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Results for “Genetic causality”

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PubMed2003

Liability to substance use disorders: 1. Common mechanisms and manifestations.

Variation in the risk for and severity of substance use disorders (SUD) in the population is caused by multiple organismic (genetic, biochemical, psychological) and environmental factors. Whereas drug- or drug-class-specific liability mechanisms exist, a substantial proportion of variance in the risk is shared between specific liabilities, reflecting mechanisms that determine common liability to SUD. Data from epidemiologic, clinical, psychological, physiological, biochemical, and family and genetic studies reviewed in this paper indicate the existence of mechanisms and characteristics shared in common by liabilities to SUD related to different drugs. These mechanisms can be conceptualized as common liability to SUD, a latent trait accounting for a substantial portion of variation in SUD risk and severity and determined by all factors influencing the probability of SUD development. An accompanying paper describes an approach to the quantitative estimation of this trait.

Brain Chemistry↗
PubMed1989

Using genetically-defined rodent strains for the identification of hippocampal traits relevant for two-way avoidance behavior: a non-invasive approach.

Genetically-defined rodent strains permit the identification of hippocampal traits which are of functional relevance for the performance of two-way avoidance behavior. This is exemplified here by analyzing the relationship between infrapyramidal mossy fibers (a tiny projection terminating upon the basal dendrites of hippocampal pyramidal neurons) and two-way avoidance learning in about 800 animals. The necessary steps include 1) identification of structural traits sensitive to selective breeding for extremes in two-way avoidance, 2) testing the robustness of the associations found by studying individual and genetical correlations between hippocampal traits and behavior, 3) establishing causal relationships by Mendelian crossing of strains with extreme structural traits and studying the behavioral consequences of such structural 'randomization', 4) confirming causal relationships by manipulating the structural variable in inbred (isogenic) strains, thereby eliminating the possibility of genetic linkage, and 5) ruling out the possibility of spurious associations by studying the correlations between the hippocampal trait and other behaviors known to depend on hippocampal functioning. In comparison with the classical lesion approach for identifying relationships between brain and behavior, the present procedure appears to be superior in two aspects: it is non-invasive, and it focuses automatically on those brain traits which are used by natural selection to shape behaviorally-defined animal populations, i.e., it reveals the natural regulators of behavior.

Animals↗
PubMed2005

Non-melanoma skin cancer: what drives tumor development and progression?

Non-melanoma skin cancer, i.e. basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most frequent tumors and their number is still increasing worldwide. Furthermore, immunosuppression in organ transplant patients strongly contributes to the increase in skin cancer incidence--being 65-250 times more frequent than in the general population. Often these patients suffer from a second and third lesion and the severity of these tumors is linked to their number. SCCs in transplant recipients also appear to be more aggressive. They tend to grow rapidly, show a higher rate of local recurrences and metastasize in 5-8% of the patients (all reviewed in Ref. 2). This largely differs from BCCs which are more frequent in the general population--at a ratio of 4:1 as compared with SCCs--but the number is only increased by a factor of 10 in transplant recipients. This may suggest that 'dormant' SCC precursor cells/lesions are present at a high frequency in the population but they are well controlled by the immune system. BCC, on the other hand, may be less dependent on immune surveillance thereby underlining its different etiology. While for BCC development the genetic hallmark is abrogation of the ptch-sonic hedgehog pathway, little is known about the causal alterations of SCCs. However, the complexity of the genetic alterations (numerical and structural aberration profiles) in SCCs argues for several levels of genomic instability involved in the generation and progression of skin cancer.

Basal Cell Carcinoma↗
PubMed2005

Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk.

Epigenetic alterations in cancer occur at least as commonly as genetic mutations, but epigenetic alterations could occur secondarily to the tumor process itself. To establish a causal role of epigenetic changes, investigators have turned to genetically engineered mouse models. Here, we review a recent study showing that a mouse model of loss of imprinting (LOI) of the insulin-like growth factor II gene (Igf2), which shows aberrant activation of the normally silent maternal allele, modifies the risk of intestinal neoplasia caused by mutations of the adenomatous polyposis coli (Apc) gene. This increased risk corresponds to the apparent increased risk of colorectal cancer in patients with LOI of IGF2. The model suggests that preexisting epigenetic alterations in normal cells increase tumor risk by expanding the target cell population and/or modulating the effect of subsequent genetic alterations on these cells, providing a novel idea for cancer risk management.

Adenomatous Polyposis Coli Protein↗
PubMed2006

Genome-wide association mapping in bacteria?

Bacteria display many interesting phenotypes such as virulence, tissue specificity and host range, for which it would be useful to know the genetic basis. Association mapping involves identifying causal variants by showing that particular genotypes are statistically associated with a phenotypic trait in a sample of strains taken from a natural population. With the advent of high-throughput genotyping, association mapping is becoming an increasingly powerful approach. However, until recently, association studies had not been used in bacteria because of their strong population structure, which can produce false positives and/or loss of statistical power unless elucidated and taken into account in analyses. Here, we describe how association mapping could be successfully applied to bacteria and outline the necessary sampling and genotyping strategies.

Bacteria↗
PubMed1991

[Structural changes of the erythrocyte membrane in myelodysplastic syndromes].

Myelodisplasic syndromes (MS) is a group of hematological alterations with well-known clinical, diagnosis, prognosis and therapeutic features. The etiology is still, however, unclear. Following the hypothesis of the lesion of the pluripotential cell, we have studied the composition of red cell membrane in 5 patients afflicted with MS (1 with refractory anemia; 3 refractory anemia plus excessive blast count and 1 chronic myelomonocytic leukemia). The red cells of the patients afflicted with MS has morphological alterations at examination in fresh. The most frequently observed being acanthocytosis and macrocytosis. Structurally, they showed an increase in the cholesterol/phospolipids (C/P) quotient, which was responsible for the increase of the cell area and macrocytosis. Meanwhile, the high level of sphingomyelin (SP) and its depletion of phosphatidil-ethanol-amine (PEA), justify the double population of red cells; one of which being acantocytes and the other has and aquired mutation of the genetic code, which confirms the chromosomic alterations widely described. We feel that our findings confirmed the hypothesis of the effects of an oncogen on the genoma of the mother cell, which can be causal of some acute leukemias and other genetically confirmed alterations.

Aged↗
PubMed1997

An exonic polymorphism (381A/G) in the choroideremia gene.

By using the single strand conformational analysis (SSCA) to search for point mutations in the choroideremia gene, we have identified a previously undescribed polymorphism within exon 5a (381A/G). We have studied the frequency of this polymorphism in a population from Southern France. The sequence variation creates a new restriction site for HhaI, allowing a convenient DNA-based genetic counseling in families in which the causal disease mutation is unknown.

Choroideremia↗
PubMed2003

MCP-1-MCP-3-Eotaxin gene cluster influences HIV-1 transmission.

BACKGROUND: MCP-1 (CCL2), MCP-3 (CCL7), and eotaxin (CCL11) are genes for CC chemokines clustered on the long arm of chromosome 17. Previous studies have implicated these chemokines in monocyte recruitment, viral replication, and anti-HIV cytotoxic T cell responses. An epidemiological analysis identified genetic variants influencing HIV-1 transmission and disease progression. METHODS: Genomic DNA from over 3000 participants enrolled in five natural history cohorts in the United States were analyzed. Nine single nucleotide polymorphisms (SNP) covering 33 kb containing these three genes were genotyped using the polymerase chain reaction. Distortions in allele, genotype, and haplotype frequencies were assessed with respect to HIV-1 transmission and rates of disease progression using categorical and survival analyses. RESULTS: Extensive linkage disequilibrium was observed. Three SNP (-2136T located in the MCP-1 promoter region, 767G in intron 1 of MCP-1, and -1385A in the Eotaxin promoter) were nearly always found together on a 31 kb haplotype (H7) containing the three genes. Frequencies of the three variants and the H7 haplotype were significantly elevated (odds ratio, 0.6; P = 0.005-0.01) in uninfected European-Americans repeatedly exposed to HIV-1 through high-risk sexual behavior or contaminated blood products. CONCLUSIONS: Although the extensive linkage disequilibrium precludes positive identification of the causal variant, the results suggest that genetic variation in the H7 region influences susceptibility to HIV-1 infection. Since these chemokines do not bind the primary HIV-1 coreceptors CCR5 or CXCR4, the observed influence on transmission may result from activation of the immune system in response to infection rather than receptor blockage.

Base Sequence↗
PubMed1992

[Ataxia telangiectasia: what impact in clinical oncology?].

Ataxia telangiectasia (AT) is a hereditary disease transmitted in a recessive mode and characterized by chromosomal instability and radiosensitivity. AT patients have a 100-fold higher risk of cancer than the general population. Although AT is a rare disease of which the frequency has been estimated to be 1/40,000, the frequency of the heterozygosity status, when assessed with the Hardy-Weinberg equation is high (about 1.4%). Parents of AT children, thus obligate AT carriers, show chromosomal instability and radiosensitivity, but at a lower level than AT patients. Assuming that these AT characteristics deal with the cancer predisposition, it can be hypothesized that AT heterozygote individuals have a higher cancer susceptibility than the general population. To test this hypothesis, M Swift's group compared cancer incidence rates from adult blood relatives of AT patients with controls. The risk of cancer in AT heterozygotes could be increased by 3.5 and, for carrier women, the breast cancer risk could be increased by 5.1. Actually, the diagnosis of the AT heterozygote status is not possible. However, the near cloning of the gene (or genes) for the disease will permit to identify the AT carriers in a population of patients suffering from cancer and to assess precisely the impact of AT heterozygosity in the genetic predisposition to cancer.

Ataxia Telangiectasia↗
PubMed1992

[Hereditary skin diseases: new genetic approaches].

New powerful techniques capable of effective genome analysis are now available for the study of inherited skin disorders. In most instances, a biochemical defect in the patient points to the responsibility of a given gene in the occurrence of the disease. The role of this candidate gene is tested by genetic linkage studies, then confirmed by identification of the molecular gene defect and collection of evidence that this gene defect is causally related to the disease phenotype. This conventional genetic approach has succeeded in identifying the genes and molecular defects responsible for X-linked ichthyosis, epidermolysis bullosa simplex of Koebner and Dowling-Meara, albinism and piebaldism. When no biochemical clue is available, reverse genetics can be used to delineate the region of the genome that contains the disease locus, thus shortening the search for the candidate gene. This approach, occasionally aided by the presence of cytogenetic anomalies, has allowed to locate and identify the gene for Von Recklinghausen neurofibromatosis (NF1) and to demonstrate the existence of two loci genetically related to tuberous sclerosis.

Arylsulfatases↗
PubMed2004

Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis.

Tissue factor (TF) is the primary cellular initiator of blood coagulation and a modulator of angiogenesis and metastasis in cancer. Indeed, systemic hypercoagulability in patients with cancer and TF overexpression by cancer cells are both closely associated with tumor progression, but their causes have been elusive. We now report that in human colorectal cancer cells, TF expression is under control of 2 major transforming events driving disease progression (activation of K-ras oncogene and inactivation of the p53 tumor suppressor), in a manner dependent on MEK/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase (PI3K). Furthermore, the levels of cell-associated as well as circulating (microvesicle-associated) TF activity are linked to the genetic status of cancer cells. Finally, RNA interference experiments suggest that TF expression is an important effector of the K-ras-dependent tumorigenic and angiogenic phenotype in vivo. Thus, this study establishes a causal link between cancer coagulopathy, angiogenesis, and genetic tumor progression.

Alleles↗
PubMed1997

[Hereditary cardiac arrhythmia].

Progress in molecular biology has advanced our medical knowledge. The identification of genetic abnormalities has been transformed into the new approach of "inverse genetic s" which is based on close collaboration between clinicians, geneticians, molecular biologists and physiologists. In monogenic affections of unknown mechanism, the scientific method of determining the culprit gene is based essentially on precise phenotypic identification of all members of a large family and on DNA studies. The following steps consist in localising the gene with polymorphic genetic probes and then demonstrate the causal mutations and, finally, reexpress the normal and abnormal genes to study their function and thereby confirm the mutation. This approach has recently been applied to cardiac arrhythmias. Genes responsible for atrioventricular conduction defects, Wolff-Parkinson-White syndromes associated with hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia have been localised in the human genome showing that these syndromes are often very variable. The greatest progress has been achieved in the congenital long QT syndrome. Four genes have been localised on chromosomes 3, 1, 7 and 11, and three have already been identified which has allowed study of their function and genotype-phenotype analysis.

Arrhythmias, Cardiac↗
PubMed2006

The temporal relationship of the onsets of alcohol dependence and major depression: using a genetically informative study design.

BACKGROUND: Although alcohol dependence (AD) and major depression (MD) are highly co-morbid, their causal relationship is unclear. In this longitudinal study, we used a genetically informative population-based twin sample to examine the age-at-onset distributions and the temporal relationship of AD and MD. METHOD: Our sample included 7477 twins, whose diagnoses of AD and MD and age-at-onset information were obtained from structured interviews. Individual-level survival analyses were conducted based on 2603 monozygotic (MZ) twins, and co-twin diagnosis was included in models as an index of familiar liability to AD and MD. RESULTS: The age-at-onset distributions of AD and MD differed substantially. Most onsets of AD were in young adulthood, whereas MD had a flatter distribution across age. Most subjects, especially women, had an onset of MD preceding AD. Prior MD significantly affected risk for developing AD, and this risk decreased over time. By contrast, preceding AD had negligible effects on the risk for future MD. Familial risk was transmitted within disorders but there was little evidence of additional familial liability shared across disorders. CONCLUSIONS: Risk for developing AD was substantially increased by a prior episode of MD. The association was only partially accounted for by familial factors, providing support for a direct causal effect such as self-medication. The etiologic path from AD to MD was insignificant.

Adult↗
PubMed2004

The current status of Alzheimer's disease genetics: what do we tell the patients?

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. Fully penetrant (causal) mutations leading to predominantly early-onset familial AD have been identified in three genes (APP, PSEN1, PSEN2), while for the more common late-onset form of the disease, only one partially penetrant genetic risk factor (APOE) has been established to date. Several lines of evidence suggest that additional susceptibility genes exist for both early- and late-onset AD, however, none of the more than three dozen putative AD loci proposed to date have been consistently replicated in follow-up analyses. Novel AD genes will not only provide valuable clues for the development of novel therapeutic approaches, but will also allow the development of new genetic risk profiling strategies that are an essential prerequisite for early prediction/prevention of this devastating disease. This review focuses on the analytic tools used to identify genes in complex diseases, and then provides a summary of recent linkage and association findings indicating the existence of novel late-onset AD genes on several chromosomes.

Alzheimer Disease↗
PubMed2002

A molecular genetic map and electrophoretic karyotype of the plant pathogenic fungus Cochliobolus sativus.

A molecular genetic map was constructed and an electrophoretic karyotype was resolved for Cochliobolus sativus, the causal agent of spot blotch of barley and wheat. The genetic map consists of 27 linkage groups with 97 amplified fragment length polymorphism (AFLP) markers, 31 restriction fragment length polymorphism (RFLP) markers, two polymerase chain reaction amplified markers, the mating type locus (CsMAT), and a gene (VHv1) conditioning high virulence on barley cv. Bowman. These linkage groups covered a map distance of 849 cM. The virulence gene VHv1 cosegregated with six AFLP markers and was mapped on one of the major linkage groups. Fifteen chromosome-sized DNAs were resolved in C. sativus isolates ND93-1 and ND9OPr with contour-clamped homogeneous electric field (CHEF) electrophoresis combined with telomere probe analysis of comigrating chromosome-sized DNAs. The chromosome sizes ranged from 1.25 to 3.80 Mbp, and the genome size of the fungus was estimated to be approximately 33 Mbp. By hybridizing genetically mapped RFLP and AFLP markers to CHEF blots, 25 of the 27 linkage groups were assigned to specific chromosomes. The barley-specific virulence locus VHv1 was localized on a chromosome of 2.80 Mbp from isolate ND9OPr in the CHEF gel. The total map length of the fungus was estimated to be at least 1,329 cM based on the map distance covered by the linked markers and the estimated gaps. Therefore, the physical to genetic distance ratio is approximately 25 kb/cM. Construction of a high-resolution map around target loci will facilitate the cloning of the genes conferring virulence and other characters in C. sativus by a map-based cloning strategy.

Ascomycota↗
PubMed2025

Admixture-mapping analysis reveals genetic determinants of the human plasma proteome.

Protein profiling and genetic findings can be integrated to define the genetic architecture of the circulating proteome in chronic diseases. Most self-identified African American (AA) individuals have both African and European genetic ancestry. Admixture mapping can detect genomic association regions in which causal variants exist with substantial differences in allele frequency or effect sizes between genetic ancestries. We performed admixture mapping of the circulating proteome in 1,989 participants from the Jackson Heart Study (JHS), investigating the relation of local African ancestry within genomic regions with levels of circulating proteins. We conditioned protein-local ancestry association models on variants previously found to be associated with those proteins in genome-wide association studies (GWASs). We replicated findings in 196 AA participants from the Multi-Ethnic Study of Atherosclerosis (MESA). 62 proteins were associated with local African ancestry. 21 of 62 remained statistically significant after conditioning on protein-associated variants observed in previous GWASs. 48 of 54 available protein-local ancestry associations were replicated in the MESA. Proteins associated with local African ancestry included chemokines, factors associated with vascular biology and inflammation, and other biologically interesting proteins. Admixture associations unexplained by previously reported protein-associated variants in conditional analysis suggest the existence of causal variants missed by standard GWAS techniques.

Aged↗
PubMed2025

No More Free Lunch: Challenges to Mendelian Randomization Due to Sample Selection and Complex Methods.

Mendelian randomization (MR) is increasingly used in epidemiological studies to investigate causal relationships. MR depends on 3 fundamental instrumental variable assumptions: relevance, independence, and exclusion restriction. Studies often assume that MR mitigates bias from confounding due to the random allocation of genetic variants at conception. In this perspective, using causal directed acyclic graphs, we discuss several scenarios where biases in MR analyses may arise due to the nature of the data or methods being used. These include (1) collider bias due to the nonrandom selection of participants into study populations used for conducting genome-wide association studies (GWAS), (2) indirect genetic effects arising from population-based GWAS rather than within-family studies, and (3) collider bias due to gene-environment interaction effects on the exposure in nonlinear MR analyses. We provide practical considerations for examining and reducing these biases in MR analyses.

Humans↗
PubMed1997

Continuity and change in children's social maladjustment: a developmental behavior genetic study.

Two developmental models were used to study genetic and environmental mechanisms underlying continuity and change in children's maladjustment. The transmission model assumed that successive levels of functioning were causally linked and that earlier experiences or prior genetic influences affected later maladjustment. The liability model related continuity in problem behavior to stable underlying environmental or genetic factors. The analyses pertained on average to 436 pairs of full siblings, 119 pairs of half siblings, and 122 pairs of cousins for whom maternal ratings of problem behaviors were available at ages 4-6, 6-8, and 8-10. Nonshared environmental influences appeared to be most important for changes in children's problem behaviors and did not have significant effects on age-to-age continuity. To represent the genetic and shared environmental mechanisms underlying stability in problem behavior, the authors preffered liability models without time specific effects.

Adult↗