M.-R. Järvelin

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western ‘obesogenic’ environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the ‘common disease, common variant’ hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI)u2009≥u200940u2009kgu2009m-2 or BMI standard deviation scoreu2009≥u20094; P = 6.4u2009×u200910-8, odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the ‘power of the extreme’ in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Maternal adiposity prior to pregnancy is associated with ADHD symptoms in offspring: evidence from three prospective pregnancy cohorts

Objectives:We examine whether pregnancy weight (pre-pregnancy body mass index (BMI) and/or weight gain) is related to core symptoms of attention deficit hyperactivity disorder (ADHD) in school-age offspring.Design:Follow-up of prospective pregnancy cohorts from Sweden, Denmark and Finland within the Nordic Network on ADHD.Methods:Maternal pregnancy and delivery data were collected prospectively. Teachers rated inattention and hyperactivity symptoms in offspring. High scores were defined as at least one core symptom rated as ‘severe’ and two as ‘present’ (approximately 10% of children scored in this range). Logistic regression and latent class analyses were used to examine maternal pregnancy weight in relation to childrens ADHD core symptoms.Results:Teacher rated 12u2009556 school-aged children. Gestational weight gain outside of the Institute of Medicine guidelines was not related to ADHD symptoms (below recommendations: odds ratio (OR): 0.96; 95% confidence interval (CI): 0.81, 1.14; above recommendations: OR: 0.98; 95% CI: 0.82, 1.16). To examine various patterns of pre-pregnancy BMI and weight gain, we used latent class analysis and found significant associations between classes that included pre-pregnancy overweight or obesity and a high ADHD symptom score in offspring, ORs ranged between 1.37 (95% CI: 1.07, 1.75) and 1.89 (95% CI: 1.13, 3.15) adjusted for gestational age, birth weight, weight gain, pregnancy smoking, maternal age, maternal education, child gender, family structure and cohort country of origin. Children of women who were both overweight and gained a large amount of weight during gestation had a 2-fold risk of ADHD symptoms (OR: 2.10, 95% CI: 1.19, 3.72) compared to normal-weight women.Conclusions:We show for the first time that pre-pregnancy BMI is associated with ADHD symptoms in children. Our results are of public health significance if the associations are causal and will then add ADHD symptoms in offspring to the list of deleterious outcomes related to overweight and obesity in the prenatal period.

Early developmental milestones in adult schizophrenia and other psychoses. A 31-year follow-up of the Northern Finland 1966 Birth Cohort.

Delayed childhood development may precede adult psychoses. We tested this hypothesis in a large, general population birth cohort (n=12058) followed to age 31 years. The ages at which individuals learned to stand, walk, speak, and became potty-trained (bowel control) and dry (bladder control), were recorded at a 1-year examination. Psychiatric outcome was ascertained through linkage to a national hospital discharge register. Cumulative incidence of DSM-III-R schizophrenia, other psychoses and non-psychotic disorders were stratified according to the timing of milestones and compared within the cohort using internal standardization. 100 cases of DSM-III-R schizophrenia, 55 other psychoses, and 315 non-psychotic disorders were identified. The ages at learning to stand, walk and become potty-trained were each related to subsequent incidence of schizophrenia and other psychoses. Compared with the whole cohort, earlier milestones reduced, and later milestones increased, the risk in a linear manner. These developmental effects were not seen for non-psychotic outcomes. The findings support hypotheses regarding psychosis as having a developmental dimension with precursors apparent in early life.

Boys have more health problems in childhood than girls - follow-up of the 1987 Finnish birth cohort.

The purpose of this study was to describe gender differences in childrens health until the age of 7 y. The study cohort consisted of all children born in Finland in 1987 (n = 60 254), of whom 99.9% were identified in the follow‐up. Childhood health data were received from five national registers (1987‐94), from regional registers of intellectual disabilities (1987‐96) and from education registers in the largest county (1996). Boys had a 20% higher risk for a low 5‐min Apgar score and an 11% higher risk for being preterm. After the perinatal period, boys had a 64% higher cumulative incidence of asthma, a 43% higher cumulative incidence of intellectual disability, a 22% higher incidence of mortality and a higher, but not statistically significant, incidence of epilepsy and vision disorders. No male excess was found for diabetes or hearing disorders. The healthcare‐related indicators showed poorer health for boys, who had a 37% higher mean of hospital days, a 28% higher risk for receiving social benefits due to health problems and a 13% higher risk for long‐term medication. The differences in the socially defined indicators were greatest, and boys had a two‐ to three‐fold risk of having delayed development, postponed school start or attendance in special education programmes. Gender differences in different social classes were similar. Boys shorter gestational age at birth did not explain the gender differences in childhood health. Some of boys poorer health seemed to be biologically based, but the social causes of health problems are amenable to change. In particular, the potential of the school system to reduce ill health among boys should be investigated.

Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms.

OBJECTIVE: To study the association between body size from birth to adulthood and self-reported symptoms of polycystic ovary syndrome (PCOS), particularly hirsutism and menstrual disturbances.DESIGN: Longitudinal, population-based study of a cohort of women born in 1966 in northern Finland. The study population included 2007 women who were not pregnant and did not use hormonal contraception. Of these 528 (26%) had self-reported symptoms of PCOS.RESULTS: Weight at birth, gestational age, being small for gestational age or growth retardation at birth were not associated with PCOS symptoms at 31u2009y. An increased risk of PCOS symptoms was observed among women with abdominal obesity (waist/hip ratio >85th percentile) at 31u2009y who had normal weight in adolescence and were overweight (body mass index (BMI) 25.0–29.9u2009kg/m2) or obese (BMI>30.0u2009kg/m2) at 31u2009y (relative risk (RR) (95% CI) 1.44(1.10–1.89)), and among women with abdominal obesity who were overweight or obese at both 14 and 31u2009y (1.71 (1.30–2.24)). A total of 30% and 41% of the women with PCOS symptoms in these groups could be attributed, respectively, to overweight, obesity and abdominal obesity at 31u2009y.CONCLUSIONS: These results suggest that obesity in adolescence and in adulthood, and also weight gain after adolescence, particularly in the presence of abdominal obesity, are associated with self-reported PCOS symptoms in adulthood. Thus, based on the results from intervention studies treating PCOS and the results of this study, the prevention of obesity and abdominal obesity is important among young women.

School performance as a predictor of psychiatric hospitalization in adult life. A 28-year follow-up in the Northern Finland 1966 Birth Cohort

BACKGROUNDnDeterioration in school achievement may pre-date adult mental disorders. We studied the association between compulsory school performance and later onset hospital-treated psychiatric morbidity experienced by the Northern Finland 1966 Birth Cohort (N = 11017) in adult life.nnnMETHODSnSchool performance was operationalized in two ways: school class level (in normal, i.e. age-appropriate class v. not in normal class, i.e. class below age level or in special school) at the age of 14, and marks for individual school subjects at the age of 16. School class level was ascertained by postal questionnaire and school marks from national application register. These were linked to data on psychiatric morbidity from the National Finnish Hospital Discharge Register. By the end of 1994 (between ages 16 and 28 years), a total of 383 subjects had psychiatric illness. DSM-III-R diagnoses were grouped into three categories: schizophrenia; other psychoses; and non-psychotic disorders. The remaining population with no psychiatric hospitalization served as a single comparison group. School class level and values of school marks in the three diagnostic categories were each compared with this comparison group, stratified by sex.nnnRESULTSnIn the comparison group 6.8% of boys and 3.4% of girls were not in their normal class. In all the diagnosis groups the proportions of those not in normal class were from 2 to 8 times higher than in the comparison group. A majority of those not in normal class and having psychiatric diagnosis were intellectually subnormal (IQ < 85). Among adolescents who later developed nonpsychotic disorders, means of school marks were lower (P < 0.05, adjusted for social class and place of residence) than in the comparison group. Lower marks were not found in categories schizophrenia or other psychoses. Logistic regression analysis confirmed these findings after adjustment for confounding factors.nnnCONCLUSIONSnNot being in the normal class at age 14 predicted future hospital-treated disorders, but low school marks at age 16 predicted only non-psychotic disorders. These findings may be an early manifestation of the disorders themselves, or a marker of vulnerability or other risk factors. The mechanisms may differ between diagnoses.

Gestational age and occurrence of atopy at age 31—a prospective birth cohort study in Finland

It has been suggested that main risk factors for development of allergic diseases operate already during pregnancy and in early childhood.

Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study

Please cite this paper as: Laitinen J, Jääskeläinen A, Hartikainen A, Sovio U, Vääräsmäki M, Pouta A, Kaakinen M, Järvelin M. Maternal weight gain during the first half of pregnancy and offspring obesity at 16u2003years: a prospective cohort study. BJOG 2012;119:716–723.

Prenatal factors and occurrence of rhinitis and eczema among offspring

Background: It has recently been suggested that an atopic phenotype may already be programmed in utero. We examine here the association between prenatal factors and the subsequent development of allergic rhinitis and eczema among offspring.

The association between anxiety and C-reactive protein (CRP) levels: Results from the Northern Finland 1966 Birth Cohort Study

BACKGROUNDnAnxiety frequently accompanies low-grade inflammation-associated conditions like depression, insulin resistance, coronary heart disease and metabolic syndrome. The association between anxiety and low-grade inflammation is, unlike between depression and low-grade inflammation, a very sparsely studied area in general populations. The aim of the present study was to investigate whether anxiety symptoms as well as comorbid anxiety and depressive symptoms are associated with low-grade inflammation at population level.nnnMETHODSnThe general population-based Northern Finland 1966 Birth Cohort was followed until age 31 (n=2688 males and 2837 females), when the highly sensitive CRP concentrations were measured. Anxiety and depressive symptoms were defined by Hopkins Symptom Checklist-25 (HSCL-25).nnnRESULTSnAfter adjusting for confounders, logistic regression analyses showed that anxiety symptoms alone increased the probability for elevated hs-CRP levels (>3.0mg/L) in males over two-fold (2.19 CI 95% 1.08-4.46), while comorbid anxiety and depressive symptoms caused a 1.7-fold (1.76 CI 95% 1.13-2.74) increase in the probability for elevated hs-CRP levels (1.0-3.0mg/L).nnnCONCLUSIONSnOur results support the hypothesis that anxiety as well as comorbid anxiety and depression can be associated with an increased risk for low-grade inflammation in males at population level.