinatal complications, including gestational diabetes mellitus (odds ratio [OR] = 1.19 [confidence interval (CI) 1.13-1.25]), gestational hypertension (OR = 1.20 [CI 1.10-1.30]), severe preeclampsia (OR = 1.38 [CI 1.15-1.65]), cesarean section (OR = 1.22 [CI 1.17-1.27]), preterm births (OR = 1.25 [CI 1.16-1.34]), large-for-gestational age newborns (OR = 1.30 [CI 1.19-1.42]), major congenital anomalies (OR = 1.14 [CI 1.06-1.22]), and neonatal intensive care unit admission (OR = 1.23 [CI 1.17-1.29]). However, among mothers with consistent LT4 purchases, only the associations between gestational diabetes mellitus (OR = 1.12 [CI 1.03-1.22]), cesarean section (OR = 1.13 [CI 1.06-1.21]), neonatal intensive care unit admission (OR = 1.09 [CI 1.01-1.29]), and large-for-gestational age newborns (OR = 1.26 [CI 1.10-1.45]) and maternal hypothyroidism remained.Maternal hypothyroidism is associated with several pregnancy and perinatal complications, but consistent LT4 use may reduce many of the risks.

Maternal hypothyroidism and/or hypothyroxinemia have been associated with child's poor neuropsychological development, but the results have been inconsistent.The Northern Finland Birth Cohort 1986 included all expected births within a year (9362 women, 9479 children) from the two northernmost provinces of Finland. Maternal serum samples (n = 5791) were obtained in early pregnancy (M ± SD = 10.7 ± 2.8 weeks' gestation), and serum samples from their children were obtained at 16 years of age (n = 5829). All samples were analyzed for thyrotropin, free thyroxine (fT4), and thyroid peroxidase antibodies. The children's school performance was evaluated by their main teachers at eight years of age, as well as by the adolescents themselves at 16 years of age. Data on possible severe intellectual deficiency and mild cognitive limitation were collected from healthcare records and registries for all children. Logistic regression estimated the odds of poor school performance or severe intellectual deficiency/mild cognitive limitation associated with exposure to maternal thyroid dysfunction. The odds of poor school performance associated with the adolescents' own thyroid function at age 16 were also estimated. Results are presented as odds ratios (OR) with confidence intervals (CI), adjusted for maternal/family covariates and child's sex.Girls of mothers with subclinical hypothyroidism had more self-evaluated difficulties in mathematics than did girls of euthyroid mothers (OR 1.62 [CI 1.06-2.49]). Boys of hypothyroxinemic mothers repeated a school class more often than did boys of euthyroid mothers (OR 5.46 [CI 1.19-25.06]). Adolescents of hyperthyroid mothers had increased odds of poor self-evaluated performance in mathematics (OR 1.61 [CI 1.01-2.49]). Maternal thyroid dysfunction did not increase the odds of a child having severe intellectual deficiency/mild cognitive limitation. At 16 years of age, girls with hyperthyroidism by laboratory measurements had more difficulties in Finnish language (OR 2.82 [CI 1.42-5.61]) than did euthyroid girls. Boys with hypothyroxinemia by laboratory measurement had higher odds of having difficulties in Finnish and/or mathematics (OR 2.13 [CI 1.26-3.62]) than did euthyroid boys.Maternal thyroid dysfunction during early pregnancy was associated with poorer scholastic performance of the adolescent. Additionally, adolescents' own thyroid dysfunction was associated with difficulties in school performance assessed by self-evaluation.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

Background: Living in a farm during early life seems to protect from development of allergic diseases during childhood. However, it remains unclear if the farm environment during early life protects from development of allergic diseases also during adulthood. Methods: In Northern Finland Birth Cohort study subjects born in the northern Finland in 1966 were followed up at the age of 46. Current analyses are based on subjects with information about doctor diagnosed asthma (N=6684) and allergic rhinitis (N=6182) at the age of 46. Prenatal exposure to the farm environment was documented before or at birth. Information on health and sosioeconomic status was collected at the age of 31 and 46 and information on current farm environment at the age of 46. Results: Being born to a family having farm animals decreased the risk of doctor-diagnosed (DD) asthma ever at the age of 46 (adjusted odds ratio [aOR] 0.80, 95% confidence interval [CI] 0.66-0.97), DD allergic rhinitis ever at the age of 46 (aOR 0.72 95% CI 0.62-0.84) and the development of new DD allergic rhinitis between the age of 31 and 46 years (aOR 0.78 95% CI 0.61-1.00). Number of animal species in farm and home environment during early childhood was inversely and dose-dependently associated with the risk of development of new allergic rhinitis between the age of 31 and 46 years. Farm environment during infancy had no effect on the development of new asthma between the age of 31 and 46. Conclusions: This prospective birth cohort study shows, that farm environment during early life may protect from allergic rhinitis, but not from asthma, throughout the life.

Context and Objective The objective of this study was to determine the effects of maternal thyroid dysfunction or antibodies during pregnancy on the cardiometabolic risk factors in children. Design, Setting, and Participants This prospective population-based cohort study, Northern Finland Birth Cohort 1986, included all pregnancies within a year in the area. Maternal serum samples were collected before the 20th week of gestation and analyzed for thyrotropin, free T4, thyroid-peroxidase antibodies (TPO-Abs), and thyroglobulin antibodies (Tg-Abs). Cardiometabolic risk factors in children at the age of 16 years were evaluated via blood sampling and clinical examination. Data were available for 3229 to 4176 mother–child pairs. Main Outcome Measures Waist circumference, blood pressure, lipids and lipoproteins, and insulin resistance were measured. Odds ratios (ORs) with 95% confidence intervals (CIs) of cardiometabolic risk factors in children with and without mothers with thyroid dysfunction or antibodies were calculated with logistic regression and adjusted for covariates. Results Children of TPO-Ab–positive mothers had higher odds of metabolic syndrome (OR, 2.57; 95%, CI 1.26 to 5.25) and waist circumference indicative of metabolic syndrome (OR, 1.69; 95% CI, 1.14 to 2.50). They were also more likely to be overweight or obese (OR, 1.56; 95% CI, 1.04 to 2.34). Maternal thyroid dysfunction or Tg-Ab positivity did not associate with cardiometabolic risk factors in children. Conclusion Metabolic syndrome, greater waist circumference, and higher body mass index were more prevalent in children of TPO-Ab–positive mothers, indicating an adverse cardiovascular health profile.

ObjectiveReduced 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.DesignObservational, cross-sectional study.SettingGeneral community.ParticipantsThe study included 2716 men aged 31 years in the Northern Finland Birth Cohort in 1996 with clinical examination data and fasting blood samples.Outcome variablesBlood pressure (BP), lipids and C-reactive protein (CRP) as biological CVD risk markers.ResultsSHBG 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 (allPPPConclusionsIn 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.

Is there a different risk for major congenital anomalies (CAs) in children born after frozen-thawed embryo transfer (FET) compared with children born after fresh embryo transfer (ET)?Children born after FET have a similar risk of developing major CAs as children born after fresh ET.The perinatal outcome in children born after FET is as good as that after fresh ET. Children born as a result of assisted reproductive technology (ART) have an increased risk for CAs when compared with spontaneously conceived children, but the knowledge on the risk for CAs in specific organ systems of children born after FET is limited.This register-based cohort study includes women who have undergone ART treatments with ET leading to singleton births (n = 4772) between the years 1995 and 2006. The women were identified from the registers of the infertility clinics, and the corresponding births were matched with data from the Finnish Medical Birth Register (FMBR). The 10% random sample of women with spontaneous pregnancies from the FMBR served as the reference group (n = 31,243). The study data were linked with the Register of Congenital Malformations using the mothers' and children's personal identification numbers to get information on CAs. Furthermore, the personal identification numbers of the ART women were linked with the Register of Induced Abortions to find their selective terminations of pregnancy for severe foetal anomalies.The study was focused on singleton births and included 1830 children born after FET, 2942 children born after fresh ET and 31 243 children born after spontaneous pregnancies. Only major CAs were analysed in keeping with European Concerted Action on Congenital Anomalies and Twins. The risk estimates for CAs were adjusted for the children's year of birth and maternal age, parity and socioeconomic status. The total prevalence of major CAs was counted, including both births and selective terminations of pregnancy for major fetal anomalies (n = 33).Among singletons at least one major CA was reported in 77 cases (4.2%) in the FET group, 132 cases (4.5%) in the fresh ET group and 994 cases (3.2%) in the reference group. The risk for at least one major CA of the children born after FET was not increased compared with the children born after fresh ET [adjusted odd ratio (aOR) 0.95; 0.71-1.27]. Furthermore, no increased risks according to the organ system affected were found between these two ART groups. When comparing the children born after ART (FET and fresh ET) with the reference group children, the risk of having at least one major CA was moderately increased in the ART group (aOR 1.24; 1.05-1.47).Because of the study design we were neither able to examine the aetiology of infertility nor could we compare the data with a group of subfertile women to account for the effect of infertility per se on CAs.Perinatal outcomes of FET children, including the risks for CAs, are good and comparable with outcomes of other ART children indicating that slow freezing is a safe method to use during ART treatments.University Hospital of Oulu and Helsinki, Finland. THL covered the data linkages and the work of Annukka Ritvanen and Mika Gissler. There are no competing interests to be reported.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.

Background— Preeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension. Methods and Results— The Northern Finland Birth Cohort 1966 included all expected births from 1 year ( N =12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 [95% CI, 1.24–1.68]), myocardial infarcts (HR, 1.75 [95% CI, 1.40–2.19]), myocardial infarct death (HR, 3.00 [95% CI, 1.98–4.55]), heart failure (HR, 1.78 [95% CI, 1.43–2.21]), ischemic stroke (HR, 1.59 [95% CI, 1.24–2.04]), kidney disease (HR, 1.91 [95% CI, 1.18–3.09]), and diabetes mellitus (HR, 1.52 [95% CI, 1.21–1.89]). Isolated systolic hypertension was associated with increased risk of myocardial infarct death (HR, 2.15 [95% CI, 1.35–3.41]), heart failure (HR, 1.43 [95% CI, 1.13–1.82]), and diabetes mellitus (HR, 1.42 [95% CI, 1.13–1.78]), whereas isolated diastolic hypertension was associated with increased risk of ischemic heart disease (HR, 1.26 [95% CI, 1.05–1.50]). Results were similar in nonsmoking women aged Conclusions— Elevated blood pressure during pregnancy, regardless of type and even without known risk factors, signals high risk of later cardiovascular disease, chronic kidney disease, and diabetes mellitus. Clinical monitoring, risk factor evaluation, and early intervention could benefit women with hypertension in pregnancy.

The aim of the study was to investigate the impact of de novo hypertension in pregnancy, i.e. gestational (non-proteinuric) hypertension (GH) and preeclampsia (PE), on the long-term metabolic outcome of the offspring. Data was obtained from the Northern Finland Birth Cohort 1986 (NFBC 1986), including 9,362 pregnancies and subsequent births between 1985 and 1986. Pregnancies were categorised into three groups: (1) GH with blood pressure (BP) ≥ 140/90 mmHg, (2) PE with BP ≥ 140/90 mmHg and proteinuria, and (3) reference group with normal BP. The final study population included 331 offspring of mothers with GH, 197 with PE and 5,045 offspring of normotensive mothers. The main outcome measures were systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), body mass index (BMI), and serum lipid, glucose and insulin levels of the 16 year-old offspring. The children of mothers with GH had higher BP compared to the reference group (SBP percentage difference 2.7 (95 % CI 1.6, 3.8); DBP 3.4 (2.1, 4.6); MAP 3.1 (2.0, 4.1), P

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10 -8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. © 2013 Nature America, Inc. All rights reserved.

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified beta-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 x 10(-12)). beta-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific beta-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

OBJECTIVE: We compared the metabolic and cardiovascular parameters of a reference group of women with those of women who used 2 contraceptive regimes that are used worldwide: the levonorgestrel-releasing intrauterine device and oral contraceptives. STUDY DESIGN: We investigated a cohort of 2814 women at age 31 years from the general population-based Northern Finland Birth Cohort who were born in 1966. Women were classified as oral contraceptive users (n = 687 women), levonorgestrel-releasing intrauterine device users (n = 168 women), or no use of hormonal contraception (reference group; n = 1959 women). The analyses were adjusted for body mass index, current alcohol use, household income, and area of residence. RESULTS: Compared with the reference group, oral contraceptive users had higher systolic and diastolic blood pressure, raised levels of inflammatory indices (C-reactive protein), and impaired insulin sensitivity. Levonorgestrel-releasing intrauterine device users displayed a lower high-density lipoprotein and total cholesterol, but a similar cholesterol/ high-density lipoprotein ratio, and higher leukocyte count compared with the reference group. Oral contraception users were insulin-resistant compared with levonorgestrel-releasing intrauterine device users with higher blood pressure, raised lipid levels (such as total cholesterol and triglycerides) and insulin levels, and lower homeostasis model assessment and insulin sensitivity, despite smaller waist and lower waist-hip ratio. CONCLUSION: Oral contraception usage was associated with adverse findings in several metabolic, cardiovascular, and inflammatory parameters, which is consistent with an increased future risk of cardiovascular and metabolic disease. These findings should invite more criticism of recent trends that encourage the prescription of oral contraceptives for years during reproductive life and especially in premenopausal women. In contrast, levonorgestrel-releasing intrauterine device or progestin-only pills may offer long-term health benefits over oral contraceptives and should be preferred to oral contraceptives for women in their forties and/or with metabolic risk factors for cardiovascular diseases and type 2 diabetes mellitus.

Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene-environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci.

Data on the birth weight–blood pressure relationship are inconsistent. Although an inverse association has been suggested in several large studies, interpretation is complicated by publication and other biases. Few data are available on the relationship between other early growth measures and blood pressure. We examined the shape and size of association between determinants of fetal growth, size at birth, growth in infancy, and adult systolic and diastolic blood pressure at 31 years in the prospective northern Finnish 1966 birth cohort of 5960 participants. Birth weight, birth length, gestational age, ponderal index, and birth weight relative to gestational age showed a significant inverse association with blood pressure at age 31. Rapid growth in infancy (“change-up”) was positively associated with blood pressure. Adjusted regression coefficients for birth weight indicated systolic/diastolic blood pressure lower by −1.7 (95% confidence interval [CI], −2.5, −1.0)/−0.7 (95% CI, −1.4, −0.02) mm Hg for 1 kg higher birth weight. The significant inverse association between birth weight and systolic blood pressure persisted without adjustment for adult body mass index for males. Among females, gestational age showed a stronger association with blood pressure than birth weight: gestational age higher by 7 weeks (equivalent to an average of 1 kg higher birth weight) among singletons associated with −2.9 (95% CI, −4.7, −1.1) mm Hg lower systolic blood pressure. Our results support the concept that birth weight, other birth measures, and infant growth are important determinants of blood pressure and hence cardiovascular disease risk in later life.

OBJECTIVE: To investigate the occurrence of oligo-amenorrhoea and hirsutism, infertility and metabolic morbidity among first-degree relatives of women with and without self-reported oligo-amenorrhoea and hirsutism. DESIGN: Nested case-control study. SETTING, POPULATION AND METHODS: A postal questionnaire about symptoms of oligo-amenorrhoea and hirsutism was sent to all women of the Northern Finland Birth Cohort 1966 (n = 5889). From this population were randomly selected 98 women with both symptoms and 163 without symptoms. A further questionnaire on the occurrence of oligo-amenorrhoea, hirsutism, infertility, early balding and metabolic morbidity in their relatives was sent to this subpopulation. MAIN FINDINGS: We obtained data on 183 relatives of 43 women with symptoms and 412 relatives of 86 symptomless women. Compared with relatives of symptomless women, mothers of women with symptoms suffered significantly more often from hirsutism and menstrual disorders, and sisters more often from hirsutism and infertility, and had fewer children and were more often childless. There was an increased prevalence of diabetes in the sisters and of hypertension in the fathers of women with symptoms. CONCLUSIONS: These results strengthen earlier findings of significantly increased metabolic and reproductive morbidity in the relatives of women with symptoms of PCOS.

Background It remains unclear whether maternal hypertensive disorders could impact cognitive development of the child. The aim of this study was to explore the association between hypertensive disorders and other maternal biological and social factors on the risk of mild cognitive limitations (intelligence quotient 50–85) in the offspring. Methods An 11.5-year follow-up study of the Northern Finland Birth Cohort 1986 (n = 9432) was utilised. The analysis included 8847 singleton children, of whom 198 had mild cognitive limitations. Gestational hypertension was defined as de novo hypertension (blood pressure ≥ 140/90), diagnosed mid-pregnancy in a previously normotensive woman. Data on intelligence level of the children were based on standardised intelligence test results. Results Eleven per cent (n = 20) of mothers having a child with mild cognitive limitations had gestational hypertension. Maternal gestational hypertension was independently associated with increased odds of mild cognitive limitation in the offspring (odds ratio 2.4 [95% confidence interval 1.4, 3.9]). Other independent maternal risk factors for mild cognitive limitation were high pre-pregnancy body mass index (≥30 kg/m2), multiparity (≥4) and low education. In addition family's socio-economic status lower than professional, male gender and small birthweight-for-gestational age appeared as independent risk factors for mild cognitive limitation. Conclusions Gestational hypertension should be considered as one of the adverse early risk factors that may predispose to impaired cognitive development in childhood.

OBJECTIVE Early pubertal onset in females is associated with increased risk for adult obesity and cardiovascular disease, but whether this relationship is independent of preceding childhood growth events is unclear. Furthermore, the association between male puberty and adult disease remains unknown. To clarify the link between puberty and adult health, we evaluated the relationship between pubertal timing and risk factors for type 2 diabetes and cardiovascular disease in both males and females from a large, prospective, and randomly ascertained birth cohort from Northern Finland. RESEARCH DESIGN AND METHODS Pubertal timing was estimated based on pubertal height growth in 5,058 subjects (2,417 males and 2,641 females), and the relationship between puberty and body weight, glucose and lipid homeostasis, and blood pressure at age 31 years was evaluated with linear regression modeling. RESULTS Earlier pubertal timing associated with higher adult BMI, fasting insulin, diastolic blood pressure, and decreased HDL cholesterol in both sexes (P < 0.002) and with higher total serum cholesterol, LDL cholesterol, and triglycerides in males. The association with BMI and diastolic blood pressure remained statistically significant in both sexes, as did the association with insulin levels and HDL cholesterol concentrations in males after adjusting for covariates reflecting both fetal and childhood growth including childhood BMI. CONCLUSIONS We demonstrate independent association between earlier pubertal timing and adult metabolic syndrome-related derangements both in males and females. The connection emphasizes that the mechanisms advancing puberty may also contribute to adult metabolic disorders.

Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P 5 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P 5 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: 24 to 14 g; P 5 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight. © The Author 2012. Published by Oxford University Press. All rights reserved.

Background— Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in 4 Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and nuclear magnetic resonance-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis, and built a genetic risk score for MetS. Methods and Results— A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184 ), was associated with MetS in all 4 study samples ( P =7.23×10 −9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 was associated with various very low density lipoprotein, triglyceride, and high-density lipoprotein metabolites ( P =0.024–1.88×10 −5 ). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these were associated with lipid phenotypes, and none with 2 or more uncorrelated MetS components. A genetic risk score, calculated as the number of risk alleles in loci associated with individual MetS traits, was strongly associated with MetS status. Conclusions— Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits, such as hypertension and glucose intolerance.

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10 -8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10 -11), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10 -12), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10 -3 for 6q22 and 1.2 × 10 -3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size. © 2012 Nature America, Inc. All rights reserved.

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 x 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Eur J Clin Invest 2012; 42 (3): 321–328 Abstract Background Polycystic ovary syndrome (PCOS) is the most common gynaecological endocrinopathy characterized by oligomenorrhea, amenorrhoea, clinical and/or biochemical hyperandrogenism and polycystic ovaries. Abdominal deposition of excess body fat and metabolic diseases like insulin resistance and compensatory hyperinsulinemia are commonly observed in PCOS subjects. It has been suggested that visfatin is an adipokine secreted from the abdominal fat influencing glucose metabolism and might therefore contribute to the metabolic disturbances in PCOS. Materials and methods We measured circulating full-length visfatin levels with a specific enzyme immunoassay (AdipoGen Inc, Incheon, South-Korea) in 57 women with self-reported symptoms of PCOS (hirsutism and/or oligomenorrhea) and ultrasound confirmed polycystic ovaries, and in 57 controls from the Northern Finland 1966 Birth Cohort and explored its association with metabolic and inflammatory parameters. Results Polycystic ovary syndrome cases had higher body mass index (BMI) (25·7 vs. 24·1 kg/m2) and waist circumference (83·2 vs. 78·8 cm) compared to controls, yet there was no difference in plasma visfatin levels between them. In contrast, visfatin significantly correlated with C-reactive protein (CRP) in the control group and with white blood cell count (WBC) in both groups. In linear regression analysis, adjusted for PCOS, smoking, socioeconomic status, BMI or waist circumference, serum lipids and markers of glucose metabolism and hormone status, only WBC remained significantly associated with plasma visfatin levels. Conclusion Our results suggest that circulating visfatin levels correlate with WBC and CRP but are not associated with PCOS, obesity or metabolic markers, suggesting that visfatin may act as a proinflammatory cytokine.

High vitamin D intake in childhood has been suggested to have an adverse influence on linear growth. In Finland, in the mid-1960s the official recommendation for infant vitamin D supplementation was 2000 IU/d (50 μg/d). We investigated whether high-dose vitamin D supplementation in infancy was associated with subsequent growth in height. We used data from a prospective population-based birth cohort study including all children due to be born in the 2 northernmost provinces in Finland in 1966 (12,058 live-births, coverage 96%). Information on each participant's height was collected at birth and ages 1, 14, and 31 y, as were possible confounding factors (data for analyses available from 10,060 singletons). Information on the frequency and dose of vitamin D supplementation was collected in 1967 when participants were 1 y of age. A weak association was found between frequency of vitamin D supplementation with greater height at age 1 y (P = 0.005), which was explained by birth characteristics and maternal and social factors (adjusted P = 0.34). Neither frequency nor dose of vitamin D supplementation was associated with height at 14 or 31 y (P > 0.13). To conclude, contrary to proposed evidence suggesting that vitamin D has a negative influence on growth rate at a dosage of ~2000 IU/d, supplementation at this level in the Northern Finland Birth Cohort was not associated with reduced height at any age studied.

Background CHRNA5-CHRNA3-CHRNB4 and TTC12-ANKK1-DRD2 gene-clusters influence smoking behavior. Our aim was to test developmental changes in their effects as well as the interplays between them and with nongenetic factors. Methods Participants included 4762 subjects from a general population-based, prospective Northern Finland 1966 Birth Cohort (NFBC 1966). Smoking behavior was collected at age 14 and 31 years. Information on maternal smoking, socioeconomic status, and novelty seeking were also collected. Structural equation modeling was used to construct an integrative etiologic model including genetic and nongenetic factors. Results Several single nucleotide polymorphisms in both gene-clusters were significantly associated with smoking. The most significant were in CHRNA3 (rs1051730, p = 1.1 × 10 −5 ) and in TTC12 (rs10502172, p = 9.1 × 10 −6 ). CHRNA3 -rs1051730[A] was more common among heavy/regular smokers than nonsmokers with similar effect-sizes at age 14 years (odds ratio [95% CI]: 1.27 [1.06–1.52]) and 31 years (1.28 [1.13–1.44]). TTC12 -rs10502172[G] was more common among smokers than nonsmokers with stronger association at 14 years (1.33 [1.11–1.60]) than 31 years (1.14 [1.02–1.28]). In adolescence, carriers of three–four risk alleles at either CHRNA3 -rs1051730 or TTC12 -rs10502172 had almost threefold odds of smoking regularly than subjects with no risk alleles. TTC12 -rs10502172 effect on smoking in adulthood was mediated by its effect on smoking in adolescence and via novelty seeking. Effect of CHRNA3 -rs1051730 on smoking in adulthood was direct. Conclusions TTC12-ANKK1-DRD2 s seemed to influence smoking behavior mainly in adolescence, and its effect is partially mediated by personality characteristics promoting drug-seeking behavior. In contrast, CHRNA5-CHRNA3-CHRNB4 is involved in the transition toward heavy smoking in mid-adulthood and in smoking persistence. Factors related to familial and social disadvantages were strong independent predictors of smoking.

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.