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1.
Background
Family studies are often conducted in a cross-sectional manner without long-term follow-up data. The relative contribution of a gene to a specific trait could change over the lifetime. The Framingham Heart Study offers a unique opportunity to investigate potential gene × time interaction. We performed linkage analysis on the body mass index (BMI) measured in 1970, 1978, and 1986 for this project.Results
We analyzed the data in two different ways: three genome-wide linkage analyses on each exam, and one genome-wide linkage analysis on the mean of the three measurements. Variance-component linkage analyses were performed by the SOLAR program. Genome-wide scans show consistent evidence of linkage of quantitative trait loci (QTLs) on chromosomes 3, 6, 9, and 16 in three measurements with a maximum multipoint LOD score > 2.2. However, only chromosome 9 has a LOD score = 2.14 when the mean values were analyzed. More interestingly, we found potential gene × environment interactions: increasing LOD scores with age on chromosomes 3, 9, and 16 and decreasing LOD scores on chromosome 6 in the three exams.Conclusion
The results indicate two points: 1) it is possible that a gene (or genes) influencing BMI is (are) up- or down-regulated as people aged due to aging process or changes in lifestyle, environments, or genetic epistasis; 2) using mean values from longitudinal data may reduce the power to detect linkage and may have no power to detect gene × time, and/or gene × gene interactions.2.
Background
Using the dataset provided for Genetic Analysis Workshop 14 by the Collaborative Study on the Genetics of Alcoholism, we performed genome-wide linkage analysis of age at onset of alcoholism to compare the utility of microsatellites and single-nucleotide polymorphisms (SNPs) in genetic linkage study.Methods
A multipoint nonparametric variance component linkage analysis method was applied to the survival distribution function obtained from semiparametric proportional hazards model of the age at onset phenotype of alcoholism. Three separate linkage analyses were carried out using 315 microsatellites, 2,467 and 9,467 SNPs, spanning the 22 autosomal chromosomes.Results
Heritability of age at onset was estimated to be approximately 12% (p < 0.001). We observed weak correlation, both in trend and strength, of genome-wide linkage signals between microsatellites and SNPs. Results from SNPs revealed more and stronger linkage signals across the genome compared with those from microsatellites. The only suggestive evidence of linkage from microsatellites was on chromosome 1 (LOD of 1.43). Differences in map densities between the two sets of SNPs used in this study did not appear to confer an advantage in terms of strength of linkage signals.Conclusion
Our study provided support for better performance of dense SNP maps compared with the sparse mirosatellite maps currently available for linkage analysis of quantitative traits. This better performance could be attributable to precise definition and high map resolutions achievable with dense SNP maps, thus resulting in increased power to detect possible loci affecting given trait or disease.3.
Background
The Framingham Heart Study has contributed a great deal to advances in medicine. Most of the phenotypes investigated have been univariate traits (quantitative or qualitative). The aims of this study are to derive multivariate traits by identifying homogeneous groups of people and assigning both qualitative and quantitative trait scores; to assess the heritability of the derived traits; and to conduct both qualitative and quantitative linkage analysis on one of the heritable traits.Methods
Multiple correspondence analysis, a nonparametric analogue of principal components analysis, was used for data reduction. Two-stage clustering, using both k-means and agglomerative hierarchical clustering, was used to cluster individuals based upon axes (factor) scores obtained from the data reduction. Probability of cluster membership was calculated using binary logistic regression. Heritability was calculated using SOLAR, which was also used for the quantitative trait analysis. GENEHUNTER-PLUS was used for the qualitative trait analysis.Results
We found four phenotypically distinct groups. Membership in the smallest group was heritable (38%, p < 1 × 10-6) and had characteristics consistent with atherogenic dyslipidemia. We found both qualitative and quantitative LOD scores above 3 on chromosomes 11 and 14 (11q13, 14q23, 14q31). There were two Kong &; Cox LOD scores above 1.0 on chromosome 6 (6p21) and chromosome 11 (11q23).Conclusion
This approach may be useful for the identification of genetic heterogeneity in complex phenotypes by clarifying the phenotype definition prior to linkage analysis. Some of our findings are in regions linked to elements of atherogenic dyslipidemia and related diagnoses, some may be novel, or may be false positives.4.
Xiaowei Wang Mingjie Wang Shuangshuang Shao Yang Zhang Siyu Liu Yue Gao Yuhang Shen Pinghui Sun 《BMC endocrine disorders》2018,18(1):89
Background
To explore the risk factors of coexisting prediabetes and prehypertension, to provide theoretical basis for early intervention.Methods
A multi-stage stratified random cluster sampling method was used to randomly select adult residents from Jilin Province in 2013 for questionnaire surveys, physical examinations, and laboratory tests.Results
The prevalence of coexisting prediabetes and prehypertension in Jilin Province was 11.3%. The binary Logistic regression results showed that age, sex, education, triglyceride (TG), BMI, waist circumference and alcohol consumption were the effects of factor coexisting prediabetes and prehypertension.Conclusion
It is important to pay attention to the early stage of hypertension and diabetes, control the transition from prehypertension and prediabetes to hypertension and diabetes, and improve the health of residents.5.
Zexi Cai Trine Michelle Villumsen Torben Asp Bernt Guldbrandtsen Goutam Sahana Mogens Sandø Lund 《BMC genetics》2018,19(1):103
Background
Identification of genes underlying production traits is a key aim of the mink research community. Recent availability of genomic tools have opened the possibility for faster genetic progress in mink breeding. Availability of mink genome assembly allows genome-wide association studies in mink.Results
In this study, we used genotyping-by-sequencing to obtain single nucleotide polymorphism (SNP) genotypes of 2496 mink. After multiple rounds of filtering, we retained 28,336 high quality SNPs and 2352 individuals for a genome-wide association study (GWAS). We performed the first GWAS for body weight, behavior, along with 10 traits related to fur quality in mink.Conclusions
Combining association results with existing functional information of genes and mammalian phenotype databases, we proposed WWC3, MAP2K4, SLC7A1 and USP22 as candidate genes for body weight and pelt length in mink.6.
Andrea Padoan Daniela Basso Carlo-Federico Zambon Tommaso Prayer-Galetti Giorgio Arrigoni Dania Bozzato Stefania Moz Filiberto Zattoni Rino Bellocco Mario Plebani 《Clinical proteomics》2018,15(1):23
Background
Lower urinary tract symptoms (LUTS) and prostate specific antigen-based parameters seem to have only a limited utility for the differential diagnosis of prostate cancer (PCa). MALDI-TOF/MS peptidomic profiling could be a useful diagnostic tool for biomarker discovery, although reproducibility issues have limited its applicability until now. The current study aimed to evaluate a new MALDI-TOF/MS candidate biomarker.Methods
Within- and between-subject variability of MALDI-TOF/MS-based peptidomic urine and serum analyses were evaluated in 20 and 15 healthy donors, respectively. Normalizations and approaches for accounting below limit of detection (LOD) values were utilized to enhance reproducibility, while Monte Carlo experiments were performed to verify whether measurement error can be dealt with LOD data. Post-prostatic massage urine and serum samples from 148 LUTS patients were analysed using MALDI-TOF/MS. Regression-calibration and simulation and extrapolation methods were used to derive the unbiased association between peptidomic features and PCa.Results
Although the median normalized peptidomic variability was 24.9%, the within- and between-subject variability showed that median normalization, LOD adjustment, and log2 data transformation were the best combination in terms of reliability; in measurement error conditions, intraclass correlation coefficient was a reliable estimate when the LOD/2 was substituted for below LOD values. In the patients studied, 43 peptides were shared by the urine and serum, and several features were found to be associated with PCa. Only few serum features, however, show statistical significance after the multiple testing procedures were completed. Two serum fragmentation patterns corresponded to the complement C4-A.Conclusions
MALDI-TOF/MS serum peptidome profiling was more efficacious with respect to post-prostatic massage urine analysis in discriminating PCa.7.
Ferran Casbas Pinto Srinivarao Ravipati David A. Barrett T. Charles Hodgman 《Metabolomics : Official journal of the Metabolomic Society》2017,13(7):81
Introduction
It is difficult to elucidate the metabolic and regulatory factors causing lipidome perturbations.Objectives
This work simplifies this process.Methods
A method has been developed to query an online holistic lipid metabolic network (of 7923 metabolites) to extract the pathways that connect the input list of lipids.Results
The output enables pathway visualisation and the querying of other databases to identify potential regulators. When used to a study a plasma lipidome dataset of polycystic ovary syndrome, 14 enzymes were identified, of which 3 are linked to ELAVL1—an mRNA stabiliser.Conclusion
This method provides a simplified approach to identifying potential regulators causing lipid-profile perturbations.8.
N. Cesbron A.-L. Royer Y. Guitton A. Sydor B. Le Bizec G. Dervilly-Pinel 《Metabolomics : Official journal of the Metabolomic Society》2017,13(8):99
Introduction
Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.Objectives
In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.Methods
The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.Results
A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.Conclusion
The workflow generated repeatable and informative fingerprints for robust metabolome characterization.9.
Auerbach Jonathan Howey Richard Jiang Lai Justice Anne Li Liming Oualkacha Karim Sayols-Baixeras Sergi Aslibekyan Stella W. 《BMC genetics》2018,19(1):73-79
Background
The GAW20 group formed on the theme of methods for association analyses of repeated measures comprised 4sets of investigators. The provided “real” data set included genotypes obtained from a human whole-genome association study based on longitudinal measurements of triglycerides (TGs) and high-density lipoprotein in addition to methylation levels before and after administration of fenofibrate. The simulated data set contained 200 replications of methylation levels and posttreatment TGs, mimicking the real data set.Results
The different investigators in the group focused on the statistical challenges unique to family-based association analyses of phenotypes measured longitudinally and applied a wide spectrum of statistical methods such as linear mixed models, generalized estimating equations, and quasi-likelihood–based regression models. This article discusses the varying strategies explored by the group’s investigators with the common goal of improving the power to detect association with repeated measures of a phenotype.Conclusions
Although it is difficult to identify a common message emanating from the different contributions because of the diversity in the issues addressed, the unifying theme of the contributions lie in the search for novel analytic strategies to circumvent the limitations of existing methodologies to detect genetic association.10.
Jiangbao Xia Jiayun Ren Ximei Zhao Fengjuan Zhao Hongjun Yang Junhua Liu 《Plant and Soil》2018,424(1-2):157-169
Background and aims
Functional traits may underlie differences in niches, which promote plant species co-existence, but also differences in competitive ability, which drive competitive exclusion. Empirical evidence concerning the contribution of different traits to niche differentiation and the ability to supress and tolerate competitors is very limited, particularly when considering belowground interactions.Methods
We grew 26 temperate grassland species along a density gradient of interspecific competitors to determine which belowground traits a) explain species’ ability to suppress and tolerate neighbours and b) contribute to niche differentiation, such that species with dissimilar trait values experience reduced competition.Results
We found that having larger root systems with extensive horizontal spread and lower root tissue density enabled efficient suppression of neighbours but did not significantly contribute to the ability to tolerate competition. Species with deeper root systems, lower specific root length and less branched roots were better at tolerating competition, but these traits did not significantly affect the ability to suppress neighbours. None of the measured traits contributed significantly to niche differentiation, either individually or in combination.Conclusions
This study provides little support for belowground traits contributing to species co-existence through niche differentiation. Instead, different sets of weakly correlated traits enable plants to either suppress or tolerate their competitors.11.
Background
With the development of high-throughput genotyping and sequencing technology, there are growing evidences of association with genetic variants and complex traits. In spite of thousands of genetic variants discovered, such genetic markers have been shown to explain only a very small proportion of the underlying genetic variance of complex traits. Gene-gene interaction (GGI) analysis is expected to unveil a large portion of unexplained heritability of complex traits.Methods
In this work, we propose IGENT, Information theory-based GEnome-wide gene-gene iNTeraction method. IGENT is an efficient algorithm for identifying genome-wide gene-gene interactions (GGI) and gene-environment interaction (GEI). For detecting significant GGIs in genome-wide scale, it is important to reduce computational burden significantly. Our method uses information gain (IG) and evaluates its significance without resampling.Results
Through our simulation studies, the power of the IGENT is shown to be better than or equivalent to that of that of BOOST. The proposed method successfully detected GGI for bipolar disorder in the Wellcome Trust Case Control Consortium (WTCCC) and age-related macular degeneration (AMD).Conclusions
The proposed method is implemented by C++ and available on Windows, Linux and MacOSX.12.
Parastoo Fazelzadeh Roland W. J. Hangelbroek Peter J. Joris Casper G. Schalkwijk Diederik Esser Lydia Afman Thomas Hankemeier Doris M. Jacobs Velitchka V. Mihaleva Sander Kersten John van Duynhoven 《Metabolomics : Official journal of the Metabolomic Society》2018,14(4):46
Introduction
The response to dietary challenges has been proposed as a more accurate measure of metabolic health than static measurements performed in the fasted state. This has prompted many groups to explore the potential of dietary challenge tests for assessment of diet and lifestyle induced shifts in metabolic phenotype.Objectives
We examined whether the response to a mixed-meal challenge could provide a readout for a weight loss (WL)-induced phenotype shift in abdominally obese male subjects. The underlying assumption of a mixed meal challenge is that it triggers all aspects of phenotypic flexibility and provokes a more prolonged insulin response, possibly allowing for better differentiation between individuals.Methods
Abdominally obese men (n?=?29, BMI?=?30.3?±?2.4 kg/m2) received a mixed-meal challenge prior to and after an 8-week WL or no-WL control intervention. Lean subjects (n?=?15, BMI?=?23.0?±?2.0 kg/m2) only received the mixed meal challenge at baseline to have a benchmark for WL-induced phenotype shifts.Results
Levels of several plasma metabolites were significantly different between lean and abdominally obese at baseline as well as during postprandial metabolic responses. Genes related to oxidative phosphorylation in peripheral blood mononuclear cells (PBMCs) were expressed at higher levels in abdominally obese subjects as compared to lean subjects at fasting, which was partially reverted after WL. The impact of WL on the postprandial response was modest, both at the metabolic and gene expression level in PBMCs.Conclusion
We conclude that mixed-meal challenges are not necessarily superior to measurements in the fasted state to assess metabolic health. Furthermore, the mechanisms accounting for the observed differences between lean and abdominally obese in the fasted state are different from those underlying the dissimilarity observed during the postprandial response.13.
Seyed Mehdi Sajjadi Abbas Khosravi Jalil Pakravesh Zahra-soheila Soheili Shahram Samiei Saeed Mohammadi Mohammad Ali Jalali far 《生物学前沿》2016,11(6):471-475
BACKGROUND
Recurrent pregnancy loss (RPL) is a heterogeneous condition and thrombophilias have been considered as a probable cause.OBJECTIVE
The aim of this study was to investigate the prevalence of the coagulation factor XIII Val34Leu polymorphism among women with unexplained RPL.METHODS
A total of 140 women with a history of unexplained RPL and 100 age-matched healthy fertile women were recruited. The presence of FXIII Val34Leu polymorphism among the cases and controls was investigated using PCR-RFLP method.RESULTS
Genotype analyses of the subjects revealed that the patients had a significantly higher prevalence of V/L and L/L than the controls (P<0.05): 33.5% vs. 15%, and 9.2% vs. 2%, respectively.CONCLUSION
These results indicate a significant association between FXIII Val34Leu polymorphism and unexplained RPL in the Iranian patient.14.
Miriam Banas Sindy Neumann Johannes Eiglsperger Eric Schiffer Franz Josef Putz Simone Reichelt-Wurm Bernhard Karl Krämer Philipp Pagel Bernhard Banas 《Metabolomics : Official journal of the Metabolomic Society》2018,14(9):116
Introduction
Allograft rejection is still an important complication after kidney transplantation. Currently, monitoring of these patients mostly relies on the measurement of serum creatinine and clinical evaluation. The gold standard for diagnosing allograft rejection, i.e. performing a renal biopsy is invasive and expensive. So far no adequate biomarkers are available for routine use.Objectives
We aimed to develop a urine metabolite constellation that is characteristic for acute renal allograft rejection.Methods
NMR-Spectroscopy was applied to a training cohort of transplant recipients with and without acute rejection.Results
We obtained a metabolite constellation of four metabolites that shows promising performance to detect renal allograft rejection in the cohorts used (AUC of 0.72 and 0.74, respectively).Conclusion
A metabolite constellation was defined with the potential for further development of an in-vitro diagnostic test that can support physicians in their clinical assessment of a kidney transplant patient.15.
Background
GAW20 working group 5 brought together researchers who contributed 7 papers with the aim of evaluating methods to detect genetic by epigenetic interactions. GAW20 distributed real data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, including single-nucleotide polymorphism (SNP) markers, methylation (cytosine-phosphate-guanine [CpG]) markers, and phenotype information on up to 995 individuals. In addition, a simulated data set based on the real data was provided.Results
The 7 contributed papers analyzed these data sets with a number of different statistical methods, including generalized linear mixed models, mediation analysis, machine learning, W-test, and sparsity-inducing regularized regression. These methods generally appeared to perform well. Several papers confirmed a number of causative SNPs in either the large number of simulation sets or the real data on chromosome 11. Findings were also reported for different SNPs, CpG sites, and SNP–CpG site interaction pairs.Conclusions
In the simulation (200 replications), power appeared generally good for large interaction effects, but smaller effects will require larger studies or consortium collaboration for realizing a sufficient power.16.
Background
The data arising from a longitudinal familial study have a complex correlation structure that cannot be modeled using classical methods for the analysis of familial data at a single time point.Methods
To fit the longitudinal systolic blood pressure (SBP) pedigree data arising from the Framingham Heart Study, we proposed to use multilevel modeling. That approach was used to distinguish multiple levels of information with individual repeated measurements (Level 1) being made within individuals (Level 2), and individuals clustered within pedigrees (Level 3). Residuals from the subject-specific and pedigree-specific regression models were summed both for the mean SBP and slope of SBP change over time, in order to define two new outcomes that were then used in a genome-wide linkage analysis.Results
Evidence for linkage for the two outcomes (mean SBP and slope) was found in several chromosomal regions with a maximum LOD score of 3.6 on chromosome 8 and 3.5 on chromosome 17 for the mean SBP, and 2.5 on chromosome 1 for SBP slope. However, the linkage on chromosome 8 was only detected when the sample was restricted to subjects between age 25 and 75 and with at least four exams (Cohort 1) or 3 exams (Cohort 2).Discussion
Multilevel modeling is a powerful approach to detect genes involved in complex traits when longitudinal data are available. It allows for complex hierarchical data structure to be taken into account and therefore, a better partitioning of random within-individual variation from other sources of variability (genetic or nongenetic).17.
Rachel A. Spicer Christoph Steinbeck 《Metabolomics : Official journal of the Metabolomic Society》2018,14(1):16
Introduction
Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.Objectives
(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.Methods
A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.Results
Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.Conclusion
Further efforts are required to improve data sharing in metabolomics.18.
Ellen L. Fry Amy L. Evans Craig J. Sturrock James M. Bullock Richard D. Bardgett 《Plant and Soil》2018,425(1-2):189-200
Aims
Fine root morphological traits are generally changed under soil nitrogen (N) enrichment, however, the underlying mechanism and functional significance are still not well understood. Our aims were to investigate the linkage of root morphology to anatomy, and its implication for root function at elevated soil N availability.Methods
Ingrowth cores were used to sample root tips (0–20 cm soil depth) from six temperate tree species growing in monoculture plantations at a common site in northeastern China. Root morphological and anatomical traits were concurrently measured, and their relationships were determined within and among species in both control and N fertilization (10 g N m?2y?1) plots.Results
Root diameter generally increased in all six species (non-significant for Phellodendron amurense) following N fertilization, which was caused by the increased root stele radius rather than cortical thickness. Congruently, N fertilization significantly decreased the ratio of cortical thickness to stele radius, but increased the ratio of total cross-sectional area of conduits to stele area in root tips across all species.Conclusions
The observed anatomical changes of root tips contributed to the alternations of morphological root traits following N fertilization, with potentially important impacts on root physiological functions, like increased water and nutrient transport.19.
Benjamin H Natelson Roxann Intriligator Neil S Cherniack Helena K Chandler Julian M Stewart 《Dynamic medicine : DM》2007,6(1):2
Context
Patients with chronic fatigue syndrome and those with orthostatic intolerance share many symptoms, yet questions exist as to whether CFS patients have physiological evidence of orthostatic intolerance.Objective
To determine if some CFS patients have increased rates of orthostatic hypotension, hypertension, tachycardia, or hypocapnia relative to age-matched controls.Design
Assess blood pressure, heart rate, respiratory rate, end tidal CO2 and visual analog scales for orthostatic symptoms when supine and when standing for 8 minutes without moving legs.Setting
Referral practice and research center.Participants
60 women and 15 men with CFS and 36 women and 4 men serving as age matched controls with analyses confined to 62 patients and 35 controls showing either normal orthostatic testing or a physiological abnormal test.Main outcome measures
Orthostatic tachycardia; orthostatic hypotension; orthostatic hypertension; orthostatic hypocapnia or combinations thereof.Results
CFS patients had higher rates of abnormal tests than controls (53% vs 20%, p < .002), but rates of orthostatic tachycardia, orthostatic hypotension, and orthostatic hypertension did not differ significantly between patients and controls (11.3% vs 5.7%, 6.5% vs 2.9%, 19.4% vs 11.4%, respectively). In contrast, rates of orthostatic hypocapnia were significantly higher in CFS than in controls (20.6% vs 2.9%, p < .02). This CFS group reported significantly more feelings of illness and shortness of breath than either controls or CFS patients with normal physiological tests.Conclusion
A substantial number of CFS patients have orthostatic intolerance in the form of orthostatic hypocapnia. This allows subgrouping of patients with CFS and thus reduces patient pool heterogeneity engendered by use of a clinical case definition.20.
E. Dervishi G. Zhang D. Hailemariam R. Mandal D. S. Wishart B. N. Ametaj 《Metabolomics : Official journal of the Metabolomic Society》2018,14(6):83