Definitions and assessment methods of fussy/picky eating are heterogeneous and remain unclear.
We aimed to identify an eating behavior profile reflecting fussy/picky eating in children and to describe characteristics of fussy eaters.
Eating behavior was assessed with the Child Eating Behavior Questionnaire (CEBQ) in 4914 4-year olds in a population-based birth cohort study. Latent Profile Analysis (LPA) was used to identify eating behavior profiles based on CEBQ subscales.
Results and discussion
We found a “fussy” eating behavior profile (5.6% of children) characterized by high food fussiness, slowness in eating, and satiety responsiveness in combination with low enjoyment of food and food responsiveness. Fussy eaters were more often from families with low household income than non-fussy eaters (42% vs. 31.8% respectively; Χ
(1) = 9.97, p < .01). When they were 14 months old, fussy eaters had a lower intake of vegetables (t  = 2.42, p < .05) and fish (t [169.77] = 2.40, p < .05) but higher intake of savory snacks (t [153.69] = -2.03, p < .05) and sweets (t  = -2.30, p < .05) compared to non-fussy eaters. Also, fussy eaters were more likely to be underweight at 4 years of age (19.3%) than non-fussy eaters (12.3%; Χ
(1) = 7.71, p < .01).
A distinct fussy eating behavior profile was identified by LPA, which was related to family and child characteristics, food intake, and BMI. This behavior profile might be used in future research and the development of interventions.
Fussy eating; Children; Latent profile analysis; Population-based cohort study; Dietary intake; BMI; Child and family characteristics
Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent–offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910–1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14–15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project.
whole-genome sequence; trio-design; population genetics
Genetic studies might provide new insights into the biological
mechanisms underlying lipid metabolism and risk of CAD. We therefore
conducted a genome-wide association study to identify novel genetic
determinants of LDL-c, HDL-c and triglycerides.
Methods and results
We combined genome-wide association data from eight studies,
comprising up to 17,723 participants with information on circulating lipid
concentrations. We did independent replication studies in up to 37,774
participants from eight populations and also in a population of Indian Asian
descent. We also assessed the association between SNPs at lipid loci and
risk of CAD in up to 9,633 cases and 38,684 controls.
We identified four novel genetic loci that showed reproducible
associations with lipids (P values 1.6 × 10−8 to
3.1 × 10−10). These include a potentially
functional SNP in the SLC39A8 gene for HDL-c, a SNP near
the MYLIP/GMPR and PPP1R3B genes for LDL-c
and at the AFF1 gene for triglycerides. SNPs showing strong
statistical association with one or more lipid traits at the
APOE-C1-C4-C2 cluster, LPL,
ZNF259-APOA5-A4-C3-A1 cluster and
TRIB1 loci were also associated with CAD risk (P values
1.1 × 10−3 to 1.2 ×
We have identified four novel loci associated with circulating
lipids. We also show that in addition to those that are largely associated
with LDL-c, genetic loci mainly associated with circulating triglycerides
and HDL-c are also associated with risk of CAD. These findings potentially
provide new insights into the biological mechanisms underlying lipid
metabolism and CAD risk.
lipids; lipoproteins; genetics; epidemiology
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischaemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n=2,100 Stage 1) were examined in ischemic stroke (n=4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases 55,000 controls) was used for replication (Stage 3).
Stage 1 identified 524 SNPs from 23 LD blocks having significant association (p<5 ×10-8) with one or more coagulation/fibrin phenotypes. Most striking associations included SNP rs5985 with factor XIII activity (p=2.6×10-186), rs10665 with FVII (p = 2.4×10-47) and rs505922 in the ABO gene with both von Willebrand Factor (vWF p=4.7×10-57) and factor VIII (p=1.2×10-36). In Stage 2, the 23 independent SNPs were examined in stroke cases/non-cases using MORGAM and WTCCC2 collections. SNP rs505922 was nominally associated with ischaemic stroke, odds ratio = 0.94 (95% confidence intervals, 0.88-0.99), p=0.023. Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta=0.066 (0.02) p = 0.001, a finding specific to large vessel and cardioembolic stroke (p = 0.001 and p = <0.001 respectively) but not seen with small vessel stroke (p=0.811).
ABO gene variants are associated with large vessel and cardioembolic stroke but not small vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
GWAS; thrombosis; stroke; coagulation factor; stroke subtype
Changes in epigenetic programming of embryonic growth genes during pregnancy seem to affect fetal growth. Therefore, in a population-based prospective birth cohort in the Netherlands, we examined associations between fetal and infant growth and DNA methylation of IGF2DMR, H19 and MTHFR. For this study, we selected 69 case children born small-for-gestational age (SGA, birth weight <-2SDS) and 471 control children. Fetal growth was assessed with serial ultrasound measurements. Information on birth outcomes was retrieved from medical records. Infant weight was assessed at three and six months. Methylation was assessed in DNA extracted from umbilical cord white blood cells. Analyses were performed using linear mixed models with DNA methylation as dependent variable. The DNA methylation levels of IGF2DMR and H19 in the control group were, median (90% range), 53.6% (44.5–61.6) and 30.0% (25.6–34.2) and in the SGA group 52.0% (43.9–60.9) and 30.5% (23.9–32.9), respectively. The MTHFR region was found to be hypomethylated with limited variability in the control and SGA group, 2.5% (1.4–4.0) and 2.4% (1.5–3.8), respectively. SGA was associated with lower IGF2DMR DNA methylation (β = −1.07, 95% CI −1.93; −0.21, P-value = 0.015), but not with H19 methylation. A weight gain in the first three months after birth was associated with lower IGF2DMR DNA methylation (β = −0.53, 95% CI −0.91; −0.16, P-value = 0.005). Genetic variants in the IGF2/H19 locus were associated with IGF2DMR DNA methylation (P-value<0.05), but not with H19 methylation. Furthermore, our results suggest a possibility of mediation of DNA methylation in the association between the genetic variants and SGA. To conclude, IGF2DMR and H19 DNA methylation is associated with fetal and infant growth.
Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.
Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.
The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.
Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders.
There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association.
We included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR<60 ml/min/1.73 m2. All associations were corrected for socio-demographic and cardiovascular factors.
Each unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m2 faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98–1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15–1.22). In the stratified analyses, we observed that the associations of serum uric acid with eGFR decline and incident CKD were stronger in hypertensive subjects (P for interaction = 0.046 and 0.024, respectively).
Our findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.
Few studies have analyzed the association of socioeconomic and sociodemographic factors with asthma related outcomes in early childhood, including Fraction of exhaled Nitric Oxide (FeNO) and airway resistance (Rint). We examined the association of socioeconomic and sociodemographic factors with wheezing, asthma, FeNO and Rint at age 6 years. Additionally, the role of potential mediating factors was studied.
The study included 6717 children participating in The Generation R Study, a prospective population-based cohort study. Data on socioeconomic and sociodemographic factors, wheezing and asthma were obtained by questionnaires. FeNO and Rint were measured at the research center. Statistical analyses were performed using logistic and linear regression models.
At age 6 years, 9% (456/5084) of the children had wheezing symptoms and 7% (328/4953) had asthma. Children from parents with financial difficulties had an increased risk of wheezing (adjusted Odds Ratio (aOR) = 1.63, 95% Confidence Interval (CI):1.18–2.24). Parental low education, paternal unemployment and child's male sex were associated with asthma, independent of other socioeconomic or sociodemographic factors (aOR = 1.63, 95% CI:1.24–2.15, aOR = 1.85, 95% CI:1.11–3.09, aOR = 1.58, 95% CI:1.24–2.01, respectively). No socioeconomic or gender differences in FeNO were found. The risks of wheezing, asthma, FeNO and Rint measurements differed between ethnic groups (p<0.05). Associations between paternal unemployment, child's sex, ethnicity and asthma related outcomes remained largely unexplained.
This study showed differences between the socioeconomic and sociodemographic correlates of wheezing and asthma compared to the correlates of FeNO and Rint at age 6 years. Several socioeconomic and sociodemographic factors were independently associated with wheezing and asthma. Child's ethnicity was the only factor independently associated with FeNO. We encourage further studies on underlying pathways and public health intervention programs, focusing on reducing socioeconomic or sociodemographic inequalities in asthma.
Thyroid disorders are associated with an increased risk of cognitive impairment and Alzheimer's disease. Both small vessel disease and neurodegeneration have a role in the pathogenesis of cognitive impairment and Alzheimer's disease. Thyroid hormone receptor alpha (TRα) is the predominant TR in brain. The circadian clock gene REV-ERBα overlaps with the TRα gene and interferes with TRα expression. Limited data are available on the role of the TRα/REV-ERBα locus in small vessel disease and neurodegeneration. We therefore studied genetic variation in the TRα/REV-ERBα locus in relation to brain imaging data, as early markers for small vessel disease and neurodegeneration.
Fifteen polymorphisms, covering the TRα/REV-ERBα locus, were studied in relation to white matter lesion (WML), total brain, and hippocampal volumes in the Rotterdam Study I (RS-I, n=454). Associations that remained significant after multiple testing correction were subsequently studied in an independent population for replication (RS-II, n=607).
No associations with total brain or hippocampal volumes were detected. A haplotype block in REV-ERBα was associated with WML volumes in RS-I. Absence of this haplotype was associated with larger WML volumes in women (0.38%±0.18% [β±SE], p=0.007), but not in men (0.04%±0.11%, p=0.24), which was replicated in RS-II (women: 0.15%±0.05%, p=0.04; men: 0.05%±0.07%, p=0.80). Meta-analysis of the two populations showed that women lacking this haplotype have a 1.9 times larger WML volume (p=0.001).
Our results suggest a role for REV-ERBα in the pathogenesis of WMLs.
Myopia is a complex inherited ocular trait resulting from an interplay of genes and environmental factors, most of which are currently unknown. In two independent population-based cohorts consisting of 5,256 and 3,938 individuals from European descent, we tested for biological interaction between genetic predisposition and level of education on the risk of myopia. A genetic risk score was calculated based on 26 myopia-associated single nucleotide polymorphisms recently discovered by the Consortium for Refractive Error and Myopia. Educational level was obtained by questionnaire and categorized into primary, intermediate, and higher education. Refractive error was measured during a standardized ophthalmological examination. Biological interaction was assessed by calculation of the synergy index. Individuals at high genetic risk in combination with university-level education had a remarkably high risk of myopia (OR 51.3; 95 % CI 18.5–142.6), while those at high genetic risk with only primary schooling were at a much lower increased risk of myopia (OR 7.2, 95 % CI 3.1–17.0). The combined effect of genetic predisposition and education on the risk of myopia was far higher than the sum of these two effects (synergy index 4.2, 95 % CI 1.9–9.5). This epidemiological study provides evidence of a gene-environment interaction in which an individual’s genetic risk of myopia is significantly affected by his or her educational level.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-013-9856-1) contains supplementary material, which is available to authorized users.
Myopia; Refractive error; GxE; Gene-environment; Environmental factors
Prenatal maternal psychopathology affects child development, but some children seem more vulnerable than others. Genetic variance in hypothalamic–pituitary–adrenal axis genes may influence the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems. This hypothesis was tested in the Generation R Study, a population-based cohort from fetal life onward. In total, 1727 children of Northern European descent and their mothers participated in this study and were genotyped for variants in the glucocorticoid receptor (GR) gene (rs6189/rs6190, rs10052957, rs41423247, rs6195, and rs6198) and the FK506-binding protein 5 (FKBP5) gene (rs1360780). Prenatal maternal psychological symptoms were assessed at 20 weeks pregnancy and child behavior was assessed by both parents at 3 years. In a subsample of 331 children, data about cortisol reactivity were available. Based on power calculations, only those genetic variants with sufficient minor allele frequencies (rs41423247, rs10052957, and rs1360780) were included in the interaction analyses. We found that variation in GR at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems (beta 0.41, SE 0.16, p=0.009). This prenatal interaction effect was independent of mother's genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. Moreover, the interaction between rs41423247 and prenatal psychological symptoms was also associated with decreased child cortisol reactivity (beta −2.30, p-value 0.05). These findings emphasize the potential effect of prenatal gene–environment interaction, and give insight in possible mechanisms accounting for children's individual vulnerability to develop emotional and behavioral problems.
glucocorticoid receptor gene; prenatal psychological symptom; gene–environment interaction; cortisol reactivity; child emotional and behavioral problem; biological psychiatry; child emotional and behavioral problems; cortisol reactivity; epidemiology; gene–environment interaction; glucocorticoid receptor gene; neuroendocrinology; prenatal psychological symptoms; psychiatry and behavioral sciences
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
Osteoporotic vertebral fractures are an increasingly active area of research. Oftentimes assessments are performed by software-assisted quantitative morphometry. Here, we will discuss multi-functionality of these data for research purposes. A team of trained research assistants processed lateral spine radiographs from the population-based Rotterdam Study with SpineAnalyzer® software (Optasia Medical Ltd, Cheadle, UK). Next, the raw coordinate data of the two upper corners of Th5 and the two lower corners of Th12 were extracted to calculate the Cobb’s kyphosis angle. In addition, two readers performed independent manual measurements of the Cobb’s kyphosis angle between Th5 and Th12 for a sample (n=99). The mean kyphosis angle and its standard deviation were 53° and 10° for the SpineAnalyzer® software measurements and 54° and 12° by manual measurements, respectively. The Pearson’s correlation coefficient was 0.65 [95% confidence interval (CI): 0.53-0.75; P=2×10–13]. There was a substantial intraclass correlation with a coefficient of 0.64 (95% CI: 0.51-0.74). The mean difference between methods was 1° (95% CI: –2°-4°), with 95% limits of agreement of –20°-17° and there were no systematic biases. In conclusion, vertebral fracture morphometry data can be used to derive the Cobb’s kyphosis angle. Even more quantitative measures could be derived from the raw data, such as vertebral wedging, intervertebral disc space, spondylolisthesis and the lordosis angle. These measures may be of interest for research into musculoskeletal disorders such as osteoporosis, degenerative disease or Scheuermann’s disease. Large-scale studies may benefit from efficient capture of multiple quantitative measures in the spine.
Vertebral fracture; quantitative; morphometry; osteoporosis; degenerative disease; spine; software; post-processing
Although clopidogrel reduces the incidence of atherothrombotic events, its use is associated with an increased risk of major bleeding. Cerebral microbleeds (CMBs) are indicative of subclinical microangiopathy in the brain and may prelude symptomatic intracerebral hemorrhage. We examined the association between use of clopidogrel and CMBs in persons without a history of stroke.
Methods and Results
We performed a cross‐sectional analysis using data from the Rotterdam Study, a prospective population‐based cohort of persons aged 45 years and older. Among 4408 stroke‐free individuals who underwent brain magnetic resonance imaging for the detection of CMBs, we identified 121 ever‐users and 4287 never‐users of clopidogrel before magnetic resonance imaging. We used multiple logistic regression to analyze the association between clopidogrel and CMBs with adjustment for age, sex, cardiovascular risk factors, and common cardiovascular medication. Users of clopidogrel had a higher prevalence of CMBs (odd ratio 1.55, 95% CI 1.01 to 2.37) than nonusers and more often had a high number (>4) of CMBs (odds ratio 3.19, 95% CI 1.52 to 6.72). Clopidogrel use was associated with a significantly higher prevalence of deep or infratentorial CMBs (odd ratio 1.90, 95% CI 1.05 to 3.45). Among clopidogrel users, we were unable to demonstrate differences in the prevalence of CMBs by indication of prescription, history of coronary heart disease, or common genetic variants in CYP2C19.
In stroke‐free individuals, clopidogrel use was associated with a higher prevalence and higher number of CMBs. Whether this association is causal requires confirmation in prospective studies, especially given the small number of participants taking clopidogrel and the possibility of residual confounding in this study.
cerebral microbleed; magnetic resonance imaging; platelet inhibitor; population studies
Lipid modification therapy (LMT) produces cardiovascular benefits principally through reductions in low density lipoprotein cholesterol (LDL-C). While recent evidence, using data from 454 participants in the Framingham Offspring Study (FOS), has suggested that increases in high density lipoprotein cholesterol (HDL-C) are also associated with a reduction in cardiovascular outcomes, independently of changes in LDL-C, replication of this finding is important. We therefore present further results using data from the EPIC Norfolk (UK) and Rotterdam (Netherlands) prospective cohort studies.
A total of 1,148 participants, 446 from the EPIC-Norfolk and 702 from the Rotterdam study were assessed for lipids before and after starting LMT. Subsequent risk of cardiovascular events, ascertained through linkage with mortality records and hospital databases, was investigated using Cox Proportional hazards regression. Random effects meta-analysis was used to combine results across studies.
Based on combined data from the EPIC-Norfolk and Rotterdam studies there was some evidence that change in HDL-C resulting from LMT was associated with reduced cardiovascular risk (hazard ratio per pooled SD (= 0. 34 mmol/l) increase = 0.74, 95% CI 0.56-0.99, adjusted for age, sex, and baseline HDL-C). However, this association was attenuated and was not (statistically) significant with further adjustments for non-HDL-C and for cigarette smoking history, prevalent diabetes, SBP, BMI, use of antihypertensive medication, previous MI, prevalent angina, previous stroke (0.92, 0.70-1.20).
Following adjustment for conventional non-lipid CVD risk factors, this study provides no evidence to support a significant benefit from increasing HDL-C independent of the effect of lowering non-HDL-C.
Lipids; Lipoproteins; HDL; Atherosclerosis; Myocardial infarction
Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants for this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch patients and 4,580 population-matched controls. We selected SNPs from 12 loci with two or more SNPs with P-values < 1 × 10−5 for follow-up in 2,508 patients and 2,652 controls. Two loci, i.e. 1q22 (MEF2D) and 3p24 (near TGFBR2) replicated convincingly (P = 4.9 × 10−4, P = 1.0 × 10−4, respectively). Meta-analysis of the discovery and replication data yielded two additional genome-wide significant (P < 5 × 10−8) loci in PHACTR1 and ASTN2. In addition, SNPs in two previously reported migraine loci in or near TRPM8 and LRP1 significantly replicated. This study reveals the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association (GWA) studies (N=10,768 from European ancestry enrolled in pregnancy/birth cohorts) and followed up three lead signals in six replication studies (combined N=19,089). Rs7980687 on chromosome 12q24 (P=8.1×10−9), and rs1042725 on chromosome 12q15 (P=2.8×10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P=3.8×10−7 for rs7980687, P=1.3×10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P=3.9×10−6). SNPs correlated to the 17q21 signal show genome-wide association with adult intra cranial volume2, Parkinson’s disease and other neurodegenerative diseases3-5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
We conducted a GWAS meta-analysis in 1,308 female CWP cases and 5,791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1,480 CWP cases and 7,989 controls (P<1×10−5). Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of CCT5 and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (MAF=43%; OR=1.30, 95%CI=1.19-1.42, P=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95%CI=1.10-1.24, P=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95%CI=1.14-1.32, P=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (P>7.7×10−4).
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
Gene Polymorphism; Fibromyalgia/Pain Syndromes; Epidemiology
Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown.
Methods and results
A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8%) met the diagnostic criteria for OH (systolic/diastolic BP drop ≥20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95% confidence interval: 0.90, 0.85–0.96; P = 0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75–0.95; P = 0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.87–0.98; P= 0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.02–1.24; P = 0.02, rs198358: 1.10, 1.01–1.20; P = 0.04, and rs5068: 1.22, 1.04–1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P= 0.04).
The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.
Orthostatic hypotension; Genetics; Single nucleotide polymorphism; Steroid 17-alpha-hydroxylase; Natriuretic peptides; Adrenomedullin
Studies suggest that neighborhood ethnic diversity may be important when it comes to understanding ethnic inequalities in mental health. The primary aim of this study was to investigate whether neighborhood ethnic diversity moderated the association between the ethnic minority status and child behavioral and emotional problems.
We included 3076 preschoolers participating in the Generation R Study, a birth cohort study in Rotterdam, the Netherlands. At child age 3-years, parents completed the Child Behavior Checklist (CBCL/1,5-5). Individual-level data, assessed with questionnaires, was combined with neighborhood-level data. Multi-level logistic regression models predicted the Odds Ratios for the CBCL total problems score as a function of maternal ethnic background and neighborhood ethnic diversity, computed with the Racial Diversity Index and categorized into tertiles. Interaction on the additive scale was assessed using Relative Access Risk due to Interaction.
Being from an ethnic minority was associated with child behavioral and emotional problems in unadjusted (OR 2.76, 95% CI 1.88–4.04) and adjusted models (OR 2.64, 95% CI 1.79–3.92). Residing in a high diversity neighborhood was associated with child behavioral and emotional problems in unadjusted (OR 2.03, 95% CI 1.13–3.64) but not in adjusted models (OR 0.89, 95% CI 0.51–1.57). When stratifying by the three levels of neighborhood ethnic diversity, ethnic inequalities in behavioral and emotional problems were greatest in low diversity neighborhoods (OR 5.24, 95%CI 2.47–11.14), smaller in high diversity neighborhoods (OR 3.15, 95% CI 1.66–5.99) and smallest in medium diversity neighborhoods (OR 1.59, 95% CI 0.90–2.82). Tests for interaction (when comparing medium to low diversity neighborhoods) trended towards negative on both the additive and multiplicative scale for the maternal-report (RERI: −3.22, 95% CI −0.70–0.59; Ratio of ORs: 0.30, 95% CI 0.12–0.76).
This study suggests that ethnic inequalities in child behavioral and emotional problems may be greatest in ethnically homogeneous neighborhoods.
To investigate the relation between retinopathy and the risk of dementia.
We investigated the associations between retinopathy and dementia and its subtypes Alzheimer disease (AD) and vascular dementia both cross-sectionally and prospectively in the Rotterdam Study, a large population-based cohort study. Digitized retinal images were available for 195 participants with prevalent dementia and 6,078 participants without dementia at baseline (1990–1993). Participants were reexamined in 1993–1994, 1997–1999, and 2002–2004 and were continuously monitored for development of dementia until January 1, 2007. Retinopathy was graded on fundus photographs and was defined as the presence of one or more dot/blot hemorrhages, microaneurysms, cotton wool spots, or evidence of laser treatment for retinopathy.
Retinopathy was associated with prevalent dementia (age and sex-adjusted odds ratio 2.04, 95% confidence interval [CI] 1.34–3.09). Results were similar for AD and vascular dementia. During a mean follow-up of 11.4 years, 735 participants developed incident dementia, of whom 583 had AD and 80 had vascular dementia. There was no association of retinopathy at baseline with the risk of incident dementia during follow-up (age- and sex-adjusted hazard ratio 1.15, 95% CI 0.88–1.48) or the risk of incident AD or vascular dementia.
Retinopathy is more prevalent in persons with dementia but is not associated with an increased risk of dementia over time.
Vascular dysfunction in atherosclerosis and diabetes, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction.
Methods and Results
In mice with genomic instability due to the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1d/− and XpdTTD mice), we explored age-dependent vascular function as compared to wild-type mice. Ercc1d/− mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness and elevated blood pressure at very young age. The vasodilator dysfunction was due to decreased endothelial eNOS levels as well as impaired smooth muscle cell function, which involved phosphodiesterase (PDE) activity. Similar to Ercc1d/− mice, age-related endothelium-dependent vasodilator dysfunction in XpdTTD animals was increased. To investigate the implications for human vascular disease, we explored associations between single nucleotide polymorphisms (SNPs) of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium, and found a significant association of a SNP (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity.
Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans, but with an accelerated progression, as compared to wild type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.
aging; cardiovascular disease; endothelial dysfunction; nitric oxide synthase; vasodilation
Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer’s disease. Few rare variants affecting the risk of late-onset Alzheimer’s disease have been found.
We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer’s disease and control participants and then tested for an association with Alzheimer’s disease. We performed replication tests using case–control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons.
A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer’s disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10−10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10−12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer’s disease had poorer cognitive function than noncarriers (P = 0.003).
Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer’s disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer’s disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.)
To investigate whether intake of different types of meat is associated with circulating C-reactive protein (CRP) and risk of type 2 diabetes in a prospective cohort study.
RESEARCH DESIGN AND METHODS
Our analysis included 4,366 Dutch participants who did not have diabetes at baseline. During a median follow-up period of 12.4 years, 456 diabetes cases were confirmed. Intake of red meat, processed meat, and poultry was derived from a food frequency questionnaire, and their association with serum high-sensitivity CRP was examined cross-sectionally using linear regression models. Their association with risk of type 2 diabetes was examined using multivariate Cox proportional hazards model, including age, sex, family history of diabetes, and lifestyle and dietary factors.
An increment of 50 g of processed meat was associated with increased CRP concentration (βprocessed meat = 0.12; P = 0.01), whereas intake of red meat and poultry was not. When comparing the highest to the lowest category of meat intake with respect to diabetes incidence, the adjusted relative risks were as follows: for red meat (1.42 [95% CI 1.06–1.91]), for processed meat (1.87 [1.26–2.78]), and for poultry (0.95 [0.74–1.22]). Additional analysis showed that the associations were not affected appreciably after inclusion of CRP into the model. After adjustment for BMI, however, the association for red meat attenuated to 1.18 (0.88–1.59).
Intake of processed meat is associated with higher risk of type 2 diabetes. It appears unlikely that CRP mediates this association.
Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.