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1.  Life-Course Analysis of a Fat Mass and Obesity-Associated (FTO) Gene Variant and Body Mass Index in the Northern Finland Birth Cohort 1966 Using Structural Equation Modeling 
American Journal of Epidemiology  2010;172(6):653-665.
The association between variation in the fat mass and obesity-associated (FTO) gene and adulthood body mass index (BMI; weight (kg)/height (m)2) is well-replicated. More thorough analyses utilizing phenotypic data over the life course may deepen our understanding of the development of BMI and thus help in the prevention of obesity. The authors used a structural equation modeling approach to explore the network of variables associated with BMI from the prenatal period to age 31 years (1965–1997) in 4,435 subjects from the Northern Finland Birth Cohort 1966. The use of structural equation modeling permitted the easy inclusion of variables with missing values in the analyses without separate imputation steps, as well as differentiation between direct and indirect effects. There was an association between the FTO single nucleotide polymorphism rs9939609 and BMI at age 31 years that persisted after controlling for several relevant factors during the life course. The total effect of the FTO variant on adult BMI was mostly composed of the direct effect, but a notable part was also arising indirectly via its effects on earlier BMI development. In addition to well-established genetic determinants, many life-course factors such as physical activity, in spite of not showing mediation or interaction, had a strong independent effect on BMI.
doi:10.1093/aje/kwq178
PMCID: PMC2938267  PMID: 20702506
body mass index; molecular epidemiology; structural equation model
2.  Early growth and adult respiratory function in men and women followed from the fetal period to adulthood 
Thorax  2006;62(5):396-402.
Background
While some studies suggest that poor fetal growth rate, as indicated by lower birth weight, is associated with poor respiratory function in childhood, findings among adults remain inconsistent. A study was undertaken to determine the association between early growth and adult respiratory function.
Methods
A longitudinal birth cohort study was performed of 5390 men and women born full term and prospectively followed from the fetal period to adulthood. Weight at birth and infancy were recorded, and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were assessed by standard spirometry at age 31 years.
Results
Adult FEV1 and FVC increased linearly with higher birth weight in both men and women with no apparent threshold. After adjustment for sex, adult height and other potential confounders operating through the life course, every 500 g higher birth weight was associated with a higher FEV1 of 53.1 ml (95% CI 38.4 to 67.7) and higher FVC of 52.5 ml (95% CI 35.5 to 69.4). These positive associations persisted across categories of smoking, physical activity and body mass index, with the lowest respiratory function noted among those with lower birth weight who were smokers, led a sedentary lifestyle or were overweight. Weight gain in infancy was also positively associated with adult lung function.
Conclusion
Birth weight is continuously and independently associated with adult respiratory function. It is plausible that poor growth in early life may restrict normal lung growth and development, which could have long‐term consequences on lung function later in life.
doi:10.1136/thx.2006.066241
PMCID: PMC2117170  PMID: 17105780
3.  Genome metabolome integrated network analysis to uncover connections between genetic variants and complex traits: an application to obesity 
Current studies of phenotype diversity by genome-wide association studies (GWAS) are mainly focused on identifying genetic variants that influence level changes of individual traits without considering additional alterations at the system-level. However, in addition to level alterations of single phenotypes, differences in association between phenotype levels are observed across different physiological states. Such differences in molecular correlations between states can potentially reveal information about the system state beyond that reported by changes in mean levels alone. In this study, we describe a novel methodological approach, which we refer to as genome metabolome integrated network analysis (GEMINi) consisting of a combination of correlation network analysis and genome-wide correlation study. The proposed methodology exploits differences in molecular associations to uncover genetic variants involved in phenotype variation. We test the performance of the GEMINi approach in a simulation study and illustrate its use in the context of obesity and detailed quantitative metabolomics data on systemic metabolism. Application of GEMINi revealed a set of metabolic associations which differ between normal and obese individuals. While no significant associations were found between genetic variants and body mass index using a standard GWAS approach, further investigation of the identified differences in metabolic association revealed a number of loci, several of which have been previously implicated with obesity-related processes. This study highlights the advantage of using molecular associations as an alternative phenotype when studying the genetic basis of complex traits and diseases.
doi:10.1098/rsif.2013.0908
PMCID: PMC3973353  PMID: 24573330
correlation analysis; differential networks; genome-wide association analysis; metabolomics; GEMINi
4.  Stress-related eating, obesity and associated behavioural traits in adolescents: a prospective population-based cohort study 
BMC Public Health  2014;14:321.
Background
Stress-related eating is associated with unhealthy eating and drinking habits and an increased risk of obesity among adults, but less is known about factors related to stress-driven eating behaviour among children and adolescents. We studied the prevalence of stress-related eating and its association with overweight, obesity, abdominal obesity, dietary and other health behaviours at the age of 16. Furthermore, we examined whether stress-related eating is predicted by early-life factors including birth size and maternal gestational health.
Methods
The study population comprised 3598 girls and 3347 boys from the Northern Finland Birth Cohort 1986 (NFBC1986). Followed up since their antenatal period, adolescents underwent a clinical examination, and their stress-related eating behaviour, dietary habits and other health behaviours were assessed using a postal questionnaire. We examined associations using cross-tabulations followed by latent class analysis and logistic regression to profile the adolescents and explain the risk of obesity with behavioural traits.
Results
Stress-related eating behaviour was more common among girls (43%) than among boys (15%). Compared with non-stress-driven eaters, stress-driven eaters had a higher prevalence of overweight, obesity and abdominal obesity. We found no significant associations between stress-eating and early-life factors. Among girls, tobacco use, shorter sleep, infrequent family meals and frequent consumption of chocolate, sweets, light sodas and alcohol were more prevalent among stress-driven eaters. Among boys, the proportions of those with frequent consumption of sausages, chocolate, sweets, hamburgers and pizza were greater among stress-driven eaters. For both genders, the proportions of those bingeing and using heavy exercise and strict diet for weight control were higher among stress-eaters. Besides a ‘healthy lifestyle’ cluster, latent class analysis revealed two other patterns (‘adverse habits’, ‘unbalanced weight control’) that significantly explained the risk of overweight among boys and girls.
Conclusions
Stress-related eating is highly prevalent among 16-year-old girls and is associated with obesity as well as adverse dietary and other health behaviours among both genders, but intrauterine conditions are seemingly uninvolved. In terms of obesity prevention and future health, adolescents who use eating as a passive way of coping could benefit from learning healthier strategies for stress and weight management.
doi:10.1186/1471-2458-14-321
PMCID: PMC3995503  PMID: 24708823
Adolescent; Body mass index; Cohort studies; Diet; Drinking behaviour; Health behaviour; Latent class analysis; Obesity; Psychological stress
5.  Genetic association analysis of vitamin D pathway with obesity traits 
Objective
Observational studies have examined the link between vitamin D deficiency and obesity traits. Some studies have reported associations between vitamin D pathway genes such as VDR, GC and CYP27B1 with body mass index (BMI) and waist circumference (WC); however, the findings have been inconsistent. Hence, we investigated the involvement of vitamin D metabolic pathway genes in obesity-related traits in a large population-based study.
Methods
We undertook a comprehensive analysis between 100 tagging polymorphisms (tagSNPs) in genes encoding for DHCR7, CYP2R1, VDBP, CYP27B1, CYP27A1, CYP24A1, VDR and RXRG and obesity traits in 5,224 participants (aged 45 years) in the 1958 British birth cohort (1958BC). We further extended our analyses to investigate the associations between SNPs and obesity traits using the summary statistics from the GIANT (Genetic Investigation of Anthropometric Traits) consortium (n=123,865).
Results
In the 1958BC (n=5,224), after Bonferroni correction, none of the tagSNPs were associated with obesity traits except for one tagSNP from CYP24A1 that was associated with waist-hip ratio (WHR) (rs2296239, P=0.001). However, the CYP24A1 SNP was not associated with BMI-adjusted WHR (WHRadj) in the 1958BC (rs2296239, P=1.00) and GIANT results (n=123,865, P=0.18). There was also no evidence for an interaction between the tagSNPs and obesity on BMI, WC, WHR and WHRadj in the 1958BC. In the GIANT consortium, none of the tagSNPs were associated with obesity traits.
Conclusions
Despite a very large study, our findings suggest that the vitamin D pathway genes are unlikely to have a major role in obesity-related traits in the general population.
doi:10.1038/ijo.2013.6
PMCID: PMC3763965  PMID: 23381556
Vitamin D pathway; 1958 British birth cohort; tagSNPs; obesity; GIANT; BMI
6.  Assessing multivariate gene-metabolome associations with rare variants using Bayesian reduced rank regression 
Bioinformatics  2014;30(14):2026-2034.
Motivation: A typical genome-wide association study searches for associations between single nucleotide polymorphisms (SNPs) and a univariate phenotype. However, there is a growing interest to investigate associations between genomics data and multivariate phenotypes, for example, in gene expression or metabolomics studies. A common approach is to perform a univariate test between each genotype–phenotype pair, and then to apply a stringent significance cutoff to account for the large number of tests performed. However, this approach has limited ability to uncover dependencies involving multiple variables. Another trend in the current genetics is the investigation of the impact of rare variants on the phenotype, where the standard methods often fail owing to lack of power when the minor allele is present in only a limited number of individuals.
Results: We propose a new statistical approach based on Bayesian reduced rank regression to assess the impact of multiple SNPs on a high-dimensional phenotype. Because of the method’s ability to combine information over multiple SNPs and phenotypes, it is particularly suitable for detecting associations involving rare variants. We demonstrate the potential of our method and compare it with alternatives using the Northern Finland Birth Cohort with 4702 individuals, for whom genome-wide SNP data along with lipoprotein profiles comprising 74 traits are available. We discovered two genes (XRCC4 and MTHFD2L) without previously reported associations, which replicated in a combined analysis of two additional cohorts: 2390 individuals from the Cardiovascular Risk in Young Finns study and 3659 individuals from the FINRISK study.
Availability and implementation: R-code freely available for download at http://users.ics.aalto.fi/pemartti/gene_metabolome/.
Contact: samuli.ripatti@helsinki.fi; samuel.kaski@aalto.fi
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu140
PMCID: PMC4080737  PMID: 24665129
7.  Preeclampsia, gestational hypertension and subsequent hypothyroidism 
Pregnancy hypertension  2012;3(1):21-27.
Objectives
To evaluate the effect of preeclampsia (PE) and gestational hypertension (GH) on subsequent hypothyroidism. Recent studies suggest that women with PE have increased risk for reduced thyroid function, but the association between PE and GH with overt hypothyroidism has not been examined.
Study design
Two prospective population-based cohort studies, the Northern Finland Birth Cohorts 1966 and 1986, followed women who had PE (N=955), GH (N=1449) or were normotensive (N=13531) during pregnancy. Finnish national registers were used to confirm subsequent hypothyroidism. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) estimated hypothyroidism risk when comparing women with PE or GH with normotensive women.
Main outcome measures
Primary hypothyroidism during follow-up of 20–40 years.
Results
The subsequent prevalence of hypothyroidism was higher among women with PE (4.0%) and GH (4.5%) compared with normotensive women (3.5%), but the risk increase was not significant (aHR for PE 1.13, 95%CI 0.80–1.59 and aHR for GH 1.11, 95%CI 0.85–1.45).
Subgroup analysis among nulliparous women revealed a significant association between late PE and subsequent hypothyroidism (aHR 1.82, 95%CI 1.04–3.19).
Early or recurrent PE were not associated with hypothyroidism (aHR 0.93, 95%CI 0.46–1.81 and aHR 1.35, 95%CI 0.63–2.88, respectively).
Conclusions
Overall, PE or GH during pregnancy was not significantly associated with subsequent hypothyroidism in Finnish women after 20–40 years of follow-up. However, late PE in nulliparous women was associated with a 1.8-fold increased risk of subsequent hypothyroidism, a finding that merits further study in other populations.
doi:10.1016/j.preghy.2012.09.001
PMCID: PMC3578699  PMID: 23439671
preeclampsia; gestational hypertension; thyroid; hypothyroidism
8.  Prenatal Glucocorticoid Treatment and Later Mental Health in Children and Adolescents 
PLoS ONE  2013;8(11):e81394.
Background
Animal studies demonstrate a clear link between prenatal exposure to glucocorticoids (GC) and altered offspring brain development. We aim to examine whether prenatal GC exposure programs long-term mental health in humans.
Methods
Using propensity-score-matching, children prenatally exposed to synthetic glucocorticoids (sGC), n=37, and controls, n=185, were balanced on important confounders related to sGC treatment - gestational age and pre-pregnancy BMI. We also used mixed-effects modeling to analyse the entire cohort – matching each sGC case, n=37, to all possible controls, n=6079, on gestational age and sex. We obtained data from the Northern Finland Birth Cohort 1986 at four waves – pregnancy, birth, 8 and 16 years. Data on pregnancy and birth outcomes came from medical records. Mental health was assessed at 8 years by teachers with the Rutter B2 scale, and at 16 years by parents with the Strengths and Weaknesses of ADHD symptoms and Normal behavior (SWAN) scale and adolescents by the Youth Self-Report (YSR) scale.
Results
Prenatal sGC treatment was consistently associated with adverse mental health in childhood and adolescence, as shown by both the propensity-score method and mixed-effects model. Using the propensity-score-matched subsample, linear multiple regression showed prenatal sGC was significantly linked with general psychiatric disturbance (B=8.34 [95% CI: .23-16.45]) and inattention (B= .97 [95% CI: .16-1.80]) at 8 years after control for relevant confounders. Similar findings were obtained at 16 years, but did not reach statistical significance. Mediation by birthweight/placental weight was not detected.
Conclusions
This study is the first to prospectively investigate the long-term associations between prenatal exposure to sGC treatment and mental health in children and adolescents. We report an association between prenatal exposure to sGC and child mental health, supportive of the idea that sGC has a programming effect on the fetal brain.
doi:10.1371/journal.pone.0081394
PMCID: PMC3838350  PMID: 24278432
9.  Long-Term Unemployment Is Associated with Short Telomeres in 31-Year-Old Men: An Observational Study in the Northern Finland Birth Cohort 1966 
PLoS ONE  2013;8(11):e80094.
Objective
Life stress resulting from early-life experiences and domestic stress is linked with shorter leukocyte telomere length (LTL), but evidence on employment-related stress is scarce. We explored whether unemployment in early adulthood is associated with shorter LTL, a potential biomarker of premature aging.
Methods
We used data from 5620 men and women belonging to the Northern Finland Birth Cohort 1966. Individually registered unemployment days in 1995–97 were compared with data on biological, behavioral and socioeconomic health predictors and existing medical conditions obtained by surveys and clinical examinations at follow-up in 1997–98. Mean LTL at follow-up was measured by multiplex quantitative real-time PCR. We calculated odds ratios and their 95% confidence intervals (CI) of belonging to the sex-stratified shortest decile of standardized relative mean LTL according to the categories of: 0, <260, <500 and over 500 unemployment days, representing 0, <1, <2 and over 2 calendar years.
Results
Among men, unemployment exceeding 500 days during three years was associated with having shorter LTL at follow-up, compared to being continuously employed. The corresponding odds ratio was 2.61 (95% CI 1.16 to 5.85) in the fully adjusted model. Such an association was not found among women in this study.
Conclusions
Long-term unemployment in early adulthood is associated with shorter LTL among men.
doi:10.1371/journal.pone.0080094
PMCID: PMC3835859  PMID: 24278245
10.  Meal Frequencies Modify the Effect of Common Genetic Variants on Body Mass Index in Adolescents of the Northern Finland Birth Cohort 1986 
PLoS ONE  2013;8(9):e73802.
Recent studies suggest that meal frequencies influence the risk of obesity in children and adolescents. It has also been shown that multiple genetic loci predispose to obesity already in youth. However, it is unknown whether meal frequencies could modulate the association between single nucleotide polymorphisms (SNPs) and the risk of obesity. We examined the effect of two meal patterns on weekdays –5 meals including breakfast (regular) and ≤4 meals with or without breakfast (meal skipping) – on the genetic susceptibility to increased body mass index (BMI) in Finnish adolescents. Eight variants representing 8 early-life obesity-susceptibility loci, including FTO and MC4R, were genotyped in 2215 boys and 2449 girls aged 16 years from the population-based Northern Finland Birth Cohort 1986. A genetic risk score (GRS) was calculated for each individual by summing the number of BMI-increasing alleles across the 8 loci. Weight and height were measured and dietary data were collected using self-administered questionnaires. Among meal skippers, the difference in BMI between high-GRS and low-GRS (<8 and ≥8 BMI-increasing alleles) groups was 0.90 (95% CI 0.63,1.17) kg/m2, whereas in regular eaters, this difference was 0.32 (95% CI 0.06,0.57) kg/m2 (pinteraction  = 0.003). The effect of each MC4R rs17782313 risk allele on BMI in meal skippers (0.47 [95% CI 0.22,0.73] kg/m2) was nearly three-fold compared with regular eaters (0.18 [95% CI -0.06,0.41] kg/m2) (pinteraction  = 0.016). Further, the per-allele effect of the FTO rs1421085 was 0.24 (95% CI 0.05,0.42) kg/m2 in regular eaters and 0.46 (95% CI 0.27,0.66) kg/m2 in meal skippers but the interaction between FTO genotype and meal frequencies on BMI was significant only in boys (pinteraction  = 0.015). In summary, the regular five-meal pattern attenuated the increasing effect of common SNPs on BMI in adolescents. Considering the epidemic of obesity in youth, the promotion of regular eating may have substantial public health implications.
doi:10.1371/journal.pone.0073802
PMCID: PMC3769374  PMID: 24040077
11.  Smoking and Early Pregnancy Thyroid Hormone and Anti-Thyroid Antibody Levels in Euthyroid Mothers of the Northern Finland Birth Cohort 1986 
Thyroid  2012;22(9):944-950.
Background
Smokers in the general population have lower thyrotropin (TSH) and higher free triiodothyronine (fT3) and free thyroxine (fT4) concentrations, but the results in pregnant population vary from no effect to a decrease in TSH and fT4 concentrations and an increase in fT3 levels. Our objective was to further evaluate the question of whether there is an association between smoking, before and during pregnancy, with maternal thyroid function during pregnancy and with the risk for subsequent hypothyroidism.
Methods
Our study population was a prospective population-based cohort (N=9362), the Northern Finland Birth Cohort 1986, with extensive data throughout gestation. The mothers underwent serum sampling in early pregnancy. The samples were assayed for TSH, fT3, fT4, thyroid-peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (TG-Abs) (n=5805). Mothers with thyroid dysfunction diagnosed before or during pregnancy were excluded, leaving 4837 euthyroid mothers. The smoking status of mothers and fathers were requested by questionnaires during pregnancy. Subsequent maternal morbidity relating to hypothyroidism 20 years after the index pregnancy was evaluated using national registers.
Results
Euthyroid mothers who smoked before, or continued smoking during first trimester of pregnancy, had higher serum fT3 (p<0.001) and lower fT4 (p=0.023) concentrations than nonsmokers. Smoking in the second trimester was associated with higher fT3 (p<0.001) concentrations, but no difference in fT4 concentrations compared with nonsmokers. TG-Abs were less common among smoking than nonsmoking mothers (2.5% vs. 4.7%, p<0.001), but the prevalence of TPO-Ab was similar. Paternal smoking had no independent effect on maternal early pregnancy thyroid hormone or antibody concentrations. The risk of subsequent maternal hypothyroidism after follow-up of 20 years was similar among prepregnancy smokers and nonsmokers.
Conclusions
In euthyroid women, smoking during pregnancy was associated with higher fT3 levels and lower fT4 levels; possibly reflecting smoking-induced changes in peripheral metabolism of thyroid hormones. No differences were found in TSH concentrations between smokers and nonsmokers. Our results differ from those of the general population, which usually have shown smoking-induced thyroidal stimulation. This is possibly due to pregnancy-induced changes in thyroid function. Decreases in fT4 levels among smokers might predispose to hypothyroidism or hypothyroxinemia during pregnancy. Despite these changes in thyroid function, smoking did not increase the woman's risk of subsequent hypothyroidism.
doi:10.1089/thy.2011.0377
PMCID: PMC3429279  PMID: 22873201
12.  The association between physical fitness and depressive symptoms among young adults: results of the Northern Finland 1966 birth cohort study 
BMC Public Health  2013;13:535.
Background
The effect of physical activity on mental health has been the subject of research for several decades. However, there is a lack of studies investigating the association between physical fitness, including both cardiorespiratory and muscular fitness and depressive symptoms among general population. The aim of this study was to determine the association between physical fitness and depressive symptoms among young adults.
Methods
The study population consists of 5497 males and females, members of the Northern Finland birth cohort of 1966, who at age 31 completed fitness tests and filled in a questionnaire including questions about depressive symptoms (Hopkins’ Symptom Checklist-25) and physical activity. Cardiorespiratory fitness was measured by a 4-min step test and muscular fitness by tests of maximal isometric handgrip and isometric trunk extension. The odds ratios (OR) with 95% confidence intervals (95% CI) for having depressive symptoms were calculated for quintiles groups of physical fitness using the third, median quintile as reference group, and the results were adjusted for potential confounding variables.
Results
Depressive symptoms were most common among males and females in the lowest quintile group of trunk extension test (OR 1.58 and 95% CI 1.07-2.32 in males and OR 1.43 and 95% CI 1.03-2.0 in females) and among males in the lowest quintile group of handgrip strength (OR 1.64 95% CI 1.11-2.42) compared to the reference group. Level of self-reported physical activity was inversely associated with depressive symptoms both in males (OR 1.74 95% CI 1.25-2.36) and females (OR 1.36 95% CI 1.05-1.75). The cardiorespiratory fitness was not associated with depressive symptoms (OR 1.01 95% CI 0.68-1.49 in males and 0.82 95% CI 0.57-1.16 in females).
Conclusions
The results indicate that low level of isometric endurance capacity of trunk extensor muscles is associated with high level of depressive symptoms in both sexes. In males, also poor handgrip strength is associated with increased levels of depressive symptoms. The physical activity level is inversely associated with the prevalence of depressive symptoms among young adults.
doi:10.1186/1471-2458-13-535
PMCID: PMC3679735  PMID: 23731782
Physical fitness; Physical activity; Cardiorespiratory fitness; Muscular fitness; Depressive symptoms; Depression; Young adults
13.  Metabolic Signatures of Insulin Resistance in 7,098 Young Adults 
Diabetes  2012;61(6):1372-1380.
Metabolite associations with insulin resistance were studied in 7,098 young Finns (age 31 ± 3 years; 52% women) to elucidate underlying metabolic pathways. Insulin resistance was assessed by the homeostasis model (HOMA-IR) and circulating metabolites quantified by high-throughput nuclear magnetic resonance spectroscopy in two population-based cohorts. Associations were analyzed using regression models adjusted for age, waist, and standard lipids. Branched-chain and aromatic amino acids, gluconeogenesis intermediates, ketone bodies, and fatty acid composition and saturation were associated with HOMA-IR (P < 0.0005 for 20 metabolite measures). Leu, Ile, Val, and Tyr displayed sex- and obesity-dependent interactions, with associations being significant for women only if they were abdominally obese. Origins of fasting metabolite levels were studied with dietary and physical activity data. Here, protein energy intake was associated with Val, Phe, Tyr, and Gln but not insulin resistance index. We further tested if 12 genetic variants regulating the metabolites also contributed to insulin resistance. The genetic determinants of metabolite levels were not associated with HOMA-IR, with the exception of a variant in GCKR associated with 12 metabolites, including amino acids (P < 0.0005). Nonetheless, metabolic signatures extending beyond obesity and lipid abnormalities reflected the degree of insulin resistance evidenced in young, normoglycemic adults with sex-specific fingerprints.
doi:10.2337/db11-1355
PMCID: PMC3357275  PMID: 22511205
14.  Pubertal Timing and Growth Influences Cardiometabolic Risk Factors in Adult Males and Females 
Diabetes Care  2012;35(4):850-856.
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.
doi:10.2337/dc11-1365
PMCID: PMC3308310  PMID: 22338106
15.  Predicting Depression with Psychopathology and Temperament Traits: The Northern Finland 1966 Birth Cohort 
We studied the concurrent, predictive, and discriminate validity of psychopathology scales (e.g., schizotypal and depressive) and temperament traits for hospitalisations due to major depression. Temperament, perceptual aberration, physical and social anhedonia, Depression Subscale of Symptom Checklist (SCL-D), Hypomanic Personality Scale, Schizoidia Scale, and Bipolar II Scale were completed as part of the 31-year follow-up survey of the prospective Northern Finland 1966 Birth Cohort (n = 4941; 2214 males). Several of the scales were related to depression. Concurrent depression was especially related to higher perceptual aberration (effect size when compared to controls, d = 1.29), subsequent depression to high scores in SCL-D (d = 0.48). Physical anhedonia was lower in subjects with subsequent depression than those with other psychiatric disorders (d = −0.33, nonsignificant). Participants with concurrent (d = 0.70) and subsequent (d = 0.54) depression had high harm avoidance compared to controls, while differences compared to other psychiatric patients were small. Subjects with depression differed from healthy controls in most of the scales. Many of the scales were useful predictors for future hospital treatments, but were not diagnosis-specific. High harm avoidance is a potential indicator for subsequent depression.
doi:10.1155/2012/160905
PMCID: PMC3431048  PMID: 22953056
16.  Placental Size Is Associated with Mental Health in Children and Adolescents 
PLoS ONE  2012;7(7):e40534.
Background
The role of the placenta in fetal programming has been recognized as a highly significant, yet often neglected area of study. We investigated placental size in relation to psychopathology, in particular attention deficit hyperactivity disorder (ADHD) symptoms, in children at 8 years of age, and later as adolescents at 16 years.
Methodology/Principal Findings
Prospective data were obtained from The Northern Finland Birth Cohort (NFBC) 1986. Placental weight, surface area and birth weight were measured according to standard procedures, within 30 minutes after birth. ADHD symptoms, probable psychiatric disturbance, antisocial disorder and neurotic disorder were assessed at 8 years (n = 8101), and ADHD symptoms were assessed again at 16 years (n = 6607), by teachers and parents respectively. We used logistic regression analyses to investigate the association between placental size and mental health outcomes, and controlled for gestational age, birth weight, socio-demographic factors and medical factors, during gestation. There were significant positive associations between placental size (weight, surface area and placental-to-birth-weight ratio) and mental health problems in boys at 8 and 16 years of age. Increased placental weight was linked with overall probable psychiatric disturbance (at 8y, OR  = 1.14 [95% CI  = 1.04–1.25]), antisocial behavior (at 8 y, OR  = 1.14 [95% CI  = 1.03–1.27]) and ADHD symptoms (inattention-hyperactivity at 16y, OR  = 1.19 [95% CI  = 1.02–1.38]). No significant associations were detected among girls.
Conclusions/Significance
Compensatory placental growth may occur in response to prenatal insults. Such overgrowth may affect fetal development, including brain development, and ultimately contribute to psychopathology.
doi:10.1371/journal.pone.0040534
PMCID: PMC3392232  PMID: 22792364
17.  DISC1 Conditioned GWAS for Psychosis Proneness in a Large Finnish Birth Cohort 
PLoS ONE  2012;7(2):e30643.
Background
Genetic evidence implicates the DISC1 gene in the etiology of a number of mental illnesses. Previously, we have reported association between DISC1 and measures of psychosis proneness, the Revised Social Anhedonia Scale (RSAS) and Revised Physical Anhedonia Scale (RPAS), in the Northern Finland Birth Cohort 1966 (NFBC66). As part of the studies of this Finnish birth cohort genome-wide association analysis has recently been performed.
Methodology
In the present study, we re-analyzed the genome-wide association data with regard to these two measures of psychosis proneness, conditioning on our previous DISC1 observation. From the original NFBC66 sample (N = 12 058), 4 561 individuals provided phenotype and genotype data. No markers were significant at the genome-wide level. However, several genes with biological relevance to mental illnesses were highlighted through loci displaying suggestive evidence for association (≥3 SNP with P<10E-4). These included the protein coding genes, CXCL3, KIAA1128, LCT, MED13L, TMCO7, TTN, and the micro RNA MIR620.
Conclusions
By conditioning a previous genome-wide association study on DISC1, we have been able to identify eight genes as associating to psychosis proneness. Further, these molecules predominantly link to the DISC1 pathway, strengthening the evidence for the role of this gene network in the etiology of mental illness. The use of quantitative measures of psychosis proneness in a large population cohort will make these findings, once verified; more generalized to a broad selection of disorders related to psychoses and psychosis proneness.
doi:10.1371/journal.pone.0030643
PMCID: PMC3281861  PMID: 22363459
18.  A Differential Network Approach to Exploring Differences between Biological States: An Application to Prediabetes 
PLoS ONE  2011;6(9):e24702.
Background
Variations in the pattern of molecular associations are observed during disease development. The comprehensive analysis of molecular association patterns and their changes in relation to different physiological conditions can yield insight into the biological basis of disease-specific phenotype variation.
Methodology
Here, we introduce a formal statistical method for the differential analysis of molecular associations via network representation. We illustrate our approach with extensive data on lipoprotein subclasses measured by NMR spectroscopy in 4,406 individuals with normal fasting glucose, and 531 subjects with impaired fasting glucose (prediabetes). We estimate the pair-wise association between measures using shrinkage estimates of partial correlations and build the differential network based on this measure of association. We explore the topological properties of the inferred network to gain insight into important metabolic differences between individuals with normal fasting glucose and prediabetes.
Conclusions/Significance
Differential networks provide new insights characterizing differences in biological states. Based on conventional statistical methods, few differences in concentration levels of lipoprotein subclasses were found between individuals with normal fasting glucose and individuals with prediabetes. By performing the differential analysis of networks, several characteristic changes in lipoprotein metabolism known to be related to diabetic dyslipidemias were identified. The results demonstrate the applicability of the new approach to identify key molecular changes inaccessible to standard approaches.
doi:10.1371/journal.pone.0024702
PMCID: PMC3181317  PMID: 21980352
19.  Interaction of early environment, gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort 
BMJ Open  2011;1(1):e000087.
Objectives
Depression is a worldwide leading cause of morbidity and disability. Genetic studies have recently begun to elucidate its molecular aetiology. The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 (12 058 live births).
Design
The authors ascertained and subdivided the study sample (n=5225) based on measures of early development and of social environment, and examined candidate genes of monoamine neurotransmission, many of which have shown prior evidence of a gene–environment interaction for affective disorders, namely SLC6A4, TPH2, COMT, MAOA and the dopamine receptor genes DRD1–DRD5.
Results and conclusion
The authors observed no major genetic effects of the analysed variants on depressiveness. However, when measures of early development and of social environment were considered, some evidence of interaction was observed. Allelic variants of COMT interacted with high early developmental risk (p=0.005 for rs2239393 and p=0.02 for rs4680) so that the association with depression was detected only in individuals at high developmental risk group (p=0.0046 and β=0.056 for rs5993883–rs2239393–rs4680 risk haplotype CGG including Val158), particularly in males (p=0.0053 and β=0.083 for the haplotype CGG). Rs4274224 from DRD2 interacted with gender (p=0.017) showing a significant association with depressiveness in males (p=0.0006 and β=0.0023; p=0.00005 and β=0.069 for rs4648318–rs4274224 haplotype GG). The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex, but not direct major effects of monoaminergic genes in this unselected population.
Article summary
Article focus
Impact on depression of monoaminergic candidate genes with prior evidence of gene–environment interaction for affective disorders, and of dopamine receptor genes.
Gene–environment and gene–gender interactions in the aetiology of depression.
Effect of measures of early development and of social environment on depression.
Key messages
Genes of monoamine neurotransmission play a role in the aetiology of depression conditional on environmental risk, especially in males and in individuals at high early developmental risk group; in particular, there is evidence of an interaction with a COMT high-risk haplotype including Val158.
Gender-specific mechanisms and responses to environmental effectors are evident in the regulation of mood.
Strengths and limitations of this study
Depression as defined does not necessarily imply clinical diagnosis of major depression but is based on a self-report or Hopkins Symptom Check List-25 score. Despite this, the prevalence of depressed mood was in the same range as that in earlier reports.
There was a notable drop-out rate of about half of the original cohort members.
The choice of measures of early development and of social environment was limited by the availability of variables collected.
Advantages include the availability of longitudinal follow-up data starting antenatally, enabling inclusion of the environmental dimension without recall bias.
The cohort’s unique genetic structure with isolation and more genetic homogeneity permits identification of genetic-risk loci that may be missed when using more heterogeneous populations.
The subjects are representative of the population, with all cohort members born in the same year and within a geographically defined area.
The study sample’s size is sufficient for identifying genetic variants of moderate impact.
Both genders are represented in almost equal amounts; gender differences exist in both depression and temperament traits such as harm avoidance.
As the sample is a 1-year birth cohort, genetic effects may be isolated from the effects of ageing; some psychiatric traits such as harm avoidance are age-dependent.
doi:10.1136/bmjopen-2011-000087
PMCID: PMC3191433  PMID: 22021758
Environment; monoamine; gene; depression; Cohort Study, Psychiatry; depression and mood disorders; genetics; mental health; child and adolescent psychiatry; schizophrenia and psychotic disorders; BMJ open
20.  Associations between pre-pregnancy obesity and asthma symptoms in adolescents 
Background
The high prevalence of children's asthma symptoms, worldwide, is unexplained. We examined the relation between maternal pre-pregnancy weight and body mass index (BMI), and asthma symptoms in adolescents.
Methods
Data from 6945 adolescents born within the Northern Finland Birth Cohort 1986 were used. Prospective antenatal and birth outcome data, including maternal pre-pregnancy weight and BMI, and asthma symptoms in adolescent offspring at age 15–16 years, were employed. Logistic regression analyses were performed to examine the associations between relevant prenatal factors and asthma symptoms during adolescence.
Results
Current wheeze (within the past year) was reported by 10.6% of adolescents, and physician-diagnosed asthma by 6.0%. High maternal pre-pregnancy BMI was a significant predictor of wheeze in the adolescents (increase per kilogram per square metre unit; 2.7%, 95% CI 0.9 to 4.4 for ever wheeze; 3.5%, 95% CI 1.3 to 5.8 for current wheeze), and adjusting for potential confounders further increased the risk (2.8%, 95% CI 0.5 to 5.1; 4.7%, 95% CI 1.9 to 7.7, respectively). High maternal pre-pregnancy weight, in the top tertile, also significantly increased the odds of current wheeze in the adolescent by 20% (95% CI 4 to 39), and adjusting for potential confounders further increased the risk (OR=1.52, 95% CI 1.19 to 1.95). Results were similar for current asthma. Furthermore, these significant associations were observed only among adolescents without parental history of atopy but not among those with parental history of atopy.
Conclusions
The association demonstrated here between maternal pre-pregnancy overweight and obesity, and asthma symptoms in adolescents suggests that increase in asthma may be partly related to the rapid rise in obesity in recent years.
doi:10.1136/jech.2011.133777
PMCID: PMC3412048  PMID: 21844604
Asthma; wheeze; prevalence; adolescent; maternal pre-pregnancy weight; BMI; obesity
21.  Risks of Overweight and Abdominal Obesity at Age 16 Years Associated With Prenatal Exposures to Maternal Prepregnancy Overweight and Gestational Diabetes Mellitus 
Diabetes Care  2010;33(5):1115-1121.
OBJECTIVE
The associations of prenatal exposures to maternal prepregnancy overweight and gestational diabetes mellitus (GDM) with offspring overweight are controversial. Research estimating risk for offspring overweight due to these exposures, separately and concomitantly, is limited.
RESEARCH DESIGN AND METHODS
Prevalence of overweight and abdominal obesity at age 16 years and odds ratios (ORs) for prenatal exposures to maternal prepregnancy overweight and GDM were estimated in participants of the prospective longitudinal Northern Finland Birth Cohort of 1986 (N = 4,168).
RESULTS
The prevalence and estimates of risk for overweight and abdominal obesity were highest in those exposed to both maternal prepregnancy overweight and GDM (overweight prevalence 40% [OR 4.05], abdominal obesity prevalence 25.7% [3.82]). Even in offspring of mothers with a normal oral glucose tolerance test during pregnancy, maternal prepregnancy overweight is associated with increased risk for these outcomes (overweight prevalence 27.9% [2.56], abdominal obesity prevalence 19.5% [2.60]). In offspring of women with prepregnancy normal weight, the prevalence or risks of the outcomes were not increased by prenatal exposure to GDM. These estimates of risk were adjusted for parental prepregnancy smoking, paternal overweight, and offspring sex and size at birth.
CONCLUSIONS
Maternal prepregnancy overweight is an independent risk factor for offspring overweight and abdominal obesity at age 16 years. The risks are highest in offspring with concomitant prenatal exposure to maternal prepregnancy overweight and GDM, whereas the risks associated with GDM are only small.
doi:10.2337/dc09-1871
PMCID: PMC2858187  PMID: 20427685
22.  Is insufficient quantity and quality of sleep a risk factor for neck, shoulder and low back pain? A longitudinal study among adolescents 
European Spine Journal  2009;19(4):641-649.
The quantity and quality of adolescents’ sleep may have changed due to new technologies. At the same time, the prevalence of neck, shoulder and low back pain has increased. However, only a few studies have investigated insufficient quantity and quality of sleep as possible risk factors for musculoskeletal pain among adolescents. The aim of the study was to assess whether insufficient quantity and quality of sleep are risk factors for neck (NP), shoulder (SP) and low back pain (LBP). A 2-year follow-up survey among adolescents aged 15–19 years was (2001–2003) carried out in a subcohort of the Northern Finland Birth Cohort 1986 (n = 1,773). The outcome measures were 6-month period prevalences of NP, SP and LBP. The quantity and quality of sleep were categorized into sufficient, intermediate or insufficient, based on average hours spent sleeping, and whether or not the subject suffered from nightmares, tiredness and sleeping problems. The odds ratios (OR) and 95% confidence intervals (CI) for having musculoskeletal pain were obtained through logistic regression analysis, adjusted for previously suggested risk factors and finally adjusted for specific pain status at 16 years. The 6-month period prevalences of neck, shoulder and low back pain were higher at the age of 18 than at 16 years. Insufficient quantity or quality of sleep at 16 years predicted NP in both girls (OR 4.4; CI 2.2–9.0) and boys (2.2; 1.2–4.1). Similarly, insufficient sleep at 16 years predicted LBP in both girls (2.9; 1.7–5.2) and boys (2.4; 1.3–4.5), but SP only in girls (2.3; 1.2–4.4). After adjustment for pain status, insufficient sleep at 16 years predicted significantly only NP (3.2; 1.5–6.7) and LBP (2.4; 1.3–4.3) in girls. Insufficient sleep quantity or quality was an independent risk factor for NP and LBP among girls. Future studies should test whether interventions aimed at improving sleep characteristics are effective in the prevention and treatment of musculoskeletal pain.
doi:10.1007/s00586-009-1215-2
PMCID: PMC2899838  PMID: 19936804
Musculoskeletal pain; Adolescent; Sleep; Risk factors; Prospective study
23.  5-HTTLPR Genotype and Anxiety-Related Personality Traits: A meta-analysis and new data 
We investigated the strength of evidence for association of the 5-HTTLPR polymorphism and the personality trait of Harm Avoidance. We used new primary data from a large sample of adults drawn from the Finnish population. We also applied meta-analytic techniques to synthesize existing published data. The large number studies of the 5-HTTLPR polymorphism allowed us to apply a formal test of publication bias, as well as formally investigate the impact of potential moderating factors such as measurement instrument.
Univariate ANOVA of primary data (n = 3,872), with 5-HTTLPR genotype as a between-groups factor, indicated no evidence of association with Harm Avoidance (p = 0.99). Meta-analysis indicated no evidence of significant association of 5-HTTLPR with Harm Avoidance (d = 0.02, p = 0.37), or EPQ Neuroticism (d = 0.01, p = 0.71), although there was evidence of association with NEO Neuroticism (d = 0.18, p < 0.001).
Our analyses indicate that the 5-HTTLPR variant is not associated with Harm Avoidance. Together with our previous analyses of a large sample of participants with extreme Neuroticism scores (defined by the EPQ), we have data that excludes a meaningful genetic effect of the 5-HTTLPR on two measures of anxiety-related personality traits. There remains the possibility that the variant influences the NEO personality questionnaire measure of Neuroticism. However, a large, well-powered primary study is required to test this hypothesis directly and adequately.
doi:10.1002/ajmg.b.30808
PMCID: PMC2819421  PMID: 18546120
5-HTTLPR; Genotype; Meta-Analysis; Neuroticism; Harm Avoidance
24.  Type 2 Diabetes Risk Alleles are Associated with Reduced Size at Birth 
Diabetes  2009;58(6):1428-1433.
Objective
Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.
Research design and methods
We genotyped single nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2 and SLC30A8) in 7986 mothers and 19200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.
Results
We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus: 21g [95%CI:11-31g], P=2×10-5 and 14g [4-23g], P=0.004 lower birth weight per risk allele, respectively. The 4% of offspring carrying four risk alleles at these two loci were 80g [39-120g] lighter at birth than the 8% carrying none (Ptrend =5×10-7). There were no associations between birth weight and fetal genotypes at the three other loci, or maternal genotypes at any locus.
Conclusions
Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
doi:10.2337/db08-1739
PMCID: PMC2682672  PMID: 19228808
25.  Association of Variants in DISC1 With Psychosis-Related Traits in a Large Population Cohort 
Archives of general psychiatry  2009;66(2):134-141.
Context
There is an abundance of data from human genetic studies and animal models that implies a role for the disrupted in schizophrenia 1 gene (DISC1) in the etiology of schizophrenia and other major mental illnesses.
Objective
To study the effect of previously identified risk alleles of DISC1 on quantitative intermediate phenotypes for psychosis in an unselected population.
Design
We examined 41 single-nucleotide polymorphisms within DISC1 and performed tests of association with 4 quantitative phenotypes.
Setting
Academic research.
Participants
Individuals from an unselected birth cohort in Finland. Originally, everyone born in the catchment area in 1966 (N=12 058) was included in the study. Of these, 4651 (38.6%) attended the 31-year follow-up and could be included in the study.
Main Outcome Measures
Scores on 4 psychometric instruments selected to function as proxies for positive and negative aspects of psychotic disorders, including the Perceptual Aberration Scale, Revised Social Anhedonia Scale, Revised Physical Anhedonia Scale, and Schizoidia Scale by Golden and Meehl.
Results
Carriers of the minor allele of marker rs821577 had significantly higher scores on social anhedonia (P<.001). The minor allele of marker rs821633 was strongly associated with lower scores on social anhedonia when analyzed dependent on the absence of the minor alleles of markers rs1538979 and rs821577 (P<.001).
Conclusions
Variants in DISC1 affect the level of social anhedonia, a cardinal symptom of schizophrenia in the general population. DISC1 might be more central to human psychological functioning than previously thought, as it seems to affect the degree to which people enjoy social interactions.
doi:10.1001/archgenpsychiatry.2008.524
PMCID: PMC2704396  PMID: 19188535

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