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PubMed2006

What is a genetic cause? The example of Alzheimer's Disease.

This paper focuses on the causation of diseases, particularly on the idea of a "genetic cause" taking Alzheimer's Disease (AD) as an example. We (1) provide some historical information and a synopsis of the current knowledge on the etiology and pathogenesis of AD, (2) analyse some conceptual problems related to the notion of "genetic disease", (3) elaborate on the alleged (genetic) cause of AD, and (4) place the discussion on the cause of AD in a broader philosophical context, paying attention to a constructivist perspective, the notions of causal connection and causal selection, and to some practical and normative consequences of our analysis. We conclude (a) that AD is not a specific disease entity with one specific cause, (b) that the idea of a single (sufficient) cause can still function as a heuristic tool in AD research and practice, and (c) that a "belief" in causation can go together with the notions of multicausality and probability.

Alzheimer Disease↗

PubMed2006

On the synthesis and interpretation of consistent but weak gene-disease associations in the era of genome-wide association studies.

Emerging technologies are allowing researchers to study hundreds of thousands of genetic variants simultaneously as risk factors for common complex diseases. Both theoretical considerations and empirical evidence suggest that specific genetic variants causally associated with common diseases will have small effects (risk ratios mostly <2.0). However, the combination of even a few small effects (e.g. effects of fewer than 20 common genetic variants) could account for a sizeable population attributable fraction of common diseases and shed important light on disease pathogenesis and environmental determinants. Nevertheless, the inauguration of genome-wide association studies only magnifies the challenge of differentiating between the expected, true weak associations from the numerous spurious effects caused by misclassification, confounding and significance-chasing biases. Standards are urgently needed for presenting and interpreting cumulative evidence on gene-disease associations, especially for consistent but weak associations. Criteria for synthesis of the evidence should include sound methods for study conduct and analysis, biological plausibility, experimental evidence and adequate replication in large-scale, collaborative studies. Efforts by the Human Genome Epidemiology Network (HuGENet) are currently ongoing to streamline and operationalize these criteria for data on genetic associations with common diseases.

Cohort Studies↗

PubMed2003

Causative and susceptibility genes for Alzheimer's disease: a review.

Alzheimer's disease (AD) is the most common type of dementia in the elderly population. Three genes have been identified as responsible for the rare early-onset familial form of the disease: the amyloid precursor protein (APP) gene, the presenilin 1 (PSEN1) gene and the presenilin 2 (PSEN2) gene. Mutations in these genes, however, account for less than 5% of the total number of AD cases. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. In this paper, we review the most important genes supposed to be involved in the pathogenesis of AD, known as susceptibility genes, in an attempt to provide a comprehensive picture of what is known about the genetic mechanisms underlying the onset and progression of AD. Hypotheses about the role of each gene in the pathogenic pathway are discussed, taking into account the functions and molecular features, if known, of the coded protein. A major susceptibility gene, the apolipoprotein E (APOE) gene, found to be associated with sporadic late-onset AD cases and the only one, whose role in AD has been confirmed in numerous studies, will be included in a specific chapter. As the results reported by association studies are conflicting, we conclude that a better understanding of the complex aetiology that underlies AD may be achieved likely through a multidisciplinary approach that combines clinical and neurophysiological characterization of AD subtypes and in vivo functional brain imaging studies with molecular investigations of genetic components.

Alzheimer Disease↗

PubMed2001

Building 'validated' mouse models of human cancer.

As a model system for the understanding of human cancer, the mouse has proved immensely valuable. Indeed, studies of mouse models have helped to define the nature of cancer as a genetic disease and demonstrated the causal role of genetic events found in tumors. As the scientific and medical community's understanding of human cancer becomes more sophisticated, however, limitations and potential weaknesses of existing models are revealed. How valid are these murine models for the understanding and treatment of human cancer? The answer, it appears, depends on the nature of the research requirement. Certain models are better suited for particular applications. Using novel molecular tools and genetic strategies, improved models have recently been described that accurately mimic many aspects of human cancer.

Animals↗

PubMed2005

Strategies in analysis of the genetic component of multifactorial diseases; biostatistical aspects.

Complex polygenic and multifactorial diseases remain a challenge for human geneticists. Here we aim to remind basic definitions of multifactorial diseases and the genetic related concepts underlying classical methods. Knowledge on pathophysiological process and the genetic information available conditions the design of study. The choice of methodology, between candidate gene approach and genome scan approach, between linkage and association studies, is the most important step. Both methods, linkage analysis and association studies are usually considered as complementary approaches for a given disease. For this reason, in this article, we present the most important classical methodologies in genetic epidemiology of complex disorders. References and examples are given to illustrate.

Biometry↗

PubMed2005

Predictors of physical health: toward an integrated model of genetic and environmental antecedents.

People in higher-income groups tend to experience better physical health, yet this does not appear to be the direct result of access to medical care. This has prompted a search for psychological factors more likely to be present in high-income environments that might help to explain the relationship. Physical health has been associated with a number of such psychological measures including positive affect and well-being, negative affect and neuroticism, positive social relationships, and perceived control. Building from recent findings of moderation of genetic variance in physical health by income and perceived control, we explore the genetic and environmental relationships among all these variables in a nationwide U.S. twin sample. These relationships suggest possible mechanisms by which psychological characteristics, behaviors, physical health, and environmental circumstances could be influenced by common groups of genes with varying degrees of activity in different environments. We discuss the implications of such mechanisms for differential expression of genetic variation in the population and suggest ways in which consideration of such effects can inform gerontology research.

Causality↗

PubMed1986

Parent to child transmission of the thrombocytopenia absent radius (TAR) syndrome.

We report on cases of the thrombocytopenia absent radius syndrome (TAR) in a family with the first documented occurrence of parent-to-child transmission. At least three other families have been reported in which TAR has been transmitted across generations. The pattern of transmission in these cases is not consistent with the simple autosomal recessive mode of inheritance which has been proposed. TAR syndrome may be a genetically heterogeneous disorder of the result of one of a group of related alleles. Given the increasing evidence for genetic and causal heterogeneity in TAR together with its similarity to conditions such as Holt-Oram, WT Limb-Blood and SC-Roberts Phocomelia syndromes it may be reasonable to view TAR as a developmental field defect rather than a genetic syndrome. Genetic counseling of affected individuals and their families should be modified to reflect the possibility of a recurrence risk as high as 50%.

Adult↗

PubMed2025

Genetic predisposition to systemic inflammatory proteins is causally associated with inflammatory bowel disease: Insights from multi-omics association study and single-cell RNA-sequencing analysis.

Systemic inflammatory proteins have been reported to be related to inflammatory bowel disease (IBD) in previous observational research. However, their causal links remain obscure. Herein, we performed a Mendelian randomization (MR) analysis to analyze the causality between systemic inflammatory proteins and IBD. Genetic variants related to systemic inflammatory proteins were extracted from a meta-analysis of genome-wide association study (GWAS) data of 8293 European participants. Summary statistics of IBD diverse subtypes were obtained from the international IBD genetic consortium (IIBDGC). We conducted multi-omics method and MR study to detect the causal links through integrating GWAS and protein quantity trait loci (pQTL) data. Inverse variance weighted (IVW) approach was utilized as the dominated analysis method. Moreover, complementary approaches such as MR-Egger intercept test, Cochran Q test and leave-one-out analysis were utilized to validate pleiotropy and heterogeneity. Finally, single-cell RNA-sequencing analysis was performed to detect the expression of significant genes. For IBD, IVW estimates suggested that genetically predicted IL-10 and IL-13 were suggestively associated with an elevated risk of IBD (IL-10: OR: 1.12, 95% CI: 1.00-1.24, P = .04; IL-13: OR: 1.09, 95% CI: 1.01-1.18, P = .023), while CXCL10 was suggestively linked to a lower risk of IBD (CXCL10: OR: 0.90, 95% CI: 0.82-0.99, P = .037). For Crohn disease (CD), the IVW approach provided evidence to sustain that genetically determined IL-13 and CCL3 had a suggestive association with a higher risk of CD (IL-13: OR: 1.13, 95% CI: 1.02-1.26, P = .023; CCL3: OR: 1.22, 95% CI: 1.03-1.45, P = .018). Sensitivity analysis did not explore any heterogeneity and pleiotropy. Our findings supported the causal relationships between 4 specific inflammatory proteins (IL-10, IL-13, CXCL10, and CCL3) and the risk of IBD and CD, thereby providing promising biomarkers of various subtypes stratification and new insights for the prevention and therapeutic target of IBD.

Humans↗

PubMed1989

Benign partial epilepsy and related conditions: multifactorial pathogenesis with hereditary impairment of brain maturation.

The main clinical and bioelectrical features of the benign partial epilepsies and related conditions are described. Based on highly selected groups, the definition of these suggested syndromes disregards the considerable overlap between borderline and intermediate cases. To understand the great phenotypic variability of these epilepsies, the complexity of causal especially genetic factors must be considered. Different genetic traits, expressed in certain EEG patterns, determine the level of cerebral excitability. These hereditary variables are widespread in the general population. Most are polygenic, focal sharp waves possibly autosomal dominant. In individuals, the coincidence of different traits with little or no clinical significance, results in additive effects lowering the seizure threshold and raising the risk of clinical manifestation. The complexity of causal factors, which, potentially include organic brain lesions, account for the wide spectrum of epileptic and non-epileptic conditions ranging from mild selective performance deficits to complex psychomental retardation, and from simple rolandic epilepsy to severe epilepsies with minor seizures or bioelectrical status. These conditions are not "syndromes" in the stricter sense, but sets of variably weighted symptoms of a complex pathogenetic background. A genetic disposition to focal pathogenetic background. A genetic disposition to focal anomalies of brain function is of decisive importance. The biological background is as of yet unknown. The marked age-dependency of symptoms and almost regular disappearance of seizures and EEG abnormalities at puberty justify the assumption of an hereditary impairment of brain maturation. The hypothesis of autosomal dominant inheritance awaits appraisal by studies of larger populations and quantitative genetic approaches.

Adolescent↗

PubMed2001

A disease by any other name: musings on the concept of a genetic disease.

What exactly is a genetic disease? For a phrase one hears on a daily basis, there has been surprisingly little analysis of the underlying concept. Medical doctors seem perfectly willing to admit that the etiology of disease is typically complex, with a great many factors interacting to bring about a given condition. On such a view, descriptions of diseases like cancer as genetic seem at best highly simplistic, and at worst philosophically indefensible. On the other hand, there is clearly some practical value to be had by classifying diseases according to their predominant cause when this can be accomplished in a theoretically satisfactory manner. The question therefore becomes exactly how one should go about selecting a single causal factor among many to explain the presence of disease. When an attempt to defend such causal selection is made at all, the standard accounts offered (Koch's postulates, Hill's epidemiological criteria, manipulability) are all clearly inadequate. I propose, however, an epidemiological account of disease causation which walks the fine line between practical applicability and theoretical considerations of causal complexity and attempts to compromise between patient-centered and population-centered concepts of disease. The epidemiological account is the most basic framework consistent with our strongly held intuitions about the causal classification of disease, yet it avoids the difficulties encountered by its competitors.

Causality↗

PubMed2004

Incidence and definition of sepsis and associated organ dysfunction.

AIMS: To discuss the incidence, outcome and predisposing factors to systemic inflammatory response syndrome (SIRS), sepsis, and multiple organ failure. METHODS: A qualitative review of the literature. RESULTS: Case definitions of sepsis and severe sepsis, though clarified recently, are still arbitrary. It seems, however, that SIRS is not useful in identifying severe sepsis while organ failure has become a cornerstone for this definition. Incidence of severe sepsis appears to be approximately 10% of all ICU admissions, totaling nearly one million cases annually in the U.S. alone, and rising. Mortality associated with these events is still high, especially among ICU patients. Recent studies have been demonstrating an association between a variety of genetic polymorphisms and progression to and dying from sepsis. CONCLUSION: Recently there has been an increasing amount of information enabling characterization of the epidemiology of sepsis, which may help to direct appropriate care in the coming years.

Biomarkers↗

PubMed1999

Homocysteine and arterial occlusive disease: a concise review.

Many cross-sectional and prospective studies have shown that raised serum/plasma levels of total homocysteine increase the risk of coronary, cerebral, and peripheral artery disease. The risk associated with hyperhomocysteinemia appears to be concentration-dependent and not attributable to traditional risk factors. The odds ratio for ischemic heart disease has been estimated to be 1.4 for every 5 mumol/l increase of total plasma homocysteine. Median fasting total plasma homocysteine in adult males is approximately 10 mumol/l. Mild hyperhomocysteinemia is estimated to occur in 5-10% of the general population. Plasma concentrations are increased as a result of age, male gender, impaired renal function, low vitamin B intake, and genetically-determined defects of the enzymes involved in homocysteine metabolism. Folate supplements can reduce total homocysteine levels by approximately 25%. Studies in vitro and in vivo indicate that homocysteine can impair endothelial function. Despite increasing recognition of hyperhomocysteinemia as a risk factor for arterial occlusive disease, irrefutable proof that mild hyperhomocysteinemia contributes directly to the pathogenesis of atherothrombosis will come if interventions to lower total homocysteine reduce cardiovascular events. Family studies may also provide evidence of causality if genetic causes of hyperhomocysteinemia are found to segregate with disease.

Arterial Occlusive Diseases↗

PubMed2025

The relationship between vitamin D levels and depression: a genetically informed study.

BACKGROUND: Low vitamin D (vitD) levels are consistently associated with an increased risk of depression. However, the biological mechanisms underlying this relationship and potential shared genetic overlap remain elusive. METHODS: We investigated the genetic overlap and causal relationships between depression (N = 589,356) and vitD levels (N = 417,580) using genome-wide association study (GWAS) summary statistics. We performed genome-wide and local genetic correlation analyses, followed by quantification of polygenic overlap variants. Shared genetic loci were identified and mapped to genes, which were further analyzed through gene expression and lifespan brain expression trajectory analyses. Bidirectional causal relationships were examined using multiple Mendelian randomization approaches. RESULTS: We observed significant negative genetic correlations (rg = -0.079) and identified genetic overlap (N = 410 variants). Genes mapped to the 13 shared loci showed opposing expression patterns. Tissue- and cell-specific functional enrichment analyses revealed significant signals related to brain development, with distinct patterns emerging between fetal development and adulthood. Shared genes (TRMT61A, ITIH4, RASGRP1, CTNND1, HERC1, IP6K1, FURIN ESR1, ZMYND and GRM5) exhibited notable expression variation in the brian throughout the lifespan, aligning with functional enrichment findings. CONCLUSIONS: Our findings elucidate the shared biological mechanisms underlying the relationship between vitD and depression, suggesting that vitD play an important role in the development of depression through altered early neurodevelopmental processes.

Humans↗

PubMed2006

A general population-genetic model for the production by population structure of spurious genotype-phenotype associations in discrete, admixed or spatially distributed populations.

In linkage disequilibrium mapping of genetic variants causally associated with phenotypes, spurious associations can potentially be generated by any of a variety of types of population structure. However, mathematical theory of the production of spurious associations has largely been restricted to population structure models that involve the sampling of individuals from a collection of discrete subpopulations. Here, we introduce a general model of spurious association in structured populations, appropriate whether the population structure involves discrete groups, admixture among such groups, or continuous variation across space. Under the assumptions of the model, we find that a single common principle--applicable to both the discrete and admixed settings as well as to spatial populations--gives a necessary and sufficient condition for the occurrence of spurious associations. Using a mathematical connection between the discrete and admixed cases, we show that in admixed populations, spurious associations are less severe than in corresponding mixtures of discrete subpopulations, especially when the variance of admixture across individuals is small. This observation, together with the results of simulations that examine the relative influences of various model parameters, has important implications for the design and analysis of genetic association studies in structured populations.

Computer Simulation↗

PubMed2006

Genetic determinants of cancer coagulopathy, angiogenesis and disease progression.

Progression of human malignancies is accompanied by vascular events, such as formation and remodeling of blood vessels and systemic coagulopathy. Though long appreciated as comorbidity of cancer (Trousseau syndrome), vascular involvement is increasingly recognized as a central pathogenetic mechanism of tumor growth, invasion and metastasis. The major outstanding question in relation to this role has been, whether vascular perturbations are simply a reaction to the conditions of the tumor microenvironment, or are linked to the known genetic lesions causal for the onset and progression of malignancy. In this regard, we have previously hypothesized, and recently demonstrated experimentally that deregulation of certain hemostatic mechanisms, namely upregulation of tissue factor (TF) and possibly other changes (e.g. expression of thrombin receptor - PAR-1) are controlled by cancer-associated oncogenic events, such as activation of K-ras, epidermal growth factor receptor (EGFR), or inactivation of the p53 tumor suppressor gene in various human cancer cells. It appears that these respective transforming alterations exert their impact on both, cell-associated and soluble/circulating (microvesicle- associated) TF, i.e. may cause a systemic hypercoagulable state. Other genes, which more recently emerged as regulators of cancer coagulopathy include: PML-RARalpha, PTEN, and MET. While the spectrum of procoagulant targets of these genes may vary somewhat it includes: TF, PAI-1, COX-2 and possibly other hemostatic proteins. It is noteworthy that these prothrombotic changes may impact the malignant process directly (e.g. stimulate angiogenesis, tumor growth or metastasis) as a consequence of both coagulation-dependent and -independent effects. The latter are mostly related to cellular signaling events and changes in gene expression which are now known to be induced by the TF/FVIIa/Xa complex, thrombin and PARs, expressed on the surface of cancer cells, as well as tumor-associated endothelium. Interestingly, certain anticoagulants possess antimetastatic and anticancer properties (e.g. LMWH), an observation that further suggests that hypercoagulability may act as an effector mechanism of genetically driven tumor progression. Conversely, we suggest that oncogene-directed (targeted) anticancer agents could, at least in some cases, ameliorate not only cellular transformation itself, but also some of the chronic components of the cancer-related coagulopathy, something that may be relevant to therapeutic efficacy of these drugs. We also postulate that since TF is the oncogene target, circulating TF (microparticles) could serve as surrogate marker of the biological activity oncogene-directed agents exert in vivo. Thus, both genetic and epigenetic factors appear to conspire to activate various components of the hemostatic system in cancer patients, both locally and systemically. These activities act as mediators of cancer coagulopathy, angiogenesis, metastasis and other events involved in disease progression and should be recognized in designing better anticancer therapies.

Animals↗

PubMed2000

Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy.

Patients with hypertrophic cardiomyopathy (HCM) exhibit variable expression of left ventricular hypertrophy (LVH), a major determinant of mortality and morbidity, which is partly due to the diversity of causal mutations, genetic background (modifier genes), and probably environmental factors. We determined association of functional variants of tumor necrosis factor (TNF)- alpha, interleukin-6 (IL6), insulin-like growth factor-2 (IGF2), transforming growth factor- beta 1 (TGFB1), and aldosterone synthase (CYP11B2) genes, all previously implicated in cardiac hypertrophy, with the severity of LVH in patients with HCM. Two-dimensional echocardiography was performed and demographic variables were recorded in 142 genetically independent patients. Indices of LVH including interventricular septal thickness (IVST), left ventricular mass index (LVMI), and LVH score were measured/calculated. TNF-alpha-308G/A, IL6-174G/C, IGF2 820G/A, TGFB1-509C/T, and CYP11B2-344T/C genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotypes were identified by the presence of specific electrophoretic patterns and their distributions were according to the Hardy-Weinberg equilibrium. Demographic variables were not significantly different among the genotypes. Subjects with the AA genotype of TNF-alpha (n=8) were approximately 13 years younger at the time of clinical diagnosis. Despite a younger age, they had a greater mean LVMI than those with the GG (n=94) or GA (n=33) genotypes (191.8+/-59.5 v 139.1+/-47.3 v 132.1+/-34.3, respectively, P=0.004). TNF-alpha-308G/A genotypes accounted for 6.0% of variability of LVMI (P=0.002). Mean IVST, LVEDD, and LVH score were not significantly different. Variants of IL6, IGF2, TGFB1, and CYP11B2 were not associated with indices of LVH. The uncommon allele of TNF-alpha-308G/A polymorphism, known to produce more TNF- alpha, was associated with greater LVMI and clinical diagnosis at a younger age in patients with HCM. Functional variants of other trophic factors, previously implicated in cardiac hypertrophy, were not associated with the indices of LVH. These results suggest that TNF-alpha is a modifier gene for HCM.

Adult↗

PubMed2000

Complete nucleotide sequence and genomic structure of the human NRAMP1 gene region on chromosome region 2q35.

Several lines of independent evidence suggest that human Natural Resistance Associated Macrophage Protein 1 gene (NRAMP1) is an important regulator of susceptibility to infectious diseases caused by certain intracellular pathogens. Here, we report the nucleotide sequence of 32198 bp of genomic DNA overlapping NRAMP1 on chromosomal region 2q35. The NRAMP1 gene spans 13604 bp. The gene and its 5' genomic region are highly enriched for DNA repeat sequences. A second gene was identified in the immediate vicinity of NRAMP1 and was tentatively named Nuclear LIM Interactor-Interacting Factor (NLI-IF) by analogy to its closest ortholog. The human NLI-IF gene begins 4721 bp downstream of the NRAMP1 stop codon and is composed of seven exons varying in size from 57 bp to 1644 bp. The gene gives rise to a 2655-bp mRNA transcript that contains a 783-bp open reading frame. The predicted molecular weight of the 261-amino acid NLI-IF protein is 29.2 kDa. Several putative gene regulatory elements were identified in the 5' upstream region of NLI-IF, including consensus binding sequences for Sp1, AP-2, NF-kappa B, and PU 1. The NLI-IF amino acid sequence has homology to proteins that have a high degree of homology with the NLI-interacting factor from Gallus gallus and are found in divergent species ranging from yeast to plants. NLI-IF is part of a human gene family encoding four related proteins of unknown function. Northern blot analysis of 15 different human tissues revealed a 2.6-kb NLI-IF mRNA that was ubiquitously expressed, but at varying levels. A second transcript with estimated size of 7 kb was expressed only in the placenta. Our data provide new sequence information about the NRAMP1 gene region that will be useful in the search for genetic variants causally involved in altered susceptibility to infectious diseases.

Amino Acid Sequence↗

PubMed1987

A membrane-specific tyrosinase chelate: the mitotic regulator?

Cancer's random, reversible, unstable transitions to "normal" structures imply their functional relation. Similar random, continuous, reversible oncogene "mutational transformation" also lacks a consistent hybrid. Positing cancer's "mutationally altered genotype" leads to medically foreign causes, qualities, inducers, suppressors, immune proteins, and viruses. Its random variation, however, opposes the functionally discrete, ordered, stable, irreversible hybrid variation and single-valued transforms of molecular genetics. There, "causal mutational operators" remain unspecified; only consistent single-valued DNA base and amino acid change, as "transform operand", are made explicit. A mitotically "blocked" (normal) and "unblocked" (malignant) stem cell "phenotype", operationally constructed from microscopic data, is therefore viewed within the homeostatic context of open-system enzyme-regulatory equilibrium. This functional, stochastic field distribution between "structurally bound" and "freely dividing" stem cell number discloses their putative regulatory mitotic-blocking factor. A tyrosinase complex, interacting by Cu2+-Fe2+ chelation with a proline hydroxylase divisional enzyme near stem cell ribosomes, maintains steady-state mitotic equilibrium. Based upon familiar medical, biochemical, and energy principles this confronts cancer's pigmentary-depigmentary signs, glycolytic metabolism, elevated serum tyrosinase, defective collagen production, exposed membrane binding sites, and tyrosine's recent growth control role.

Catechol Oxidase↗