Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this ...study we directly compared a number of multivariate GWAS methods using simulated data. We focused on six methods that are implemented in the software packages PLINK, SNPTEST, MultiPhen, BIMBAM, PCHAT and TATES, and also compared them to standard univariate GWAS, analysis of the first principal component of the traits, and meta-analysis of univariate results. We simulated data (N = 1000) for three quantitative traits and one bi-allelic quantitative trait locus (QTL), and varied the number of traits associated with the QTL (explained variance 0.1%), minor allele frequency of the QTL, residual correlation between the traits, and the sign of the correlation induced by the QTL relative to the residual correlation. We compared the power of the methods using empirically fixed significance thresholds (α = 0.05). Our results showed that the multivariate methods implemented in PLINK, SNPTEST, MultiPhen and BIMBAM performed best for the majority of the tested scenarios, with a notable increase in power for scenarios with an opposite sign of genetic and residual correlation. All multivariate analyses resulted in a higher power than univariate analyses, even when only one of the traits was associated with the QTL. Hence, use of multivariate GWAS methods can be recommended, even when genetic correlations between traits are weak.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To date, concentrations of the promising biomarker hepcidin have only been assessed in serum of relatively small series of healthy volunteers and patients. We assessed age- and sex-stratified ...reference ranges of serum hepcidin concentration in a selected reference set and performed regression analyses to study associations between hepcidin and (biochemical) variables in a large, well-phenotyped sample of the general population (n = 2998). All participants filled out a questionnaire on lifestyle, health status, and medical history. Serum measurements of iron parameters, liver enzyme alanine aminotransferase, creatinine and C-reactive protein were available. Serum hepcidin concentrations were lower for premenopausal than for postmenopausal women (median, 4.1nM vs 8.5nM, respectively). Hepcidin concentrations in men were constant over age (median, 7.8nM). Serum hepcidin was strongly associated with serum ferritin in men and women: β-coefficient of log-transformed variables (95% confidence interval): 0.78 (0.74-0.82) and 0.83 (0.78-0.88), respectively. Additional significant, though less strong, associations were observed for C-reactive protein and total iron binding capacity in men and for total iron binding capacity, alanine aminotransferase, and glomerular filtration rate in women. Our study provides age- and sex-specific reference ranges of serum hepcidin concentration and indicates ferritin as the primary correlate of serum hepcidin concentration.
OBJECTIVE:Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is ...being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity.
APPROACH AND RESULTS:Three hundred two individuals were included, half with a BMI 27 to 30 kg/m and half with a BMI>30 kg/m, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed.Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and menwomen with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity.
CONCLUSIONS:We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.
PurposeTo identify associations of common, low-frequency, and rare variants with advanced age-related macular degeneration (AMD) using whole genome sequencing (WGS).MethodsWGS data were obtained for ...2123 advanced AMD patients (participants of clinical trials for advanced AMD) and 2704 controls (participants of clinical trials for asthma N = 2518 and Alzheimer's disease N = 186), and joint genotype calling was performed, followed by quality control of the dataset. Single variant association analyses were performed for all identified common, low-frequency, and rare variants. Gene-based tests were executed for rare and low-frequency variants using SKAT-O and three groups of variants based on putative impact information: (1) all variants, (2) modifier impact variants, and (3) high- and moderate-impact variants. To ascertain independence of the identified associations from previously reported AMD and asthma loci, conditional analyses were performed.ResultsPreviously identified AMD variants at the CFH, ARMS2/HTRA1, APOE, and C3 loci were associated with AMD at a genome-wide significance level. We identified new single variant associations for common variants near the PARK7 gene and in the long non-coding RNA AC103876.1, and for a rare variant near the TENM3 gene. In addition, gene-based association analyses identified a burden of modifier variants in eight intergenic and gene-spanning regions and of high- and moderate-impact variants in the C3, CFHR5, SLC16A8, and CFI genes.ConclusionsWe describe the largest WGS study in AMD to date. We confirmed previously identified associations and identified several novel associations that are worth exploring in further follow-up studies.
Previous studies regarding cigarette smoking causing a lower risk of melanoma are inconclusive. Here, we re-examined melanoma risk in relation to cigarette smoking in a large, case-control study.
In ...total 1,157 patients with melanoma diagnosed between 2003 and 2011 in the Netherlands and 5,595 controls from the Nijmegen Biomedical Study were included. Information concerning smoking habits and known risk factors for melanoma were obtained through self-administered questionnaires. Logistic regression analyses stratified by gender were performed to study the risk of cigarette smoking on melanoma risk, adjusted for age, marital status, highest level of education, skin type, sun vacation, use of solarium, time spent outdoors, and sun protective measures.
Among men, current and former smokers did not have a higher risk of melanoma compared to never smokers: adjusted odds ratio (OR) = 0.56 (95% confidence interval CI: 0.40-0.79) and adjusted OR = 0.50 (95% CI: 0.39-0.64), respectively. With an increasing number of years smoked the risk of melanoma decreased: <20 years: OR = 0.61 (95% CI: 0.46-0.80); 21-40 years: OR = 0.50 (95% CI: 0.37-0.68); >40 years: OR = 0.26 (95% CI: 0.15-0.44). No clear trend was found for the number of cigarettes smoked. Results for females were less clear and not statistically significant (current smoker: adjusted OR = 0.96, 95% CI: 0.74-1.26, former smoker: adjusted OR = 0.89, 95% CI: 0.73-1.08).
This study shows a strong inverse association between cigarette smoking and melanoma risk in men. Fundamental laboratory research is necessary to investigate the biological relation between smoking cigarettes and melanoma.
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children and adults. It is characterized by inappropriate levels of inattention (IA) and/or hyperactivity and ...impulsivity (HI). The ADHD diagnosis is hypothesized to represent the extreme of a continuous distribution of ADHD symptoms in the general population. In this study, we investigated whether factors linked to adult ADHD as a disorder are associated with adult ADHD symptoms in the general population. Our population-based sample included 4987 adults (mean age 56.1 years; 53.8% female) recruited by the Nijmegen Biomedical Study (NBS). Participants completed the Dutch ADHD DSM-IV Rating Scale for current and childhood ADHD symptoms, the Symptom Check List-90-R (SCL-90-R) anxiety subscale, and the Eysenk Personality Questionnaire (EPQR-S). Partial Spearman correlation and Hurdle negative binomial regression analysis were used to assess how age, sex, childhood ADHD symptoms, anxiety symptoms, and personality traits (neuroticism, extraversion, and psychoticism) are associated with current IA and HI symptoms. Increasing age was associated with a lower proportion of participants reporting HI symptoms and with reduced levels of HI; IA levels remained fairly stable over the age-range, but the probability of reporting IA symptoms increased throughout middle/late adulthood. Females were more likely to report IA symptoms than males. Childhood ADHD symptoms, neuroticism, and psychoticism were positively associated with current IA and HI symptoms, while extraversion had an opposite association with these symptom domains. Anxiety symptoms affected HI symptoms in females. Our results indicate that factors associated with categorical ADHD are also correlated with ADHD symptoms in the adult population.
The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to ...determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways.
Case-control association analysis of metabolomics data.
Five European cohorts consisting of 2267 AMD patients and 4266 control participants.
Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. Metabolome-AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression.
Metabolites associated with AMD.
We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high-density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation.
Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD.
Many diseases recur after recovery, for example, recurrences in cancer and infections. However, research is often focused on analysing only time‐to‐first recurrence, thereby ignoring any subsequent ...recurrences that may occur after the first. Statistical models for the analysis of recurrent events are available, of which the extended Cox proportional hazards frailty model is the current state‐of‐the‐art. However, this model is too statistically complex for computationally efficient application in high‐dimensional data sets, including genome‐wide association studies (GWAS). Here, we develop an application for fast and accurate recurrent event analysis in GWAS, called SPARE (SaddlePoint Approximation for Recurrent Event analysis). In SPARE, every DNA variant is tested for association with recurrence risk using a modified score statistic. A saddlepoint approximation is implemented to achieve statistical accuracy. SPARE controls the Type I error, and its statistical power is similar to existing recurrent event models, yet SPARE is significantly faster. An application of SPARE in a recurrent event GWAS on bladder cancer for 6.2 million DNA variants in 1,443 individuals required less than 15 min, whereas existing recurrent event methods would require several weeks.
Pathogenic
variants impairing matriptase-2 function result in inappropriately high hepcidin levels relative to body iron status, leading to iron refractory iron deficiency anemia (IRIDA). As ...diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the transferrin saturation (TSAT)/hepcidin ratio to distinguish IRIDA from multi-causal iron deficiency anemia (IDA). We included 20 IRIDA patients from a registry for rare inherited iron disorders and then enrolled 39 controls with IDA due to other causes. Plasma hepcidin-25 levels were measured by standardized isotope dilution mass spectrometry. IDA controls had not received iron therapy in the last 3 months and C-reactive protein levels were <10.0 mg/L. IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and 16.7%/nM (IQR, 12.0-24.0%/nM), respectively. The area under the curve for the TSAT/hepcidin ratio was 1.000 with 100% sensitivity and specificity (95% confidence intervals 84-100% and 91-100%, respectively) at an optimal cut-off point of 5.6%/nM. The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA from
-unrelated IDA early in the diagnostic work-up of IDA provided that recent iron therapy and moderate-to-severe inflammation are absent. These observations warrant further exploration in a broader IDA population.
Abstract
Background
People with cancer experience high rates of venous thromboembolism (VTE). Risk of subsequent cancer is also increased in people experiencing their first VTE. The causal mechanisms ...underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer.
Methods
We used data from large genome-wide association study meta-analyses to perform bidirectional Mendelian randomization analyses to estimate causal associations between genetic liability to VTE and risk of 18 different cancers.
Results
We found no conclusive evidence that genetic liability to VTE was causally associated with an increased incidence of cancer, or vice versa. We observed an association between liability to VTE and pancreatic cancer risk odds ratio for pancreatic cancer: 1.23 (95% confidence interval: 1.08–1.40) per log-odds increase in VTE risk, P = 0.002. However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence to suggest a causal relationship.
Conclusions
These findings do not support the hypothesis that genetic liability to VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesize evidence for these mechanisms.
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