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Results for “Mendelian Randomization Analysis”

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PubMed2006

Strategy for mapping quantitative trait loci (QTL) by using human metapopulations.

AIM: To present a novel strategy for mapping quantitative trait loci (QTL), using human metapopulations. The strategy is based on the expectation that in geographic clusters of small and distinct human isolates, a combination of founder effect and genetic drift can dramatically increase population frequency of rare QTL variants with large effect. In such cases, the distribution of QT measurements in an (affected) isolate is expected to deviate from that observed in neighboring isolates. METHODS: We tested this hypothesis in 9 villages from a larger Croatian isolate resource, where 7 Mendelian disorders have been previously reported. The values of 10 physiological and biochemical QTs were measured in a random sample of 1001 individuals (100 inhabitants of each of 9 villages and 101 immigrant controls). RESULTS: Significant over- or under- representation of individuals from specific villages in extreme ends of standardized QT measurement distribution was found 10 times more frequently than expected by chance. The large majority of such clusters of individuals with extreme QT values (34/36, 94.4%) originated from the 6 villages with the most pronounced geographic isolation and endogamy. CONCLUSION: Early epidemiological assessment supports the feasibility of the proposed strategy. Clusters of individuals with extreme QT values responsible for over-representation of single villages can usually be linked to a larger pedigree and may be useful for further QTL mapping, using linkage analysis.

Body Height↗

PubMed2005

Trans events associated with crossovers are revealed in the absence of mismatch repair genes in Saccharomyces cerevisiae.

Genetic analysis of recombination in Saccharomyces cerevisiae has revealed products with structures not predicted by the double-strand break repair model of meiotic recombination. A particular type of recombinant containing trans heteroduplex DNA has been observed at two loci. Trans events were originally identified only in tetrads in which the non-Mendelian segregations were not associated with a crossover. Because of this, these events were proposed to have arisen from the unwinding of double Holliday junctions. Previous studies used palindromes, refractory to mismatch repair, as genetic markers whereas we have used a complementary approach of deleting mismatch repair proteins to identify heteroduplex DNA. We found that the markers occurred in trans and were associated with crossovers. In both mlh1Delta and msh2Delta strains, the frequency of trans events associated with a crossover exceeded that predicted from the random association of crossovers with noncrossover trans events. We propose two different models to account for trans events associated with crossovers and discuss the relevance to wild-type DSB repair.

Alcohol Oxidoreductases↗

PubMed2026

Active components and potential mechanisms of Wuzhuyu decoction in the treatment of ethanol-induced acute gastric mucosal injury: a network pharmacology and experimental verification.

OBJECTIVE: To investigate the underlying mechanisms and active components of Wuzhuyu decoction (, WD) in alleviating ethanol-induced acute gastric mucosal injury (GMI) using an integrated approach of network pharmacology and experimental verification. METHODS: Sprague-Dawley rats were randomly divided into six groups: control (Con), model (Mod), bismuth potassium citrate (BPC), WD at low (WD-L), medium (WD-M), and high (WD-H) doses. Following seven days of continuous intragastric administration of the respective treatments, an ethanol-induced gastric mucosal injury model was established in all groups except the control group by oral gavage of anhydrous ethanol. The gastric mucosal injury index was evaluated, and pathological changes were assessed viahematoxylin and eosin (HE) staining. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were measured by enzyme-linked immunosorbent assay (ELISA). The chemical composition was identified by ultra-performance liquid chromatography-tandem mass spectrometry. Active compounds were screened using the Swiss-absorption, distribution, metabolism, and excretion database, and their potential targets were predicted using the Swiss Target Prediction database and bioinformatics annotation database for molecular mechanism. Simultaneously, disease targets related to GMI were retrieved from the online mendelian inheritance in man and GeneCards databases. A protein-protein interaction (PPI) network was constructed, and functional enrichment analyses of gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed using the Metascape database. Key predictions from the network pharmacology analysis were subsequently verified through animal experiments. Protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Cleaved Caspase-3, and Cleaved Caspase-9 were analyzed by Western blot. Finally, molecular docking was performed using AutoDock Vina to investigate the interactions between the active components and core targets. RESULTS: WD treatment significantly reduced the gastric mucosal injury index and the levels of TNF-α, IL-1β, MDA, while it increased the activities of SOD and GSH-Px. Histopathological examination revealed marked improvement in gastric tissue morphology. A total of 145 compounds were identified in WD. Network pharmacology analysis identified 440 overlapping targets between WD and GMI. GO and KEGG enrichment analyses highlighted the apoptosis signaling pathway as a key mechanism for WD's protective effect against ethanol-induced GMI. Experimental validation demonstrated that WD treatment reduced the apoptosis of gastric mucosal epithelial cells, promoted the expression of Bcl-2, and inhibited the expression of Bax, Cleaved Caspase-3 and Cleaved Caspase-9. Molecular docking results indicated that dehydroevodiamine, rutaecarpine, evodiamine, hexahydrocurcumin, and isorhamnetin are potential active components in WD that contribute to the inhibition of apoptosis. CONCLUSIONS: WD alleviates ethanol-induced acute GMI, at least in part, by inhibiting the apoptosis. The primary active components responsible for this effect are dehydroevodiamine, rutaecarpine, evodiamine, hexahydrocurcumin, and isorhamnetin.

Drugs, Chinese Herbal↗

PubMed2026

Integrated bioinformatics and SEM analysis reveal GPAM as a key mediator of fibrosis in NAFLD with metabolic dysfunction.

Nonalcoholic fatty liver disease (NAFLD) is a complex condition influenced by metabolic and genetic factors, yet the shared genetic architecture underlying its progression remains poorly understood. The aim of this study was to employ genomic structural equation modeling (GSEM) to elucidate the genetic architecture linking NAFLD with key metabolic traits-including insulin resistance, body mass index (BMI), hemoglobin A1c (HbA1c), and liver fibrosis using summary statistics from large-scale genome-wide association studies. By harmonizing 2.18 million variants across five genome-wide association studies (GWAS) datasets, we identified 134 genome-wide significant loci that mapped to 24 genes. GSEM revealed a latent genetic structure composed of two distinct dimensions: a metabolic regulation factor primarily driven by insulin resistance, BMI, and HbA1c; and a structural pathology factor specifically associated with liver fibrosis. These factors explained 65.5% and 78.1% of the genetic variance in BMI and fibrosis, respectively, with minimal correlation (rg = 0:07), indicating their genetic distinctness. Additionally, integrating Mendelian randomization with liver transcriptome profiling, we characterized how the 24 genes contribute to disease and identified mitochondrial glycerol-3-phosphate acyltransferase (GPAM) as the key gene that causally links lipid metabolism to fibrogenesis. In conclusion, we present the first genetically grounded mechanism for the progression of NAFLD to fibrosis. This mechanism encompasssses genetic variants, dysregulated gene expression, metabolic disturbances, and the processes involved in fibrotic remodeling. This research establishes a genetic framework for understanding the pathogenesis of NAFLD and highlights novel therapeutic targets for intervention.

Non-alcoholic Fatty Liver Disease↗

PubMed1996

Allelic association of gene markers on chromosomes 5q and 11q with atopy and bronchial hyperresponsiveness.

To investigate genetic factors in asthma and atopy, we sought allelic associations for 12 markers near candidate loci for serum total, immunoglobulin E (IgE), and bronchial hyperresponsiveness (BHR) to inhaled histamine in 131 families comprising 685 individuals, selected randomly without regard to atopy or asthma. Nonparametric linkage and association analyses were performed with the Nonparametric Analysis of Lineage and Association (NOPAR) program, and parametric analyses were performed with the Complex Inheritance with Diathesis and Severity (COMDS) program on an ordered polychotomy of ranked scores. On chromosome 11q, allele 168 at the D11S527 locus was significantly associated with BHR (p<0.0003) but not with log IgE. At the D11S534 locus, allele 235 was significantly associated with log IgE (p = 0.007) but not with BHR. Both D11S527 and D11S534 were too distant from the gene encoding the high-affinity IgE receptor FcepsilonRIbeta to account for the association. At the interleukin-9 (IL-9) locus, the 118 allele showed significant association with serum total IgE (p<0.003) but not with histamine BHR. Parametric tests are more conservative, perhaps because they demand consistency with mendelian inheritance and tight linkage. These findings provide support for the view that both chromosomes 5 and 11 may contain genes relevant to asthma and atopy, a possible candidate being the interleukin-4 (IL-4) gene cluster. Because these associations are extremes in a large number of tests, they require confirmation in other samples.

Adolescent↗

PubMed2026

Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease.

The molecular pathways linking genetic variants to Parkinson's disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analysed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer's disease metabolome. A PD acylcarnitine signature was further replicated in human post-mortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.

Humans↗

PubMed1987

Segregation analysis of low levels of high-density lipoprotein cholesterol in the collaborative Lipid Research Clinics Program Family Study.

Complex segregation analysis with the unified mixed model in white families from nine lipid research clinics was carried out to delineate the mode of familial transmission of plasma high-density-lipoprotein cholesterol (HDL-C). Three groups of families from the collaborative Lipid Research Clinics Program Family Study were assessed: 1,146 selected at random, 483 obtained through hypercholesterolemic probands, and 177 selected from the random sample because a number had low HDL-C, the sample sizes being 4,279, 1,807 and 735, respectively. The data were first transformed and adjusted for effects of covariates. Analyses were performed within clinic and selection strata and also pooled across clinics within strata. The results were consistent across strata and identified two major HDL-C clusters with means separated by approximately 3 SD. There was significant evidence of transmission of a major factor for low HDL-C, but transmission did not conform to Mendelian segregation expectations. There was also evidence of significant multifactorial transmission. Since low HDL-C levels are a major independent risk factor for coronary heart disease, the association of a major factor with familial aggregation of low HDL-C emphasizes the importance of detailed within-family sampling for low HDL-C after identifying a proband whose predominant dyslipoproteinemia is low HDL-C.

Cholesterol, HDL↗

PubMed2000

Evidence for major genes influencing pulmonary function in the NHLBI family heart study.

Segregation analysis was performed on the pulmonary measures forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of FEV1/FVC in 455 randomly ascertained families from the NHLBI Family Heart Study (FHS). Gender specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analyses. These residuals represented adjustments for the effects of age, age(2), age(3), Body Mass Index (BMI, kg/m(2)), height, the ratio of waist to hip measurements (WHR), the presence of coronary heart disease, smoking history, and pack years for current smokers. Sibling correlations were not different from parent-offspring correlations for all three traits, and heritability estimates for FEV1, FVC, and the FEV1/FVC ratio were 0. 515, 0.540, and 0.449, respectively. Segregation analysis of FEV1, a trait that measures airflow, indicated that a dominant major gene best fits the data, although a residual familial correlation supports the presence of an additional polygenic or common environmental component. For FVC, a trait that measures lung volume, alternative models could not be statistically differentiated, but the transmission probabilities do not support a Mendelian major gene. The best model for FEV1/FVC ratio is a non-Mendelian codominant model, perhaps due to the mixing of the individual underlying distributions influencing airflow and lung volume. These results support the hypothesis that complex relationships exist for lung function traits and that multiple genes and environmental factors influence lung function.

Anthropometry↗

PubMed1999

An apparent excess of sex- and reproduction-related genes on the human X chromosome.

We describe here the results of a search of Mendelian inheritance in man, GENDIAG and other sources which suggest that, in comparison with autosomes 1, 2, 3, 4 and 11, the X chromosome may contain a significantly higher number of sex- and reproduction-related (SRR) genes. A similar comparison between X-linked entries and a subset of randomly chosen entries from the remaining autosomes also indicates an excess of genes on the X chromosome with one or more mutations affecting sex determination (e.g. DAX1), sexual differentiation (e.g. androgen receptor) or reproduction (e.g. POF1). A possible reason for disproportionate occurrence of such genes on the X chromosome could be that, during evolution, the 'choice' of a particular pair of homomorphic chromosomes for specialization as sex chromosomes may be related to the number of such genes initially present in it or, since sex determination and sexual dimorphism are often gene dose-dependent processes, the number of such genes necessary to be regulated in a dose-dependent manner. Further analysis of these data shows that XAR, the region which has been added on to the short arm of the X chromosome subsequent to eutherian-marsupial divergence, has nearly as high a proportion of SRR genes as XCR, the conserved region of the X chromosome. These observations are consistent with current hypotheses on the evolution of sexually antagonistic traits on sex chromosomes and suggest that both XCR and XAR may have accumulated SRR traits relatively rapidly because of X linkage.

Databases, Factual↗

PubMed2006

"Anti-inflammatory" drugs and their effects on type 2 diabetes.

There is a growing body of evidence for the role of inflammation in type 2 diabetes. In addition to the evidence presented elsewhere, evidence is emerging that many drugs that have apparent "anti-inflammatory" properties may reduce the incidence and/or delay the onset of type 2 diabetes. Statins have been found to lower inflammatory markers, and a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS) suggested that pravastatin may reduce the risk of developing diabetes, although the Lipid Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) found no statistically significant effect of atorvastatin on risk of developing diabetes. Fibrates have been found to lower some markers of inflammation, and a prospective trial found that bezafibrate reduces risk of developing diabetes. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers appear to reduce some markers of inflammation, and a meta-analysis concluded that ACE inhibitors and angiotensin receptor blockers reduce risk of developing type 2 diabetes. Metformin is known to reduce the risk of developing diabetes, and more recent evidence suggests it also lowers C-reactive protein, in part because of its modest weight-reducing effect. Thiazolidinediones reduce risk of developing diabetes, and consistently lower inflammatory markers independent of adiposity effects. High-dose aspirin inhibits cyclooxygenase and IkappaB kinase-beta and reduces fasting plasma glucose concentration, although there has not, as yet, been a large-scale trial to examine the effect of aspirin on the risk of developing diabetes. We conclude that although many drugs with potential anti-inflammatory properties reduce the risk of developing diabetes, it is difficult to prove that such anti-inflammatory properties contribute to their diabetes prevention since nearly all drugs have other, often more pronounced, actions. Studies with more specific inhibitors of inflammatory pathways (e.g., interleukin- 6 blockers) and mendelian randomization (genetic studies) will help determine whether targeting the inflammation axis is a fertile mechanism to treat or prevent type 2 diabetes.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes.

Positional cloning studies to identify disease genes are being carried out for many human genetic diseases. Such studies often include a genome-scan linkage analysis to identify the rough chromosomal location of a disease gene, fine structure genetic mapping to define and narrow the chromosomal interval in which the disease gene may be located, and physical mapping and gene identification in the genetically defined interval to clone the disease gene. During the planning of a positional cloning study, it is important to know that, if linkage is found, the genetic interval identified is likely to be sufficiently narrow to be dissected efficiently by methods of physical mapping and gene identification. Thus, we wish to know the limits of resolution of a genetic linkage study. In this paper, I determine for Mendelian diseases the distributions and moments of three measures of linkage resolution: (1) in a set of N chromosomes, the distance between the nearest crossovers that flank a disease locus, (2) the distance between the nearest genetic markers that flank the pair of flanking crossovers after a genome scan, and (3) the distance between the nearest flanking markers after additional randomly placed markers are generated and typed in an identified interval. These results provide explicit sample-size guidelines for future positional cloning studies of Mendelian diseases and make possible a more objective evaluation of whether a proposed positional cloning study is likely to be successful. I also briefly discuss the more difficult problem of linkage resolution for complex genetic diseases.

Chromosome Mapping↗

PubMed1996

Overall informativity, OI, in DNA polymorphisms revealed by inter-Alu PCR: detection of genomic rearrangements.

We studied two systems of multilocus markers revealed by PCR using primers directing amplification between Alu repeats in a tail-to-tail orientation. Genomic polymorphisms were detected as the presence or absence of the electrophoretic bands representing DNA fragments of a given length. A total of 104 such fragments segregating as Mendelian markers in a panel of eight CEPH families were analyzed by two-point linkage analysis. Fifty-one of these fragments were localized with respect to CEPH markers; they represented 33 loci, 7 of which were multiallelic. Locus-specific oligonucleotides were developed and used as hybridization probes to identify the mapped loci within a complex pattern of inter-Alu PCR products. A great proportion of inter-Alu PCR polymorphisms represented length variants within amplified DNA segments, while others were presumably due to mutations within the priming sites. To describe the expected number of informative loci per typing experiment we introduced a parameter called overall informativity (OI), which provides a single measure of the multiplex ratio and the informativity of markers contributing to a multilocus system (OI of a single locus is equivalent to its heterozygosity and cannot exceed 0.5 for a biallelic codominant marker). High OI values (5.8 and 11.5) of the two presented systems of inter-Alu PCR markers of random chromosomal distribution render them suitable for mapping genomic rearrangements such as genomic deletions in tumoral tissues. This was illustrated by the detection of loss of heterozygosity in the 9q22-qter region in sporadic colon cancer.

Animals↗

PubMed1977

The specific antigen-binding cell populations of individual fetal mouse spleens: repertoire composition, size, and genetic control.

In order to analyze the genetic and physiological basis of controls affecting the generation of the repertoire of antigen-binding cells in fetal mice, we have measured the numbers of spleen cells specific for each of four antigens as a function of the total numbers of nucleated and Ig-bearing cells in inbred, hybrid, and random bred fetuses. For each of the two inbred strains BALB/c and CBA/J, the proportion of nucleated cells specific for a given antigen was the same for all individuals of the strain at the 18th day of gestation. The proportion did vary from antigen to antigen, however, and for each antigen the proportion of specific cells observed in CBA/J fetuses was approximately four times that observed in BALB/c fetuses. This difference appeared to be due to a difference between the two strains in the relative size of the repertoire of antigen-binding spleen cells at this stage of development, inasmuch as the frequency of Ig-bearing spleen cells in CBA/J fetuses was likewise approximately four times that observed in BALB/c fetuses. In random bred Swiss-L fetal mice at the 18th day of gestation, the proportion of cells specific for a given antigen varied significantly from one individual to the next. The ratio of proportions of the two antigens observed was constant from individual to individual, however, and this constant ratio differed significantly from the ratio observed for the same two antigens in fetal BALB/c and CBA/J inbred mice. These data suggest that the ontogeny of the repertoire of antigen-binding cells in fetal mice is subject to at least two independent sets of controls, one affecting the relative size of the repertoire in the spleen, and the other affecting the distribution of antigen-binding specificities within that repertoire. Analysis of repertoire size and composition in the spleens of hybrid fetuses confirmed the observation that the two parameters are controlled independently, and suggested further that the control of repertoire size in these fetuses is due to the action of one or a few closely-linked autosomal Mendelian genes. These data are consistent with models for the origin of antibody diversity in which the genes coding for the full repertoire of antibodies are generated somatically from a small number of germ-line genes early in development and in the absence of any strong positive or negative selection with respect to antigenic specificity.

Animals↗

PubMed2026

Multivariate, Multi-Omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits.

INTRODUCTION: Somatoform traits (e.g., health anxiety, somatic preoccupation, and bodily distress symptoms) are prevalent and pose challenges to clinical practice. Understanding their genetic basis could improve diagnostic and therapeutic approaches. METHODS: Using available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits - fatigue, irritable bowel syndrome, pain intensity, and health satisfaction - in 799,429 individuals genetically similar to European reference panels. RESULTS: The GWAS identified 134 loci associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Novel loci were mechanistically informative, mapping to the DNM1 gene and the protocadherin gene cluster (PCDHA1-4), which are involved in nociceptor sensitization and synaptogenesis, respectively. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched expression in 11 brain tissues and the pituitary. Across two brain transcriptomic datasets, we identified 16 high-confidence genes whose expression in enriched tissues was associated with somatoform traits. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated with obesity, type 2 diabetes, and tobacco use disorder in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors, while Mendelian randomization analyses indicated potentially protective effects of gut microbiota. DISCUSSION: Consistent with emerging medical and genetic knowledge, somatoform traits have a shared etiology and considerable polygenic overlap with psychopathology. The biological insights from drug repurposing and Mendelian randomization analyses could provide promising avenues for treatment development.

Genetics↗

PubMed2026

Genetically Proxied Inhibition of Cholesterol-Lowering Drug Targets and Survival in HPV-Positive and Non-HPV-Driven Head and Neck Cancer: A Multicentre MR Study.

BACKGROUND: Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major low-density lipoprotein cholesterol (LDL-C)-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV-driven HNSCCs. METHODS: We proxied lifelong LDL-C lowering using 55 cis-acting single-nucleotide polymorphisms in HMGCR, NPC1L1, PCSK9, and LDL-receptor (LDLR) from the updated 2021 Global Lipids Genetics Consortium and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multicentre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV-driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumor stage and treatment, assessed collider bias using an external HNSCC incidence genome-wide association study, and examined between-center heterogeneity and colocalization. RESULTS: Using the updated Global Lipids Genetic Consortium 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but nonsignificant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis [inverse variance weighted (IVW) HR = 0.19; 95% confidence interval (CI), 0.03-1.18; P = 0.08], with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR = 1.68; 95% CI, 0.78-3.63; P = 0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. CONCLUSIONS: These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. IMPACT: HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.

Humans↗

PubMed2002

Detection rates for genotyping errors in SNPs using the trio design.

One well-known approach for the analysis of transmission-disequilibrium is the investigation of single nucleotide polymorphisms (SNPs) in trios consisting of an affected child and its parents. Results may be biased by erroneously given genotypes. Various reasons, among them sample swap or wrong pedigree structure, represent a possible source for biased results. As these can be partly ruled out by good study conditions together with checks for correct pedigree structure by a series of independent markers, the remaining main cause for errors is genotyping errors. Some of the errors can be detected by Mendelian checks whilst others are compatible with the pedigree structure. The extent of genotyping errors can be estimated by investigating the rate of detected genotyping errors by Mendelian checks. In many studies only one SNP of a specific genomic region is investigated by TDT which leaves Mendelian checks as the only tool to control genotyping errors. From the rate of detected errors the true error rate can be estimated. Gordon et al. [Hum Hered 1999;49:65-70] considered the case of genotyping errors that occur randomly and independently with some fixed probability for the wrong ascertainment of an allele. In practice, instead of single alleles, SNP genotypes are determined. Therefore, we study the proportion of detected errors (detection rate) based on genotypes. In contrast to Gordon et al., who reported detection rates between 25 and 30%, we obtain higher detection rates ranging from 39 up to 61% considering likely error structures in the data. We conclude that detection rates are probably substantially higher than those reported by Gordon et al.

Genotype↗

PubMed1991

Characterization of the level, target sites and inheritance of cytosine methylation in tomato nuclear DNA.

The tomato nuclear genome was determined to have a G + C content of 37% which is among the lowest reported for any plant species. Non-coding regions have a G + C content even lower (32% average) whereas coding regions are considerably richer in G + C (46%). 5-methyl cytosine was the only modified base detected and on average 23% of the cytosine residues are methylated. Immature tissues and protoplasts have significantly lower levels of cytosine methylation (average 20%) than mature tissues (average 25%). Mature pollen has an intermediate level of methylation (22%). Seeds gave the highest value (27%), suggesting de novo methylation after pollination and during seed development. Based on isoschizomer studies we estimate 55% of the CpG target sites (detected by Msp I/Hpa II) and 85% of the CpNpG target sites (detected by Bst NI/Eco RI) are methylated. Unmethylated target sites (both CpG and CpNpG) are not randomly distributed throughout the genome, but frequently occur in clusters. These clusters resemble CpG islands recently reported in maize and tobacco. The low G + C content and high levels of cytosine methylation in tomato may be due to previous transitions of 5mC----T. This is supported by the fact that G + C levels are lowest in non-coding portions of the genome in which selection is relaxed and thus transitions are more likely to be tolerated. This hypothesis is also supported by the general deficiency of methylation target sites in the tomato genome, especially in non-coding regions. Using methylation isoschizomers and RFLP analysis we have also determined that polymorphism between plants, for cytosine methylation at allelic sites, is common in tomato. Comparing DNA from two tomato species, 20% of the polymorphisms detected by Bst NI/Eco RII could be attributed to differential methylation at the CpNpG target sites. With Msp I/Hpa II, 50% of the polymorphisms were attributable to methylation (CpG and CpNpG sites). Moreover, these polymorphisms were demonstrated to be inherited in a mendelian fashion and to co-segregate with the methylation target site and thus do not represent variation for transacting factors that might be involved in methylation of DNA. The potential role of heritable methylation polymorphism in evolution of gene regulation and in RFLP studies is discussed.

Base Composition↗

PubMed2004

A survey of genetic and epigenetic variation affecting human gene expression.

The identification of human sequence polymorphisms that regulate gene expression is key to understanding human genetic diseases. We report a survey of human genes that demonstrate allelic differences in gene expression, reflecting the presence of putative allele-specific cis-acting factors of either genetic or epigenetic nature. The expression of allelic transcripts in heterozygous samples is assessed directly by relative quantitation of intragenic marker alleles in messenger or heteronuclear RNA derived from cells or tissues. This survey used 193 single-nucleotide polymorphisms (SNPs) from 129 genes expressed in lymphoblastoid cell lines, to identify 23 genes (18%) with common allele-specific transcripts whose expression deviated from the expected equimolar ratio. A subset of these deviations, or "allelic imbalances," can be observed in multiple samples derived from reference CEPH ("Centre d'Etude du Polymorphisme Humain") pedigrees and demonstrate a spectrum of patterns of transmission, including cosegregation of allelic skewing across generations compatible with Mendelian inheritance as well as random monoallelic expression for three genes (IL1A, HTR2A, and FGB). Additional studies for BTN3A2 provide evidence of SNPs and haplotypes in complete linkage disequilibrium with high- and low-expressing transcripts. The pipeline described herein offers tools for efficient identification and characterization of allelic expression allowing identification of regulatory sequence variants as well as epigenetic variation affecting human gene expression.

Allelic Imbalance↗