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PubMed2004

Genetic factors in nickel allergy evaluated in a population-based female twin sample.

Environmental exposures are important for development of allergic contact dermatitis, but genetic factors have been proposed to be of additional importance for contact sensitization. Recently genetic factors were shown to be of significance for hand eczema. In this study, a sample of twins recruited on the basis of hand eczema has been evaluated with respect to influence of genetic factors on development of nickel sensitization. A total of 1076 individual twins were patch tested and underwent clinical examination, and in the final genetic statistical analysis 630 females were available, of which 146 had a positive patch test to nickel. The aggregation of nickel allergy among twin pairs was measured by the casewise concordance and the twin odds ratio. The twin odds ratio were adjusted for effects of risk factors known to be associated with nickel allergy, namely, wet work, atopic dermatitis, and self-reported hand eczema. There was a small tendency for larger odds ratio among monozygotic twins than among dizygotic twins, which was not statistically significant. As a result of the statistical analysis, it is concluded that allergic nickel contact dermatitis is mainly caused by environmental and only to a lesser degree genetic factors. The selection of twins on the basis of hand eczema may theoretically influence the prevalence of nickel allergy and concordance estimates, which should be considered before extrapolating the data to a random population-based twin sample.

Adult↗
PubMed2006

Pancreatic cancer genetic epidemiology consortium.

We have organized the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium to identify susceptibility genes in familial pancreatic cancer (FPC). The Consortium comprises seven data collection centers, a statistical genetics core, and a pathology/archival genotyping core. We recruit kindreds containing two or more affected blood relatives ascertained through incident pancreatic adenocarcinoma cases, physician referrals, and/or through Internet recruitment. Accrual to a database containing core clinical, demographic, lifestyle, and family history information from questionnaires is ongoing, along with biospecimen collection. To date, 13,147 patients have been screened for family history, of whom 476 (50% male) probands and 1,912 of their adult (99% unaffected) relatives have been enrolled. Of these, 379 kindreds meet criteria for FPC, having at least two first-degree relatives with pancreatic cancer. Cumulative incidence curves using available age of diagnosis (onset) among and affected relatives were compared with those for incident pancreatic cancer cases reported to 13 U.S. Surveillance Epidemiology and End Results (SEER) sites from 1973 to 2000 (N = 72,700). The mean age +/- SD at diagnosis among 466 PACGENE probands and 670 affected relatives was 64.1 +/- 11.8 and was 65.4 +/- 11.6 for the subset of 369 FPC probands and 429 relatives. Both samples were significantly younger than the mean age at diagnosis in the SEER population (70.0 +/- 12.1 years; differences in curves versus SEER, P < 0.001). Age at diagnosis (excluding probands) in FPC kindreds does not decrease with increasing number of affected individuals. In our sample, younger age at diagnosis was observed whether we grouped probands by recruitment sites that predominantly recruited through high-risk referrals, or through screening all pancreatic cancer patients for family history. Linkage studies are ongoing. The PACGENE Consortium will be a valuable family-based resource that will greatly enhance genetic epidemiology research in pancreatic cancer.

Age of Onset↗
PubMed2003

Genetics of preeclampsia: what are the challenges?

Despite recent efforts to identify susceptibility genes of preeclampsia, the genetic determinants of the condition remain ill-defined, as is the situation for most disorders of complex inheritance patterns. The angiotensinogen, factor V, and methylenetetrahydrofolate reductase genes have been investigated in different populations, as have other genes involved in blood pressure, vascular volume control, thrombophilia, lipid metabolism, oxidative stress, and endothelial dysfunction. The study of the genetics of complex traits is faced with both methodological and genetic issues; these include adequate sample size to allow for the identification of modest genetic effects, of gene-gene and gene-environment interactions, the study of adequate quantitative traits and extreme phenotypes, haplotype analyses, statistical genetics, genome-wide (hypothesis-free) versus candidate-gene (hypothesis-driven) approaches, and the validation of positive associations. The use of genetically well-characterized populations showing a founder effect, such as the French-Canadian population of Quebec, in genetic association studies, may help to unravel the susceptibility genes of disorders showing complex inheritance, such as preeclampsia. It is necessary to better evaluate the role of the fetal genome in the resulting predisposition to preeclampsia and its complications. Eventually, we may be able to integrate genetic information to better identify the women at risk of developing preeclampsia, and to improve the management of those suffering from this condition.

Adult↗
PubMed2004

Encoded evidence: DNA in forensic analysis.

Sherlock Holmes said "it has long been an axiom of mine that the little things are infinitely the most important", but never imagined that such a little thing, the DNA molecule, could become perhaps the most powerful single tool in the multifaceted fight against crime. Twenty years after the development of DNA fingerprinting, forensic DNA analysis is key to the conviction or exoneration of suspects and the identification of victims of crimes, accidents and disasters, driving the development of innovative methods in molecular genetics, statistics and the use of massive intelligence databases.

DNA Fingerprinting↗
PubMedDate not supplied

A mechanistic study of evolvability using the mitogen-activated protein kinase cascade.

Evolvability is a function of the way genetic variation interacts with the mechanisms that produce the phenotype. We explore an explicitly mechanistic way of studying the evolvability of phenotypes that are produced by a relatively simple genetic mechanism, the mitogen-activated protein kinase (MAPK) cascade. We developed a quantitative model of MAPK activation that can be used to study the effects of genetic variation on the various components of this signaling cascade. We show how some standard tools of applied mathematics, such as steady-state formulations and nondimensionalization, can be used to elucidate the relative importance of variation in each gene of this mechanism. We also give insights into non-intuitive patterns of dependence and trade-off among the genes. The mechanism produces several different phenotypes (ultrasensitivity to stimulation, switch-like behavior, amount of MAPK-PP delivered, persistence of MAPK-PP activity), each of which is sensitive to different (but partially overlapping) combinations of genes. We show that the mechanism imposes clear limitations on the evolvability of each of the different phenotypes of the pathway, even in the presence of genetic variation in the components of the mechanism. This approach to the study of evolvability is generally applicable and complements the traditional approach through statistical genetics by providing a mechanistic understanding of the genetic interactions that produce the phenotype.

Biological Evolution↗
PubMed2005

[Linking quantitation of electrophoresis pattern and data analysis in AFLP for Oncomelania hupensis].

OBJECTIVE: To search into a method for analyzing the quantitative data in amplified fragment length polymorphism (AFLP) electrophoresis. METHODS: Oncomelania snails collected from the field were screened. Forty snails found uninfected with schistosomiasis were divided randomly into two groups and used to isolate genomic DNA. AFLP electrophoresis pattern was first transformed into quantitative data by Glyko BandScan software, and the bands were read according to different standards of band-reading to acquire the corresponding data. These data sets were analyzed by genetic statistics to get an inference set, and the analysis of this inference set was performed to reach a summary description. RESULTS: The results of genetic variation from different standards of band-reading were different With the increase of the standard value of band-reading, the indices indicating the genetic polymorphism of Oncomelania hupensis population (e.g. Shannon's information index) also increased. When the standard value reached at certain level, the values of these indices began to decrease. Compared with the above indices, the change for gene flow turned out contrary to the genetic identity. The distributions of inference results from different standards of band-reading all showed significant normal distribution. The mean value of genetic variation based on total grey was very close to that on the proportion of total grey. The average genetic identity between the "subpopulations" was 0.956 according to proportion of total grey or 0.958 from the total grey with an average genetic distance between the "subpopulations" of 0.045 and 0.043 respectively. CONCLUSION: It seems to be a reasonable and accurate method by quantifying the AFLP electrophoresis pattern followed by analyzing the data through the use of the different standards of band-reading.

Animals↗
PubMed1982

Some applications of inequalities for extreme order statistics to a genetic selection problem.

Two inequalities are derived for the extreme order statistics in a special case of unequally-correlated multivariate normal variables, and their implications in a genetic selection problem which was considered recently by Rawlings (1976, Biometrics 32, 875-887) and Hill (1976, Biometrics 32, 889-902; 1977, Biometrics 33, 703-712) are discussed. The inequalities establish a monotonicity property of the extreme order statistics as a function of the intraclass correlation, and they yield a chain of bounds when the family sizes are not all equal. Thus the inequalities extend the applicability of the results given by Rawlings and Hill to the more general case.

Animals↗
PubMed1989

Genetics and psychiatry: past discoveries, current dilemmas, and future directions.

Family, twin, and adoption studies have suggested an important role for hereditary factors in the etiology and pathogenesis of several psychiatric disorders. Advances in molecular and statistical genetics may very well reveal the identity of these factors, which may include single genes. Linked markers, critical to the discovery of abnormal genes in several medical conditions, have been reported for Huntington's disease, Alzheimer's disease, bipolar disorder, and schizophrenia. Psychiatric disorders pose particular problems (etiologic heterogeneity, incomplete penetrance, variable expressivity) for genetic research. New practical and ethical questions also arise. Nevertheless, knowledge may emerge that will suggest new approaches to diagnosis, prevention, and treatment.

Diseases in Twins↗
PubMed2006

The effect of assortative mating upon genetic association studies: spurious associations and population substructure in the absence of admixture.

Spurious associations due to confounding factors are an often cited and intensely debated concern for genetic association studies. Great attention has been focused upon the specific threat of confounding due to population stratification. This emphasis has spurred the development of many statistical genetic methods to detect and correct for the potentially confounding effects of admixture. Unfortunately, this emphasis on admixture has led some authors to suggest that if ethnically homogenous populations are used, spurious associations are unlikely to occur. We show that under small and realistic degrees of assortative mating over time, spurious associations arise even in ethnically homogeneous populations. We demonstrate that structured association and genomic control tests can, under certain conditions, correct for these spurious associations. We conclude that investigators should not assume spurious associations will not occur in association studies using ethnically homogenous populations and recommend the use of genomic control methods and/or family-based association tests within genetic association studies.

Chromosome Mapping↗
PubMed1993

Identification and simulation of new non-random statistical properties common to different eukaryotic gene subpopulations.

The nucleotide distribution in protein coding genes, introns and transfer RNA genes of eukaryotic subpopulations (primates, rodent and mammals) is studied by autocorrelation functions. The autocorrelation function analysing the occurrence probability of the i-motif YRY(N)iYRY (YRY-function) in protein coding genes and transfer RNA genes of these three eukaryotic subpopulations retrieves the preferential occurrence of YRY(N)6YRY (R = purine = adenine or guanine, Y = pyrimidine = cytosine or thymine, N = R or Y). The autocorrelation functions analysing the occurrence probability of the i-motifs RRR(N)iRRR (RRR-function) and YYY(N)iYYY (YYY-function) identify new non-random genetic statistical properties in these three eukaryotic subpopulations, mainly: i) in their protein coding genes: local maxima for i identical to 6 [12] (peaks for i = 6, 18, 30, 42) with the RRR-function and local maxima for i identical to 8 [10] (peaks for i = 8, 18, 28) with the YYY-function; and ii) in their introns: local maxima for i identical to 3 [6] (peaks for i = 3, 9, 15) and a short linear decrease followed by a large exponential decrease both with the RRR- and YYY-functions. The non-random properties identified in eukaryotic intron subpopulations are modelised with a process of random insertions and deletions of nucleotides simulating the RNA editing.

Animals↗
PubMed2004

Development of an integrated genome informatics, data management and workflow infrastructure: a toolbox for the study of complex disease genetics.

The genetic dissection of complex disease remains a significant challenge. Sample-tracking and the recording, processing and storage of high-throughput laboratory data with public domain data, require integration of databases, genome informatics and genetic analyses in an easily updated and scaleable format. To find genes involved in multifactorial diseases such as type 1 diabetes (T1D), chromosome regions are defined based on functional candidate gene content, linkage information from humans and animal model mapping information. For each region, genomic information is extracted from Ensembl, converted and loaded into ACeDB for manual gene annotation. Homology information is examined using ACeDB tools and the gene structure verified. Manually curated genes are extracted from ACeDB and read into the feature database, which holds relevant local genomic feature data and an audit trail of laboratory investigations. Public domain information, manually curated genes, polymorphisms, primers, linkage and association analyses, with links to our genotyping database, are shown in Gbrowse. This system scales to include genetic, statistical, quality control (QC) and biological data such as expression analyses of RNA or protein, all linked from a genomics integrative display. Our system is applicable to any genetic study of complex disease, of either large or small scale.

Animals↗
PubMed2026

Causal Relationship Between Ischemic Stroke and Vascular Dementia: A Mendelian Randomization Study.

Ischemic stroke (IS) is a major cause of disability and mortality worldwide, and vascular dementia (VaD) is a common dementia subtype associated with cerebrovascular injury. Observational studies have suggested a relationship between IS and VaD, but these studies are vulnerable to confounding and reverse causality. This protocol describes a reproducible two-sample Mendelian randomization (MR) workflow for evaluating the potential causal association between IS and VaD using publicly available genome-wide association study (GWAS) summary statistics. Genetic instruments associated with IS were extracted from a public GWAS dataset, and outcome associations for VaD were obtained from a public VaD GWAS dataset. The corresponding dataset IDs are provided in the Protocol section. After outcome matching and allele harmonization, 51 single-nucleotide polymorphisms (SNPs) were retained for the final MR analysis. The workflow includes instrumental variable selection, linkage disequilibrium clumping, allele harmonization, instrument strength assessment, inverse variance weighted (IVW) analysis, weighted median analysis, MR-Egger analysis, heterogeneity testing, horizontal pleiotropy assessment, and leave-one-out sensitivity analysis. In the representative analysis, the IVW method showed a positive association between genetically predicted IS and VaD risk, and the weighted median method yielded a directionally concordant result. The MR-Egger estimate was directionally consistent but did not reach statistical significance. Therefore, these findings should be interpreted as suggestive evidence of a possible causal effect, rather than definitive proof of causality. This protocol may help researchers apply a transparent and reproducible MR workflow to investigate cerebrovascular disease-related outcomes using public GWAS data.

Humans↗
PubMed2025

The role of the brain-bone axis in skeletal degenerative diseases and psychiatric disorders, A genome-wide pleiotropic analysis.

INTRODUCTION: Skeletal degenerative diseases and psychiatric disorders often coexist clinically. However, the genetic correlations and underlying biological mechanisms between these two types of diseases remain unclear. OBJECTIVES: To investigate the genetic correlations between skeletal degenerative diseases and psychiatric disorders and to identify shared genomic loci, genes, and pathways. METHODS: This comprehensive genome-wide pleiotropic association study utilized summary statistics from publicly available genome-wide association data. Various statistical genetic correlation methods were employed, including LDSC, HDL, PLACO, Coloc, Hyprcoloc, and Mendelian randomization (MR) analysis, along with immune cell colocalization analysis. The study aimed to identify potential shared genetic factors among three skeletal degenerative diseases (osteoarthritis, intervertebral disc degeneration, and osteoporosis) and three psychiatric disorders (schizophrenia, anxiety disorder, and major depressive disorder). RESULTS: Analyses using LDSC, HDL, and Bonferroni corrections revealed significant genetic correlations between intervertebral disc degeneration (IVDD) and anxiety disorder (ANX); fractures, IVDD, and arthritis with major depressive disorder (MDD); and arthritis with schizophrenia (SCZ). Significant genetic correlations were also observed between VDD and ANX, fractures, IVDD, hip osteoarthritis (HipOA), knee osteoarthritis (KneeOA) and MDD, and KneeOA and SCZ. Pleiotropy analysis using PLACO, MAGMA, and multitrait colocalization Hyprcoloc identified 65 pleiotropic loci, 27 shared causal loci, and 9 shared risk loci involving immune cells related to both psychiatric and bone-related diseases. Additionally, tissue-specific enrichment analysis showed that genes mapped to these loci were enriched in brain, cardiovascular, pancreatic, and other tissues. The IVW method demonstrated that MDD increased the risk of IVDD and KneeOA, while IVDD increased the risk of ANX and MDD. Conversely, SCZ was associated with a reduced risk of KneeOA. Multiple sensitivity analyses further supported a positive causal effect of IVDD on MDD. CONCLUSION: These findings suggest significant genetic correlations between skeletal degenerative diseases and psychiatric disorders, highlighting multiple shared comorbid genes and key immune cell types. Importantly, the study supports the role of the brain-bone axis in the regulation of skeletal degenerative diseases and psychiatric disorders, which could provide valuable insights for potential therapeutic targets and interventions for these conditions.

Humans↗
PubMed2025

Tsbrowse: an interactive browser for ancestral recombination graphs.

SUMMARY: Ancestral recombination graphs (ARGs) represent the interwoven paths of genetic ancestry of a set of recombining sequences. The ability to capture the evolutionary history of samples makes ARGs valuable in a wide range of applications in population and statistical genetics. ARG-based approaches are increasingly becoming a part of genetic data analysis pipelines due to breakthroughs enabling ARG inference at biobank-scale. However, there is a lack of visualization tools, which are crucial for validating inferences and generating hypotheses. We present tsbrowse, an open-source, web-based Python application for the interactive visualization of the fundamental building blocks of ARGs, i.e. nodes, edges and mutations. We demonstrate the application of tsbrowse to various data sources and scenarios, and highlight its key features of browsability along the genome, user interactivity, and scalability to very large sample sizes. AVAILABILITY AND IMPLEMENTATION: Tsbrowse is installed as a Python package from PyPI (https://pypi.org/project/tsbrowse/), while a development version is maintained at https://github.com/tskit-dev/tsbrowse. Documentation is available at https://tskit.dev/tsbrowse/docs/. Source code is archived on Zenodo with DOI, https://doi.org/10.5281/zenodo.15683039.

Software↗
PubMed2007

Genetic and environmental determinants of circulating resistin level in a community-based sample.

OBJECTIVE: Resistin is a hormone secreted by adipose tissue, monocytes, bone marrow, and other tissues. It was also proclaimed as an important link between obesity and diabetes. The main objective of this study was to elucidate the contribution of a number of endogenous factors, such as sex, age, obesity characteristics, and genetic effects to the production of resistin in apparently healthy individuals. We also tested the possible relationships between circulating levels of resistin and other adipokines (leptin, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)). MEASUREMENTS: The plasma levels of studied adipokines were determined by enzyme-linked immunoassay in pedigree-based sample (n = 616), and subjected to model-based quantitative genetic analysis. RESULTS: Resistin levels were significantly higher in women than in men (3.60 +/- 2.53 vs 3.15 +/- 2.48 ng/ml, P < 0.001), and varied independently of age in either sex. Statistical-genetic analysis revealed significant familial correlations (P < 0.01) for resistin. Adjusted for covariates, 66.38 +/- 10.28% of the resistin variation was attributable to putative genetic factors. A relatively small portion of the resistin variation (11.54 +/- 5.77%) was attributable to sharing a common household environment. The remaining variation, 22.12 +/- 17.69% was due to random environmental (i.e., unmeasured non-additive genetic) effects. The results of our analysis showed modest significant correlation of resistin with TNF-alpha and IL-6, and only in some groups; thus, while resistin was correlated with TNF-alpha in men, the correlation with IL-6 was significant only in the post-menopausal women group. CONCLUSIONS: Our observations indicate that resistin is strongly influenced by genetic factors. The high heritability estimates for resistin concentrations clearly suggest the continuing need for further molecular genetic investigations.

Adolescent↗
PubMed1993

Genetics of essential hypertension.

Blood pressure is a complex quantitative trait that is determined by multiple environmental and genetic factors. Although some simple Mendelian forms of high blood pressure have been described, essential hypertension is characterized by a complex mode of inheritance. Based on recent advances in molecular biology and statistical genetics, it has become feasible to search for chromosome regions that may contain genes contributing to the pathogenesis of hypertension in humans. For example, recent linkage and association studies have raised the possibility that a blood pressure regulatory locus may exist in or near the angiotensinogen gene on chromosome 1. Detailed genetic experiments in animal models of hypertension may help to guide further clinical studies and lead to an improved understanding of gene action in the pathogenesis of essential hypertension.

Animals↗
PubMed1984

Genetic Analysis Workshop II: segregation and linkage analysis.

Familial segregation and linkage analyses were performed on two sets of the Genetic Analyses Workshop II data. The salient features of the mode of inheritance of the disease trait and its linkage/association with polymorphic markers and also marker-marker linkages were delineated using statistical-genetic techniques.

Adult↗
PubMed2001

Phenotypes and genetic analysis of psychiatric and neuropsychiatric traits.

A workshop was held at Rockefeller University entitled "Phenotypes and Genetic Analysis of Complex Traits." The purpose of the workshop was to examine phenotype definition for complex traits, in particular, psychiatric and neuropsychiatric traits. An additional goal of the workshop was to examine statistical genetic approaches that specifically address the oligogenic nature of psychiatric traits. An overview of topics that were addressed and discussed at the workshop is presented in this article.

Animals↗