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Results for “Genetic causality”

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PubMed2026

Integrating Genetics and Environment to Find Causal Mechanisms for Multiple Sclerosis.

Genome-wide association studies (GWAS) have identified hundreds of risk loci for multiple sclerosis (MS), but we have limited knowledge of the mechanisms through which genetic variants mediate risk. Similarly, epidemiological studies implicate numerous environmental risk factors in MS risk, but these cannot identify specific causal mechanisms. We review our current knowledge of genetic mechanisms in MS, including the critical role of expression quantitative trait locus (eQTL) mapping in translating genetic risk loci into causal mechanisms. Molecular and functional context has emerged as an important missing component of these studies, and we discuss how environmental risk factors can be modelled in a quantitative genetic context to identify disease mechanisms. In parallel, we highlight recent advances in which quantitative genetic methods establish a causal role for low vitamin D and obesity in MS, and to dissect the mechanisms through which these operate. As genetic, transcriptional, and epigenetic studies continue to expand, further mechanistic insights for MS are likely to come from the integration of genetic and environmental data.

Humans↗
PubMed2006

A nine-year genetic survey of the causal agent of Dutch elm disease, Ophiostoma novo-ulmi in Winnipeg, Canada.

The causal agent of Dutch elm disease, Ophiostoma ulmi s. lat., has been spreading across North America since the 1920s. The population of the pathogen in Winnipeg, Manitoba, Canada was surveyed in 1993 and 2002 using a combination of RAPD marker analysis, vegetative compatibility tests, and surveys for viral double-stranded RNA (dsRNA). The data presented here show that the population, based on the vegetative compatibility and RAPD analysis, was highly genetically uniform, and has remained so for the nine-year duration of the study. The pathogen population was also monitored for the presence and spread of dsRNA molecules that, depending on identity, can be associated with a diseased phenotype and reduction of virulence in the pathogen. The current study found a very low incidence of dsRNA, and did not find any evidence for spread of these molecules through the population, even though there appeared to be no barriers to the transfer of the dsRNA between Winnipeg isolates. Despite the observation that isolates infected with the Winnipeg dsRNA showed no obvious phenotypic differences, the low incidence of dsRNA in general suggests that infected isolates do not compete as successfully as the uninfected isolates. The highly clonal nature of the pathogen population may be exploited in a control strategy.

Ascomycota↗
PubMed2003

Psychiatric symptoms in patients with asthma causality, comorbidity, or shared genetic etiology.

Despite the range of diverse studies that attempt to understand the comorbidity of asthma and psychiatric diagnoses, it is still not possible to provide a reliable quantitative estimate of the increased risk for anxiety and mood disorders in children with asthma. A new hypothesis for this comorbidity has evolved, however. It is likely that the stress of having a chronic illness increases the likelihood of the development of anxiety and depressive symptoms. If this were a sufficient etiologic explanation, however, increased comorbidities of psychiatric illnesses would be found in all chronic pediatric illnesses. More precise prevalence estimates of these comorbidities require the completion of large studies that use a longitudinal design and reliable and well-validated assessment instruments. The most promising direction for future research is the definition of underlying genetic vulnerabilities that reflect autonomic regulation, may contribute to the onset of some forms of asthma, and are associated with increased risk for anxiety and mood disorders.

Anxiety Disorders↗
PubMed1995

What does it mean to be a cancer gene carrier? Problems in establishing causality from the molecular genetics of cancer.

This article addresses the following question: What does it mean to be a cancer gene carrier? The existence of families prone to cancer has prompted an intense search for predisposing heritable gene mutations. Genes that impart susceptibility to colorectal, breast, and ovarian cancers have been recently identified. It is doubtful, however, that the action of a single mutant gene totally accounts for the development of malignant disease. The mutant gene likely causes cancer in these family members only in conjunction with other genes, environmental factors, or both. Furthermore, although an individual carrier of a mutant gene within a cancer-prone family has an increased risk of malignancy, nutritional, pharmacologic, or other interventions may still confer protection. Extrapolations from cancer-prone families to the general population are even more problematic. The excess risk of malignancy among carriers of mutant genes who are not members of cancer-prone families is unknown. Large-scale epidemiologic studies are needed to determine the magnitude (or even the existence) of such excess risk.

Environmental Exposure↗
PubMed1996

Cyclophosphamide-induced acute liver failure requiring transplantation in a patient with genetically deficient debrisoquine metabolism: a causal relationship?

Severe liver damage can occur after treatment with cyclophosphamide. The possible linkage to genetically deficient drug metabolic capacity is unknown. A 58-year-old woman with rheumatoid arthritis was treated with oral cyclophosphamide 50 mg twice daily for 2 months. Due to poor response the dose was doubled and liver failure requiring transplantation developed within weeks. After surgery PCR amplification using DNA from leukocytes showed that she was homozygous for the mutated allele CYP2D6B, which is predictive of the poor metaboliser phenotype for debrisoquine, occurring in 7% of Caucasians. Our patient may have accumulated high levels of the hepatotoxic 4-hydroxylated cyclophosphamide metabolite. Pharmacogenetic methods can help in exploring mechanisms of unexpected severe adverse effects.

Antirheumatic Agents↗
PubMed2001

Molecular genetics and pathogenesis of hypertrophic cardiomyopathy.

Advances in molecular genetics of hypertrophic cardiomyopathy (HCM) have led to identification of mutations in 11 genes coding for sarcomeric proteins. In addition, mutations in gene coding for the gamma subunit of AMP-activated protein kinase and triplet-repeat syndromes, as well as in mitochondrial DNA have been identified in patients with HCM. Mutations in genes coding for the beta-myosin heavy chain, myosin binding protein-C, and cardiac troponin T account for approximately 2/3 of all HCM cases. Accordingly, HCM is considered a disease of contractile sarcomeric proteins. Genotype-phenotype correlation studies show mutations and the genetic background affect the phenotypic expression of HCM. The final phenotype is the result of interactions between the causal genes, genetic background (modifier genes), and probably the environmental factors. The molecular pathogenesis of HCM is not completely understood. The initial defects caused by the mutant proteins are diverse. However, despite their diversity, they converge into common final pathway of impaired cardiac myocyte function. The latter leads to an increased myocyte stress and subsequent activation of stress-responsive signaling kinases and trophic factors, which activate the transcriptional machinery inducing cardiac hypertrophy, interstitial fibrosis and myocyte disarray, the pathological characteristics of HCM. Studies in transgenic animal models show that cardiac hypertrophy, interstitial fibrosis, and myocyte disarray are potentially reversible. These findings raise the possibility of reversal of evolving phenotype or prevention of phenotypes in human patients with HCM. Elucidation of the molecular genetic basis and the pathogenesis of HCM could provide the opportunity for genetic based diagnosis, risk stratification, and implementation of preventive and therapeutic measures in those who have inherited the causal mutations for HCM.

Animals↗
PubMed2025

Circulating inflammatory proteins as causal drivers and therapeutic targets in asthma: insights from genetic and pathway-based analyses.

OBJECTIVE: To identify circulating inflammatory proteins with potential causal roles in asthma development through integrated genetic and pathway-based analyses, and to evaluate their potential as therapeutic targets. METHODS: We used genetically anchored instrumental variables from 180 protein quantitative trait loci (pQTLs) to assess the causal effects of 91 circulating inflammatory proteins on asthma risk, using large-scale GWAS datasets. Analytical robustness was evaluated through pleiotropy and heterogeneity testing. Functional enrichment and literature-based pathway analyses were performed to support biological plausibility and validate findings. RESULTS: Four proteins showed significant causal effects on asthma: CCL19 and LIFR were protective (OR = 0.89 and 0.91, p&#x2009;&#x2264;&#x2009;6.8E-03), while ARTN and IL6 were associated with increased risk (OR = 1.15 and 1.18, p&#x2009;&#x2264;&#x2009;1.1E-04). We also identified reverse causal effects of asthma on 11 cytokines, including MMP10, TGFB1, IL33, and IL18R1. Most of these proteins were enriched in pathways related to cytokine signaling and immune response (p&#x2009;<&#x2009;0.001). All identified proteins had prior literature support linking them to asthma or airway inflammation. CONCLUSIONS: Our findings highlight a subset of circulating inflammatory proteins that are likely causal in asthma pathogenesis and may serve as promising targets for therapeutic intervention. These results offer novel insights into the immunological mechanisms underlying asthma and support the utility of genetic causal inference in target prioritization.

Asthma↗
PubMed1995

Chromosome engineering in mice.

Chromosomal rearrangements are the major cause of inherited human disease and fetal loss. Translocations and loss of heterozygosity are important genetic changes causally involved in neoplasia. Chromosomal variants, such as deficiencies, are commonly exploited in genetic screens in organisms such as Drosophila because a small portion of the genome is functionally hemizygous. In the mouse, deficiencies are not generally available, thus genetic screens for recessive mutations are cumbersome. We report here that defined deficiencies, inversions and duplications extending to 3-4 cM can be constructed in embryonic stem cells. This was achieved by consecutive targeting of loxP recombination substrates to the end points of a genetic interval followed by Cre-induced recombination. This reconstructs a positive selectable marker which facilitates direct selection of clones with a chromosome structure specific to the relative orientation of the loxP sites. Duplication and deletion alleles have been transmitted into the mouse germ line. The availability of mice with defined regions of segmental haploidy will allow their use in genetic screens and enable accurate models of human 'chromosomal' diseases to be generated.

Animals↗
PubMed2005

The 'geneticisation' of heart disease: a network analysis of the production of new genetic knowledge.

Genetic science is making ever-expanding claims about the (mal)functioning of the body. The 'geneticisation' of health and medicine is extending from rare single gene conditions to more common multi-factorial disease, such as heart disease. The dominant behavioural and socio-spatial explanations of heart disease are now being challenged by genetic claims of deterministic biological causes. This paper builds an account of the transformation of heart disease in the new genetics era, by applying actor network theory (ANT) to the production of genetic knowledge of one aspect of heart disease-hypertension-within a medical genetics laboratory in Glasgow, Scotland. Using this approach, the paper shows that there is no straightforward geneticisation of heart disease. Instead, there is a contested, complex and uncertain understanding of heart disease as genetic, a product of the many people, technologies, natural elements and spaces involved in the network of genetic science knowledge making. The paper concludes that a 'critical' ANT could be developed that acknowledges the inherent unevenness of the network, and connects genetic and socio-spatial explanations of heart disease.

Causality↗
PubMed2006

Mouse models of lung cancer.

Human lung cancer is responsible for approximately 30% of all cancer deaths worldwide with >160,000 deaths in the United States alone annually. Recent advances in the identification of novel mutations relevant to lung cancer from a myriad of genomic studies might translate into meaningful diagnostic and therapeutic progress. Towards this end, a genetic model animal system that can validate the oncogenic roles of these mutations in vivo would facilitate the understanding of the pathogenesis of lung cancer as well as provide ideal preclinical models for targeted therapy testing. The mouse is a promising model system, as complex human genetic traits causal to lung cancer, from inherited polymorphisms to somatic mutations, can be recapitulated in its genome via genetic manipulation. We present here a brief overview of the existing mouse models of lung cancers and the challenges and opportunities for building the next generation of lung cancer mouse models.

Animals↗
PubMed2025

Association between NAFLD and liver cancer: A two-sample Mendelian randomization study.

Observational studies suggest an association between nonalcoholic fatty liver disease (NAFLD) and liver cancer, but its causal nature remains unclear. A 2-sample Mendelian randomization (MR) analysis was performed using NAFLD and liver cancer summary statistics from genome-wide association study databases. Instrumental variables satisfying the 3 core MR assumptions were selected. Causal effects were estimated using inverse-variance weighted, MR-Egger, weighted median, and other methods, followed by sensitivity and power analyses. All 4 MR analyses demonstrated a positive causal association between NAFLD and liver cancer risk [odds ratio&#x2005;>&#x2005;1, inverse-variance weighted P&#x2005;<&#x2005;.001]. Sensitivity analysis indicated no significant level of multiplicity or heterogeneity in the instrumental variables, and individual single nucleotide polymorphisms had no significant impact on the results. However, statistical power was insufficient. This study provides the first MR evidence demonstrating a genetically predicted causal relationship between NAFLD and liver cancer that is consistent across subtypes. Sensitivity analyses confirmed the absence of horizontal pleiotropy or heterogeneity, strengthening the robustness of the findings. These results offer genetic support for early NAFLD intervention to reduce the risk of liver cancer. However, the limited statistical power highlights the need for larger-scale genome-wide association study to identify more and stronger genetic instruments for a more precise quantification of the causal effect of NAFLD on liver cancer risk.

Humans↗
PubMed2001

Sources of structure: genetic, environmental, and artifactual influences on the covariation of personality traits.

The phenotypic structure of personality traits has been well described, but it has not yet been explained causally. Behavior genetic covariance analyses can identify the underlying causes of phenotypic structure; previous behavior genetic research has suggested that the effects from both genetic and nonshared environmental influences mirror the phenotype. However, nonshared environmental effects are usually estimated as a residualterm that may also include systematic bias, such as that introduced by implicit personality theory. To reduce that bias, we supplemented data from Canadian and German twin studies with cross-observer correlations on the Revised NEO Personality Inventory. The hypothesized five-factor structure was found in both the phenotypic and genetic/familial covariances. When the residual covariance was decomposed into true nonshared environmental influences and method bias, only the latter showed the five-factor structure. True nonshared environmental influences are not structured as genetic influences are, although there was some suggestion that they do affect two personality dimensions, Conscientiousness and Love. These data reaffirm the value of behavior genetic analyses for research on the underlying causes of personality traits.

Adolescent↗
PubMed2000

Epidemiology of schizophrenia: the global burden of disease and disability.

Evidence from nearly a century of epidemiological research indicates that schizophrenia occurs in all populations with a prevalence in the range of 1.4 to 4.6 per 1000 and incidence rates in the range of 0.16-0.42 per 1000 population. Multi-centre studies conducted by the World Health Organization have highlighted important differences between 'Western' and 'Third World' populations as regards the course and outcome of the disorder, with a significantly better prognosis in the developing countries. The factors underlying the better outcome of schizophrenia in developing countries remain essentially unknown but are likely to involve interactions between genetic variation and specific aspects of the environment. These features place schizophrenia, along with diabetes, cancer and hypertension, into the group of genetically complex diseases which are characterised by polygenic transmission, locus heterogeneity and environmental contribution to causation. The emerging pattern of risk factors and antecedents of schizophrenia suggests multiple, mainly quantitative deviations from the average developmental trajectory, primarily in the areas of early neurodevelopment, cognitive ability and social behaviour. These deviations are compatible with the notion of non-specific background factors facilitating the operation of genetically determined causal pathways. Research likely to result in new insights should focus on the population distribution and behavioural effects of potential risk factors and markers suggested by biological and genetic research.

Cross-Cultural Comparison↗