A Hofman

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (787)4964.2 Total impact

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    ABSTRACT: High body mass index is associated with increased C-reactive protein levels in childhood and adulthood. Little is known about the associations of detailed adiposity measures with C-reactive protein levels in childhood. We examined the associations of general and abdominal adiposity measures with C-reactive protein levels at school-age. To gain insight into the direction of causality, we used genetic risk scores based on known genetic variants in adults as proxies for child adiposity measures and C-reactive protein levels. Within a population-based cohort study among 4338 children at the median age of 6.2 years, we measured body mass index, fat mass percentage, android/gynoid fat mass ratio and pre-peritoneal abdominal fat mass. We also measured C-reactive protein blood levels and defined increased levels as ⩾3.0 mg/l. Single nucleotide polymorphisms (SNPs) for the weighted genetic risk scores were extracted from large genome-wide association studies on adult body mass index, waist-hip ratio and C-reactive protein levels. All fat mass measures were associated with increased C-reactive protein levels, even after adjusting for multiple confounders. Fat mass percentage was most strongly associated with increased C-reactive protein levels (Odds Ratio (OR) 1.46 (95% Confidence Interval (CI) 1.30-1.65) per increase SDS in fat mass percentage). The association was independent of body mass index. The genetic risk score based on adult body mass index SNPs, but not adult waist-hip ratio SNPs, tended to be associated with increased C-reactive protein levels at school-age. The genetic risk score based on adult C-reactive protein level SNPs was not associated with adiposity measures at school-age. Our results suggest that higher general and abdominal fat mass may lead to increased C-reactive protein levels at school-age. Further studies are needed to replicate these results and explore the causality and long-term consequences.International Journal of Obesity accepted article preview online, 29 April 2015. doi:10.1038/ijo.2015.73.
    International journal of obesity (2005) 04/2015; DOI:10.1038/ijo.2015.73 · 5.39 Impact Factor
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    ABSTRACT: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts. Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism. We performed nested case-control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800-829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961). Meta-analysis of the two nested case-control studies showed pooled odds ratios of 0.98 (0.91-1.05, p = 0.52), 1.04 (0.97-1.12, p = 0.28), and 1.16 (0.83-1.62, p = 0.38) for the associations between rs1042713, rs1042714, and rs1800888 per minor allele and fractures, respectively. There were no significant associations of the polymorphisms and BMD in GEFOS. In conclusion, polymorphisms in the beta-2 adrenergic receptor gene are not associated with fracture risk or BMD.
    Osteoporosis International 04/2015; DOI:10.1007/s00198-015-3087-0 · 4.17 Impact Factor
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    ABSTRACT: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37.
    Molecular Psychiatry 04/2015; DOI:10.1038/mp.2015.37 · 15.15 Impact Factor
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    Molecular Psychiatry 04/2015; · 15.15 Impact Factor
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    ABSTRACT: What are the effects of maternal and fetal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) concentrations on fetal and childhood growth patterns? An angiogenic profile that is characterized by both low early pregnancy maternal sFlt-1 and PlGF concentrations and higher sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio in umbilical cord blood is associated with a reduced fetal and childhood growth. An imbalance in maternal and fetal sFlt-1 and PlGF concentrations has been suggested to affect pregnancy outcomes. However, their effects on longitudinal fetal and childhood growth remain largely unknown. This study was performed in 5980 mothers and 4108 of their children, participating in the Generation R Study; a population-based prospective cohort study from fetal life onwards in Rotterdam, the Netherlands (2001-2005). Blood samples were obtained from mothers in early and mid-pregnancy and from the umbilical vein at delivery. Fetal and childhood growth characteristics (weight and length) were measured repeatedly by ultrasound and physical examinations until the age of 6 years. We assessed the associations of maternal and fetal angiogenic factors with fetal and childhood growth using repeated measurement regression models. Logistic regression models were used to determine associations between angiogenic factors and small for gestational age at birth (SGA). Compared with early pregnancy maternal sFlt-1 concentrations in the lowest quintile, early pregnancy maternal sFlt-1 concentrations in the highest quintile were associated with a higher fetal weight growth resulting in a higher birthweight (difference in birthweight 0.33 standard deviation score (SDS); 95% Confidence Interval (CI) 0.25-0.41), a lower risk of SGA (Odds Ratio (OR) 0.36; 95% CI 0.27-0.48) and a subsequent higher weight growth until the age of 6 years. Early pregnancy maternal PlGF concentrations in the lowest quintile were associated with a reduced weight growth pattern resulting in a smaller birthweight (difference in birthweight -0.34 SDS; 95% CI -0.44, -0.25), an increased risk of SGA (OR 3.48; 95% CI 2.39-5.08) and a lower weight growth throughout childhood. An early pregnancy maternal sFlt-1:PlGF ratio in the highest quintile was associated with a higher fetal weight growth pattern from 30 weeks onwards, resulting in a higher weight at birth (difference in birthweight 0.09 SDS; P-value <0.05), which remained present until the age of 2 years. Newborns with higher umbilical cord sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio showed a lower fetal and childhood weight growth from 30 weeks gestation onwards until the age of 6 years (P-value <0.05). Similar patterns were observed in relation to fetal and childhood length growth. The study is an observational study. Therefore, no causal relationships can be established. Both a maternal and fetal angiogenic imbalance may affect fetal and childhood growth. Changes in angiogenic profiles may be involved in the pathways linking fetal growth restriction with the long-term risk of vascular disease in adulthood. The first phase of the Generation R Study is made possible by financial support from The Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.W.V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw VIDI). M.I.B.-B. is financially supported by the Bo Hjelt foundation (grant 2009). The authors have no competing interests. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Reproduction 04/2015; DOI:10.1093/humrep/dev070 · 4.59 Impact Factor
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    ABSTRACT: Early life nutrition affects peak bone mass attainment. In this prospective cohort study, children with high adherence to a "dairy and whole grains" pattern in infancy had higher bone mineral density at the age of 6 years. Although the observed effects are small, our study provides insight into mechanisms linking early nutrition to bone acquisition in childhood. Nutrition in early life may affect peak bone mass attainment. Previous studies on childhood nutrition and skeletal health mainly focused on individual nutrients, which does not consider the cumulative effects of nutrients. We investigated the associations between dietary patterns in infancy and childhood bone health. This study included 2850 children participating in a population-based prospective cohort study. Dietary information was obtained from a food frequency questionnaire at the age of 13 months. Using principal component analysis, three major dietary patterns were extracted, explaining in total 30 % of the variation in dietary intake. At the age of 6 years, a total body dual-energy X-ray absorptiometry (DXA) scan was performed, and bone mineral density (BMD), bone mineral content (BMC), area-adjusted BMC (aBMC), and bone area (BA) were analyzed. Higher adherence score to a "dairy and whole grains" pattern was positively associated with BMD and aBMC, but not with BMC and BA. Accordingly, children in the highest quartile of the "dairy and whole grains" pattern had higher BMD (difference 3.98 mg/cm(2), 95 % confidence interval (CI) 0.36 to 7.61) and aBMC (difference 4.96 g, 95 % CI 1.27 to 8.64) than children in the lowest quartile. Stratification for vitamin D supplementation showed that the positive associations between the "dairy and whole grains" pattern and bone outcomes were only observed in children who did not receive vitamin D supplementation. A "potatoes, rice, and vegetables" and a "refined grains and confectionery" pattern were not consistently associated with bone outcomes. An infant dietary pattern characterized by high intakes of dairy and cheese, whole grains, and eggs is positively associated with bone development in childhood. Further research is needed to investigate the consequences for bone health in later life.
    Osteoporosis International 03/2015; 26(5). DOI:10.1007/s00198-015-3033-1 · 4.17 Impact Factor
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    ABSTRACT: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10(-8)), frontal cortex (P⩽1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.23.
    Molecular Psychiatry 03/2015; DOI:10.1038/mp.2015.23 · 15.15 Impact Factor
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    ABSTRACT: The effects of child care services on several domains of child development have been extensively investigated, but evidence regarding the effects of child care on language development remains inconclusive. Within a large-scale population-based study, we examined the longitudinal associations between non-parental child care and language development from 1 to 6 years (n = 5375). Results showed that more hours in non-parental child care were associated with better language abilities. However, more hours in care in the first year of life were associated with less language proficiency at ages 1 to 1.5. At later ages, this effect disappeared and language proficiency increased. Furthermore, children who spent more hours in centre-based care had better language scores than children in home-based care. Ethnicity, socio-economic status, gender or parity did not change these results. This large, multi-ethnic study demonstrates beneficial effects of non-parental child care, particularly centre-based care, on language proficiency later in childhood. © 2015 John Wiley & Sons Ltd.
    Child Care Health and Development 02/2015; DOI:10.1111/cch.12238 · 1.83 Impact Factor
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    ABSTRACT: Background/Objective:Intake of sugar-containing beverages (SCBs) has been associated with higher body mass index (BMI) in childhood. The potential effect of SCB intake during infancy is unclear. We examined the association of SCB intake at 13 months with BMI development until 6 years and body composition at age 6 years.Subjects/Methods:This study included 2371 Dutch children from a population-based prospective cohort study. SCB intake at 13 months was assessed using a Food Frequency Questionnaire with validation against 24-h recalls and was standardized for total energy. BMI was calculated from repeated weight and height measurements, and age- and sex-specific s.d. scores were calculated. Adiposity was measured using Dual-energy X-ray absorptiometry.Results:In girls, higher SCB intake at 13 months was significantly associated with higher BMI at ages 2, 3, 4 and 6 years (at age 6 years BMI (s.d. score) increase 0.11 (95% confidence interval (CI) +0.00; 0.23), high versus low intake). We observed a tendency towards higher android/gynoid fat ratio in girls with high intake (s.d. increase 0.14 (95% CI -0.02; 0.29), versus low intake) but not with body fat percentage. In boys, there was no association with BMI or body composition, but boys with high SCB intake at 13 months were taller at age 6 years (s.d. increase 0.14 (95% CI +0.00; 0.27), versus low intake).Conclusions:Higher SCB intake at 13 months was associated with higher BMI up to age 6 years in girls but not in boys. Our results imply that the unfavorable effects of SCB intake start early in life and that dietary advice regarding limiting SCB intake should already be given early in life.European Journal of Clinical Nutrition advance online publication, 4 February 2015; doi:10.1038/ejcn.2015.2.
    European Journal of Clinical Nutrition 02/2015; DOI:10.1038/ejcn.2015.2 · 2.95 Impact Factor
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    ABSTRACT: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.
    Molecular Psychiatry 02/2015; DOI:10.1038/mp.2014.188 · 15.15 Impact Factor
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    ABSTRACT: Background Genome wide association studies in adults have identified genetic loci associated with adiposity measures. Little is known about the effects of these loci on growth and body fat distribution from early childhood onwards.Methods In a population-based prospective cohort study among 4 144 children, we examined the associations of weighted risk scores combining 29 known genetic markers of adult body mass index and 14 known genetic markers of adult waist hip ratio with peak weight velocity, peak height velocity, age at adiposity peak, and body mass index at adiposity peak in early infancy and additionally with body mass index, total fat mass, android/gynoid fat ratio, and preperitoneal fat area at the median age of 6.0 years (95% range 5.7, 7.8).ResultsA higher adult body mass index genetic risk score was associated with a higher age at adiposity peak in infancy and a higher body mass index, total fat mass, android/gynoid fat ratio, and preperitoneal fat area in childhood (P=0.05, 1.5 × 10(-24), 3.6 × 10(-18), 4.0 × 10(-11), and 1.3 × 10(-5), respectively), with the strongest association for childhood body mass index with a 0.04 higher SDS body mass index (95% Confidence Interval 0.03, 0.05) per additional risk allele. A higher adult waist-hip ratio genetic risk score was not associated with infant growth measures or childhood body mass index and total fat mass, but was associated with childhood android/gynoid fat ratio and preperitoneal fat area (P<0.05).Conclusion Genetic variants associated with body mass index and waist-hip ratio in adults influence growth patterns and general and abdominal fat development from early childhood onwards.International Journal of Obesity accepted article preview online, 02 February 2015. doi:10.1038/ijo.2015.12.
    International journal of obesity (2005) 02/2015; DOI:10.1038/ijo.2015.12 · 5.39 Impact Factor
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    ABSTRACT: We assessed the intrauterine influence of maternal smoking on childhood bone mass by comparing parental prenatal and postnatal smoking habits. We observed higher bone mass in children exposed to maternal smoking, explained by higher body weight. Maternal smoking or related lifestyle factors may affect childhood weight gain rather than skeletal growth. Maternal smoking during pregnancy may adversely affect bone health in later life. By comparing the associations of maternal and paternal smoking and of prenatal and postnatal exposure with childhood bone measures, we aimed to explore whether the suggested association could be explained by fetal programming or reflects confounding by familial factors. In 5565 mothers, fathers and children participating in a population-based prospective cohort study, parental smoking habits during pregnancy and current household smoking habits were assessed by postal questionnaires. Total body bone mineral content (BMC), bone area (BA) and bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry (DXA) at the median age of 6.0 years (IQR 0.37). In confounder-adjusted models, maternal smoking during pregnancy was associated with a higher BMC of 11.6 g (95 % confidence interval (CI) 5.6, 17.5), a larger BA of 9.7 cm(2) (95 % CI 3.0, 16.4), a higher BMD of 6.7 g/cm(2) (95 % CI 2.4, 11.0) and a higher BMC of 5.4 g (95 % CI 1.3, 9.6) adjusted for BA of the child. Current weight turned out to mediate these associations. Among mothers who did not smoke, paternal smoking did not show evident associations with childhood bone measures. Also, household smoking practices during childhood were not associated with childhood bone measures. Our results do not support the hypothesis of fetal smoke exposure affecting childhood bone mass via intrauterine mechanisms. Maternal smoking or related lifestyle factors may affect childhood weight gain rather than skeletal growth.
    Osteoporosis International 01/2015; 26(4). DOI:10.1007/s00198-014-3011-z · 4.17 Impact Factor
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    ABSTRACT: Background and purposeAmino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of heart disease. It has also been related to stroke, but its association with transient ischaemic attacks (TIAs) is unclear. Moreover, it is unknown how clinical heart disease influences this relation. Within the prospective population-based Rotterdam Study, the association of NT-proBNP with stroke and TIA was examined and the role of heart disease on this association was investigated.MethodsNT-proBNP was measured in 1997–2001 in 5611 participants (mean age 68.7 years; 57.7% women) without a history of stroke, TIA or heart failure. Follow-up for stroke and TIA finished in 2012. Models were adjusted for age and cardiovascular risk factors, and were stratified by sex.ResultsDuring 22 058 person-years 195 men suffered a stroke and 118 a TIA. During 31 825 person-years 230 women suffered a stroke and 187 a TIA. Higher NT-proBNP was associated with a higher risk of stroke in men [hazard ratio (HR) per SD increase 1.50; 95% confidence interval (CI) 1.29–1.76] and in women (HR 1.24; 95% CI 1.05–1.46). Associations with TIA were only present in women (HR 1.51; 95% CI 1.26–1.82) but not in men (HR 1.02; 95% CI 0.83–1.26). Excluding persons with a history of clinical coronary heart disease, heart failure or atrial fibrillation and censoring for clinical heart disease during follow-up did not change the associations.Conclusions Higher NT-proBNP is associated with incident stroke in men and women and with incident TIA only in women. These associations are independent of clinical heart disease preceding cerebrovascular disease.
    European Journal of Neurology 01/2015; 22(4). DOI:10.1111/ene.12633 · 3.85 Impact Factor
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    ABSTRACT: BACKGROUND: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. METHODS: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. RESULTS: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). CONCLUSIONS: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
    Alzheimer's and Dementia 12/2014; DOI:10.1016/j.jalz.2014.05.1757 · 17.47 Impact Factor
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    ABSTRACT: Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.133.
    Molecular Psychiatry 12/2014; DOI:10.1038/mp.2014.133 · 15.15 Impact Factor
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    ABSTRACT: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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    ABSTRACT: Background. Several psychosocial risk factors for complicated grief have been described. However, the association of complicated grief with cognitive and biological risk factors is unclear. The present study examined whether complicated grief and normal grief are related to cognitive performance or structural brain volumes in a large population-based study. Method. The present research comprised cross-sectional analyses embedded in the Rotterdam Study. The study included 5501 non-demented persons. Participants were classified as experiencing no grief (n = 4731), normal grief (n = 615) or complicated grief (n = 155) as assessed with the Inventory of Complicated Grief. All persons underwent cognitive testing (Mini-Mental State Examination, Letter-Digit Substitution Test, Stroop Test, Word Fluency Task, word learning test - immediate and delayed recall), and magnetic resonance imaging to measure general brain parameters (white matter, gray matter), and white matter lesions. Total brain volume was defined as the sum of gray matter plus normal white matter and white matter lesion volume. Persons with depressive disorders were excluded and analyses were adjusted for depressive symptoms. Results. Compared with no-grief participants, participants with complicated grief had lower scores for the Letter-Digit Substitution Test [Z-score -0.16 v. 0.04, 95% confidence interval (CI) -0.36 to -0.04, p = 0.01] and Word Fluency Task (Z-score -0.15 v. 0.03, 95% CI -0.35 to -0.02, p = 0.02) and smaller total volumes of brain matter (933.53 ml v. 952.42 ml, 95% CI -37.6 to -0.10, p = 0.04). Conclusions. Participants with complicated grief performed poorly in cognitive tests and had a smaller total brain volume. Although the effect sizes were small, these findings suggest that there may be a neurological correlate of complicated grief, but not of normal grief, in the general population.
    Psychological Medicine 11/2014; 45(07):1-11. DOI:10.1017/S0033291714002499 · 5.43 Impact Factor
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    ABSTRACT: Background Excessive gestational weight gain seems to be associated with offspring cardio-metabolic risk factors. Little is known about critical periods of gestational weight gain. We examined the associations of maternal weight gain in different periods of pregnancy with childhood cardio-metabolic risk factors.Methods In a population-based prospective cohort study from early-pregnancy onwards among 5,908 mothers and their children, we obtained maternal prepregnancy weight and weight in early-, mid- and late-pregnancy. At the age of 6 years (median: 72.6 months; 95% range: 67.9, 95.8), we measured childhood BMI, total body and abdominal fat distribution, blood pressure and blood levels of lipids, insulin and c-peptide.ResultsOverall, the associations of maternal prepregnancy weight with childhood outcomes were stronger than the associations of maternal gestational weight gain. Independent from maternal prepregnancy weight and weight gain in other periods, higher weight gain in early-pregnancy was associated with higher childhood BMI, total fat mass, android/gynoid fat mass ratio, abdominal subcutaneous fat mass and systolic blood pressure (P-values<0.05). Independent associations of maternal weight gain in early-pregnancy with childhood abdominal preperitoneal fat mass, insulin and c-peptide were of borderline significance. Higher weight gain in mid-pregnancy was independently associated with higher childhood BMI, total and abdominal subcutaneous fat mass and systolic blood pressure (P-values<0.05). The associations for childhood cardio-metabolic outcomes attenuated after adjustment for childhood BMI. Weight gain in late-pregnancy was not associated with childhood outcomes. Higher weight gain in early-, but not in mid- or late-pregnancy, was associated with increased risks of childhood overweight and clustering of cardio-metabolic risk factors (Odds Ratio (OR) 1.19 (95% Confidence Interval (CI): 1.10, 1.29) and OR 1.20 (95% CI: 1.07, 1.35) per standard deviation increase in early-gestational weight gain, respectively).Conclusions Higher weight gain in early-pregnancy is associated with an adverse cardio-metabolic profile in offspring. This association is largely mediated by childhood adiposity.International Journal of Obesity accepted article preview online, 07 October 2014. doi:10.1038/ijo.2014.175.
    International journal of obesity (2005) 10/2014; DOI:10.1038/ijo.2014.175 · 5.39 Impact Factor
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    ABSTRACT: BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.
    Circulation 10/2014; 130(15):1225-1235. DOI:10.1161/CIRCULATIONAHA.114.009892. · 14.95 Impact Factor

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38k Citations
4,964.20 Total Impact Points


  • 2000–2015
    • Erasmus MC
      • • Department of Epidemiology
      • • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands
    • University of Münster
      • Institute of Epidemiology and Social Medicine
      Münster, North Rhine-Westphalia, Germany
    • University of Zaragoza
      Caesaraugusta, Aragon, Spain
    • University of Leicester
      Leiscester, England, United Kingdom
  • 1986–2015
    • Erasmus Universiteit Rotterdam
      • • Department of Epidemiology
      • • Department of Internal Medicine
      • • Department of Medical Informatics
      • • Department of Ophthalmology
      Rotterdam, South Holland, Netherlands
  • 2013
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 2012
    • McGill University
      Montréal, Quebec, Canada
  • 2009
    • Universitair Ziekenhuis Ghent
      Gand, Flanders, Belgium
  • 2006
    • National Institute on Aging
      Baltimore, Maryland, United States
  • 2002–2006
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 2000–2003
    • University Medical Center Utrecht
      • Julius Center for Health Sciences and Primary Care
      Utrecht, Utrecht, Netherlands
  • 1999–2002
    • Utrecht University
      • Department of General Practice
      Utrecht, Utrecht, Netherlands
  • 1990–1998
    • Wageningen University
      • Division of Human Nutrition
      Wageningen, Gelderland, Netherlands
    • TNO
      Delft, South Holland, Netherlands
  • 1994
    • Rode Kruis Ziekenhuis Beverwijk
      Berverwyk, North Holland, Netherlands