[show abstract][hide abstract] ABSTRACT: The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality.We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16121 younger controls (< 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases≥90 years.We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR=1.10, P =1.74 x 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR=0.72, P=3.40 x 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n=34103) the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR=0.95, P=0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure.We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
Human Molecular Genetics 03/2014; · 7.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: We analysed single nucleotide polymorphisms (SNPs) tagging the genetic variability of six candidate genes (ATF6, FABP1, LPIN2, LPIN3, MLXIPL and MTTP) involved in the regulation of hepatic lipid metabolism, an important regulatory site of energy balance for associations with body mass index (BMI) and changes in weight and waist circumference. We also investigated effect modification by sex and dietary intake. Data of 6,287 individuals participating in the European prospective investigation into cancer and nutrition were included in the analyses. Data on weight and waist circumference were followed up for 6.9 ± 2.5 years. Association of 69 tagSNPs with baseline BMI and annual changes in weight as well as waist circumference were investigated using linear regression analysis. Interactions with sex, GI and intake of carbohydrates, fat as well as saturated, monounsaturated and polyunsaturated fatty acids were examined by including multiplicative SNP-covariate terms into the regression model. Neither baseline BMI nor annual weight or waist circumference changes were significantly associated with variation in the selected genes in the entire study population after correction for multiple testing. One SNP (rs1164) in LPIN2 appeared to be significantly interacting with sex (p = 0.0003) and was associated with greater annual weight gain in men (56.8 ± 23.7 g/year per allele, p = 0.02) than in women (-25.5 ± 19.8 g/year per allele, p = 0.2). With respect to gene-nutrient interaction, we could not detect any significant interactions when accounting for multiple testing. Therefore, out of our six candidate genes, LPIN2 may be considered as a candidate for further studies.
[show abstract][hide abstract] ABSTRACT: BACKGROUND:
Studies indicate an effect of dietary calcium on change in body weight (BW) and waist circumference (WC), but the results are inconsistent. Furthermore, a relation could depend on genetic predisposition to obesity.
The objective was to examine whether genetic predisposition to higher body mass index (BMI), WC, or waist-hip ratio (WHR) interacts with dietary calcium in relation to subsequent annual change in BW (ΔBW) and WC (ΔWC).
The study is based on 7569 individuals from the MONItoring trends and determinants of CArdiovascular disease Study, a sample from the Danish Diet, Cancer and Health Study and the INTER99 study, with information on diet; 54 single-nucleotide polymorphisms (SNPs) associated with BMI, WC, or WHR adjusted for BMI; and potential confounders. The SNPs were combined in 4 scores as indicators of genetic predisposition; all SNPs in a general score and a score for each of 3 phenotype: BMI, WC, and WHR. Linear regression was used to examine the association between calcium intake and ΔBW or ΔWC adjusted for concurrent ΔBW. SNP score × calcium interactions were examined by adding product terms to the models.
We found a significant ΔBW of -0.076 kg (P = 0.021; 95% CI: -0.140, -0.012) per 1000 mg Ca. No significant association was observed between dietary calcium and ΔWC. In the analyses with ΔBW as outcome, we found no significant interactions between the developed predisposition scores and calcium. However, we found a significant interaction between a score of 6 WC-associated SNPs and calcium in relation to ΔWC. Each risk allele was associated with a ΔWC of -0.043 cm (P = 0.038; 95% CI: -0.083, -0.002) per 1000 mg Ca.
Our study suggests that dietary calcium relates weakly to BW loss. We found no evidence of a general association between calcium and ΔWC, but calcium may reduce WC among people genetically predisposed to a high WC. However, further replication of this finding is needed.
American Journal of Clinical Nutrition 02/2014; · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Social inequalities in overweight and obesity (OWOB) have persisted in the affluent and reputedly egalitarian Nordic countries. In this review we examine associations between socioeconomic position (SEP) and OWOB, and secular trends in such associations. Determinants and possible causes of the relations are discussed together with opportunities to cope with OWOB as a public health problem. The findings show a persisting inverse social gradient. An interaction between SEP and gender is noted for adults in Denmark, Finland and Iceland and for children in Sweden. There are overall tendencies for increased inequality, however no consistent trend for an increased social gradient in OWOB. Reasons that increased inequality does not unequivocally mirror in a steepened social gradient in obesity may include methodological questions as well as societal efforts to counteract obesity. Multi-level efforts are needed to prevent OWOB.
[show abstract][hide abstract] ABSTRACT: If preschool measures of body size routinely collected at preventive health examinations are associated with adult central obesity and metabolic syndrome, a focused use of these data for the identification of high risk children is possible. The aim of this study was to test the associations between preschool weight and body mass index (BMI) and adult BMI, central obesity and metabolic alterations.
The Northern Finland Birth Cohort 1966 (NFBC1966) (N = 4111) is a population-based cohort. Preschool weight (age 5 months and 1 year) and BMI (age 2-5 years) were studied in relation to metabolic syndrome as well as BMI, waist circumference, lipoproteins, blood pressure, and fasting glucose at the age of 31 years. Linear regression models and generalized linear regression models with log link were used.
Throughout preschool ages, weight and BMI were significantly linearly associated with adult BMI and waist circumference. Preschool BMI was inversely associated with high-density lipoprotein levels from the age of 3 years. Compared with children in the lower half of the BMI range, the group of children with the 5% highest BMI at the age of 5 years had a relative risk of adult obesity of 6.2(95% CI:4.2-9.3), of adult central obesity of 2.4(95% CI:2.0-2.9), and of early onset adult metabolic syndrome of 2.5(95% CI:1.7-3.8).
High preschool BMI is consistently associated with adult obesity, central obesity and early onset metabolic syndrome. Routinely collected measures of body size in preschool ages can help to identify children in need of focused prevention due to their increased risk of adverse metabolic alterations in adulthood.
PLoS ONE 01/2014; 9(3):e89986. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: An association between maternal pre-pregnancy BMI and childhood intelligence quotient (IQ) has repeatedly been found but it is unknown if this association is causal or due to confounding caused by genetic or social factors.
We used a cohort of 1,783 mothers and their 5-year-old children sampled from the Danish National Birth Cohort. The children participated between 2003 and 2008 in a neuropsychological assessment of cognitive ability including IQ tests taken by both the mother and the child. Linear regression analyses were used to estimate the associations between parental BMI and child IQ adjusted for a comprehensive set of potential confounders. Child IQ was assessed with the Wechsler Primary and Preschool Scales of Intelligence - Revised (WPPSI-R).
The crude association between maternal BMI and child IQ showed that BMI was adversely associated with child IQ with a reduction in IQ of -0.40 point for each one unit increase in BMI. This association was attenuated after adjustment for social factors and maternal IQ to a value of -0.27 (-0.50 to -0.03). After mutual adjustment for the father's BMI and all other factors except maternal IQ, the association between paternal BMI and child IQ yielded a regression coefficient of -0.26 (-0.59 to 0.07), which was comparable to that seen for maternal BMI (-0.20 (-0.44 to 0.04)).
Although maternal pre-pregnancy BMI was inversely associated with the IQ of her child, the similar association with paternal BMI suggests that it is not a specific pregnancy related adiposity effect.
PLoS ONE 01/2014; 9(4):e94498. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: What is already known about this subject Large maternal gestational weight gain (GWG) is associated with increased birth weight and increased risk of obesity in offspring later in life. Pregnancies after bariatric surgery are associated with lower birth weight and lower risk of metabolic pregnancy complications compared with pre-surgery pregnancies. What this study adds Exploring differences in GWG through the three trimesters in the same women, before and after bariatric surgery, revealed a positive association between differences in second trimester GWG and differences in children's birth weight, but no association with differences in first and third trimester GWG. No associations were found between differences in GWG and differences in children's scores on the body mass index in pre-school age.
Large maternal gestational weight gain (GWG) is associated with increased birth weight and increased risk of obesity in offspring, but these associations may be confounded by genetic and environmental factors. The aim was to investigate the effects of differences in GWG in all three trimesters on differences in birth weight and in body mass index (BMI) scores at 4 and 6 years of age, within siblings born before and after bariatric surgery.
Women with at least one child born before and one after bariatric surgery were identified in national Swedish registers. Series of weight (and height) measurements were collected from antenatal medical records, with data on the nearest pregnancies before and after bariatric surgery.
The age-adjusted means of pre- and post-operative GWG of 124 women were 11.3 (standard deviation [SD] 7.2) and 8.3 (SD 6.4) kg, respectively (P = 0.01). Adjusted fixed effects regression models showed positive associations of differences in mean total GWG with differences in siblings' birth weight, 0.023 kg per 1-kg greater weight gain (95% confidence interval [CI]: 0.014-0.069) and for second trimester 0.53 kg for each 1-kg greater weight per week (95% CI: 0.32-1.61), whereas no associations were found with BMI in pre-school age.
This study showed positive associations between differences in total and second trimester maternal GWG and differences in children's birth weight, but no association with BMI scores in pre-school age. Maternal genetic, social and lifestyle factors fixed from one pregnancy to the next were taken into account in the analyses by the study design.
[show abstract][hide abstract] ABSTRACT: Previous studies have suggested that the intake of trans-fatty acids (TFA) plays a role in the development of obesity. The proportions of adipose tissue fatty acids not synthesised endogenously in humans, such as TFA, usually correlate well with the dietary intake. Hence, the use of these biomarkers may provide a more accurate measure of habitual TFA intake than that obtained with dietary questionnaires. The objective of the present study was to investigate the associations between the proportions of specific TFA in adipose tissue and subsequent changes in weight and waist circumference (WC). The relative content of fatty acids in adipose tissue biopsies from a random sample of 996 men and women aged 50-64 years drawn from a Danish cohort study was determined by GC. Baseline data on weight, WC and potential confounders were available together with information on weight and WC 5 years after enrolment. The exposure measures were total trans-octadecenoic acids (18 : 1t), 18 : 1 Δ6-10t, vaccenic acid (18 : 1 Δ11t) and rumenic acid (18 : 2 Δ9c, 11t). Data were analysed using multiple regression with cubic spline modelling. The median proportion of total adipose tissue 18 : 1t was 1·52 % (90 % central range 0·98, 2·19) in men and 1·47 % (1·01, 2·19) in women. No significant associations were observed between the proportions of total 18 : 1t, 18 : 1 Δ6-10t, vaccenic acid or rumenic acid and changes in weight or WC. The present study suggests that the proportions of specific TFA in adipose tissue are not associated with subsequent changes in weight or WC within the exposure range observed in this population.
The British journal of nutrition 11/2013; · 3.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: Genetic factors have been found to influence the risk of suicide. It is less clear if this also applies to attempted suicide. We have investigated genetic and familial environmental factors by studying the occurrence of suicide attempts in biological and adoptive siblings of adoptees who attempted suicide compared to siblings of adoptees with no suicide attempts.
We used a random sample of 1933 adoptees from the Danish Adoption Register, a register of non-familial adoptions of Danish children, i.e. the adoptive parents are biologically unrelated to the adoptee. Analyses were conducted on incidence rates of attempted suicide in biological and adoptive siblings given occurrence of attempted suicide in the adoptees while also taking into account psychiatric disorders. Information about suicidal attempt and history of psychiatric disorder was based on hospital admissions.
The rate of attempted suicide in full siblings of adoptees who attempted suicide before age 60 years was higher than in full siblings of adoptees who had not attempted suicide (incidence rate ratios (IRR)=3.45; 95% confidence interval [CI]=0.94-12.7). After adjustment for history of psychiatric admission of siblings the increased rate was statistically significant (IRR=3.88; 95% CI-1.42-10.6).
Information on attempted suicide and psychiatric history was limited to that which involved hospitalisation.
Genetic factors influence risk of suicide attempts.
Journal of affective disorders 11/2013; · 3.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Taller stature and obesity in adulthood have been consistently associated with an increased risk of thyroid cancer, but few studies have investigated the role of childhood body size. Using data from a large prospective cohort, we examined associations for height and body mass index (BMI) at ages 7-13 with risk of thyroid cancer in later life. The study population included 321,085 children from the Copenhagen School Health Records Register, born between 1930 and 1989 in Copenhagen, Denmark, with measurements of height and weight from 7-13 years of age. These data were linked with the Danish Cancer Registry to identify incident thyroid cancer cases (1968-2010). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for age- and sex-specific height and BMI standard deviation scores (SDSs) using proportional hazards models stratified by birth cohort and sex. During follow-up (median=38.6 years), 171 women and 64 men were diagnosed with thyroid cancer. Both height and BMI were positively associated with thyroid cancer risk, and these associations were similar by age at measurement. Using age 10 as an example, HRs per 1-unit increase in SDS for height (approximately 6-7 cm) and BMI (approximately 1.5-2 kg/m2) were 1.22 (95% CI: 1.07-1.40) and 1.15 (95% CI: 1.00-1.34), respectively. These results, together with the relatively young ages at which thyroid cancers are diagnosed compared with other malignancies, suggest a potential link between early-life factors related to growth and body weight and thyroid carcinogenesis.
[show abstract][hide abstract] ABSTRACT: To investigate a possible association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and childhood overweight at 7 years of age.
Information on pregnancy exposures and prevalence of childhood overweight at 7 years of age was obtained from the Danish National Birth Cohort. Overweight was classified as body mass index >85th percentile, based on age and sex. Based on an a priori hypothesis, we conducted analyses stratified by child sex to examine sex-specific differences.
Of eligible pregnant women, 127 reported using an SSRI, 490 reported having a psychiatric illness but no psychotropic medication use, and 35,568 reported no psychiatric illness and no psychotropic medication use. In comparison to children of mothers with a psychiatric illness but no SSRI use during pregnancy, prenatal SSRI exposure overall was not associated with an increased risk of childhood overweight (adjusted prevalence ratio [aPR] 1.12; 95% confidence interval 0.71 to 1.77). However, when stratified according to child sex, an increased risk was observed among males (aPR 1.78; 95% CI, 1.01 to 3.12) but not females (aPR 0.86; 95% CI, 0.37 to 1.99). In contrast, female children of mothers with a psychiatric illness but no SSRI use during pregnancy were more likely to be overweight than female children of unexposed mothers (aPR 1.45; 95% CI, 1.05 to 2.02). This association was not mirrored among males (aPR 1.06; 95% CI, 0.76 to 1.50).
We observed the potential for opposing sex-specific differences in the long-term effects of prenatal exposure to SSRI use and/or maternal psychiatric illness on childhood overweight. Limitations of the present study suggest that further research in this area may be warranted with larger sample sizes and longer follow-up.
Annals of epidemiology 10/2013; · 2.95 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Adult height has been positively associated with prostate cancer risk. However, the exposure window of importance is currently unknown and assessments of height during earlier growth periods are scarce. In addition, the association between birth weight and prostate cancer remains undetermined. We assessed these relationships a cohort of the Copenhagen School Health Records Register (CSHRR). Methods: The CSHRR comprises 372,636 school children. For boys born between the 1930's and 1969, birth weight and annual childhood heights-measured between ages 7 and 13 years-were analyzed in relation to prostate cancer risk. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95 percent confidence intervals (95%CI). Results: There were 125,211 males for analysis, 2,987 of who were subsequently diagnosed with prostate cancer during 2.57 million person-years of follow-up. Height z-score was significantly associated with prostate cancer risk at all ages (HR~1.13). Height at age 13 years was more important than height change (p=0.024) and height at age 7 years (p=0.024), when estimates from mutually adjusted models were compared. Adjustment of birth weight did not alter estimates ascertained. Birth weight was not associated with prostate cancer risk. Conclusions: The association between childhood height and prostate cancer risk was driven by height at age 13 years. Impact: Our findings implicate late childhood, adolescence and adulthood growth periods as containing the exposure window(s) of interest that underlies the association between height and prostate cancer. The causal factor may not be singular given the complexity of both human growth and carcinogenesis.
Cancer Epidemiology Biomarkers & Prevention 10/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Childhood overweight increases the risk of early development of non-alcoholic fatty liver disease, which may predispose to carcinogenesis. We investigated if childhood body size during school ages was associated with the risk of primary liver cancer in adults.
A cohort of 285,884 boys and girls, born 1930 through 1980, who attended school in Copenhagen, were followed from 1977 to 31 December 2010. Their heights and weights were measured by school doctors or nurses at ages 7 through 13 years. Body mass index (BMI) z-scores were calculated from an internal age- and sex-specific reference. Information on liver cancer was obtained from the National Cancer Registry. Hazard ratios and 95% confidence intervals (95%CI) of liver cancer were estimated by Cox regression.
During 6,963,105 person-years of follow-up, 438 cases of primary liver cancer were recorded. The hazard ratio (95%CI) of adult liver cancer was 1.20 (1.07-1.33) and 1.30 (1.16-1.46) per 1-unit BMI z-score at 7 years and 13 years of age, respectively. Similar associations were found in boys and girls, for hepatocellular carcinoma only, across years of birth, and after accounting for diagnoses of viral hepatitis, alcohol-related disorders, and biliary cirrhosis.
Higher BMI in childhood increases the risk of primary liver cancer in adults. In view of the high case fatality of primary liver cancer, this result adds to the future negative health outcomes of the epidemic of childhood overweight, reinforcing the need for its prevention. Abbreviations BMI, body mass index; NAFLD, non-alcoholic fatty liver disease; HCC, hepatocellular carcinoma; CSHRR, Copenhagen School Health Records Register; ICD, International Classification of Diseases; HR, hazard ratios.
Journal of Hepatology 09/2013; · 9.86 Impact Factor