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Results for “Genetic causality”

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PubMed1979

Genetic epidemiology and the prevention of functional mental disorders and alcoholism: family study and biological predictors.

1. This review intends to present some theoretical and practical considerations which appear essential for the development of rational research strategies in the field of primary and secondary prevention of mental disorders and alcoholism. 2. The various advances and trends regarding the nosology and diagnosis of these disorders are discussed. Integrative epidemiological models for relating the multifactorial causation and the heterogeneity (multidimensionality) of these disorders are presented. 3. It is emphasized that alcoholism and the functional mental disorders occur in families as shown by (i) the increased incidence of these disorders among relatives and (ii) the existence of various clinical categories genetically associated. 4. Current methodology in clinical diagnosis and genetic epidemiology represent powerful procedures for typing and subtyping of these disorders. Family studies could identify more homogeneous subgroups and generate hypotheses as to the mode of transmission of mental disorders and alcoholism. 5. Real progress could be made in prevention only if the search for predictors is carried out in homogeneous subgroups. 6. There is a lack of knowledge regarding biological predictors. An urgent need for association studies and linkage analysis should be carried out in order to identify genetic markers (causal relationship) and chromosomal markers. These could provide for the specification of a constellation of markers and the development of appropriate tests to identify subjects at risk likely to develop alcoholism and mental disorders. 7. The immediate issues in secondary prevention and the later outcomes in primary prevention are outlined.

Alcoholism↗
PubMed1995

The rise of neurogenetic determinism.

Dramatic advances in neuroscience are changing and enriching our understanding of brain and behaviour. But reductionist interpretations of these advances can cause great harm.

Behavior↗
PubMed2001

Retinopathy of prematurity: causation.

The incidence of ROP is birth weight dependent and restricting therapeutic oxygen levels has dramatically reduced the incidence of ROP in infants of birth weight >1000 g. However, the incidence of ROP has remained high in very low birth weight (VLBW) infants and this appears to be related to these babies being more ill. Several risk factors have been identified in this group, however oxygen variability, rather than high levels, has been correlated with severity of disease in recent clinical and animal studies. Difficulties in defining 'normal' oxygen in this group has meant the optimal range of oxygen therapy has not yet been defined. Clinical studies are now underway using even lower oxygen therapy ranges. The impact this may have on ROP, neurological and respiratory outcomes will require further study.

Animals↗
PubMed1999

Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease.

The brains of Alzheimer's disease patients contain extracellular Abeta amyloid deposits (senile plaques). Although genetic evidence causally links Abeta deposition to the disease, the mechanism by which Abeta disrupts cortical function is unknown. Using triple immunofluorescent confocal microscopy and three-dimensional reconstructions, we found that neuronal processes that cross through an Abeta deposit are likely to have a radically changed morphology. We modeled the electrophysiological effect of this changed morphology and found a predicted delay of several milliseconds over an average plaque. We propose that this type of delay, played out among thousands of plaques throughout neocortical areas, disrupts the precise temporal firing patterns of action potentials, contributing directly to neural system failure and dementia.

Aged↗
PubMed2001

Evidence of genetic instability in 3 Gy X-ray-induced mouse leukaemias and 3 Gy X-irradiated haemopoietic stem cells.

PURPOSE: If radiation-induced genetic instability is causal in mouse radiation leukaemogenesis, then genetic instability should be detectable in the irradiated target untransformed haemopoietic stem cell, and evidence of genetic instability detected in the clonal radiation-induced leukaemia. We have tested this hypothesis using the CBA/H mouse model of radiation-induced acute myeloid leukaemia (r-AML). MATERIALS AND METHODS: Fluorescence in situ hybridisation (FISH) was employed to screen for chromosomal aberrations in mouse 3 Gy X-ray-induced r-AMLs and in the clonal descendents of control and 3 Gy X-irradiated bone marrow haemopoietic stem cells using the in vitro clonogenic CFU-A colony assay. RESULTS: High levels of clonal non-specific chromosomal aberrations were detected in the r-AML (approximately 4-5 aberrations/r-AML), and ongoing chromosomal instability as defined by subclonal variants detected in 5/10 r-AML. A similar analysis of CFU-A colonies revealed chromosomal aberrations in 25% of colonies derived from irradiated bone marrow (2% in controls). However, 66% of the aberrant colonies (2% in controls) exhibited ongoing genetic instability as defined by non-clonal chromosomal aberrations. Overall, 6% (121/1884) of the CFU-A cells derived from irradiated bone marrow were aberrant (0.05% in controls) of which 12% (15/121) were subclonal. No one CFU-A cell exhibited aberrations on more than one of the three chromosomes painted. CONCLUSIONS: The high levels of non-specific genetic damage observed in the r-AMLs is therefore attributed to the accumulation of genetic lesions in the target haemopoietic stem cell over a longer time-scale after exposure than assessed in the in vitro CFU-A clonogenic assay. This is consistent with the long latency of the multi-stage radiation leukaemogenic process, and a role for radiation-induced genetic instability is inferred.

Animals↗
PubMed1992

Human apurinic endonuclease gene (APE): structure and genomic mapping (chromosome 14q11.2-12).

Abasic (AP) sites in DNA are produced spontaneously and by many genotoxic agents. The repair of such damages is initiated by AP endonucleases, which are evidently ubiquitous. We employed the recently cloned cDNA, APE, that encodes the major human AP endonuclease, to isolate large genomic fragments that contain the intact APE gene. The sequence of 3 kb encompassing APE was determined (GenBank Accession No. M99703). The APE gene contains four small introns (ranging 130 to 566 bp) and five exons, the first of which is untranslated. The 0.5 kb of DNA sequence upstream of APE did revealed only a possible CCAAT box, but no other regulatory sites or a TATA box, consistent with the constitutive expression of AP endonuclease activity observed in other studies. The location of APE in the human genome was mapped to chromosome 14, bands q11.2-12, by fluorescence in situ hybridization of metaphase cells with DNA from the genomic clones and subclones. Although this locus has not been associated causally with genetic diseases of DNA repair, some translocations that affect 14q11.2-12 could compromise APE and lead to genetic instability.

Base Sequence↗
PubMedDate not supplied

The development of psychopathy.

The current review focuses on the construct of psychopathy, conceptualized as a clinical entity that is fundamentally distinct from a heterogeneous collection of syndromes encompassed by the term 'conduct disorder'. We will provide an account of the development of psychopathy at multiple levels: ultimate causal (the genetic or social primary cause), molecular, neural, cognitive and behavioral. The following main claims will be made: (1) that there is a stronger genetic as opposed to social ultimate cause to this disorder. The types of social causes proposed (e.g., childhood sexual/physical abuse) should elevate emotional responsiveness, not lead to the specific form of reduced responsiveness seen in psychopathy; (2) The genetic influence leads to the emotional dysfunction that is the core of psychopathy; (3) The genetic influence at the molecular level remains unknown. However, it appears to impact the functional integrity of the amygdala and orbital/ventrolateral frontal cortex (and possibly additional systems); (4) Disruption within these two neural systems leads to impairment in the ability to form stimulus-reinforcement associations and to alter stimulus-response associations as a function of contingency change. These impairments disrupt the impact of standard socialization techniques and increase the risk for frustration-induced reactive aggression respectively.

Amygdala↗
PubMed1975

Some epidemiologic evidence on the etiology of caries.

While laboratory research has identified multiple causal factors in dental caries, few epidemiologic studies have been conducted on large representative populations that have utilized enough variables to test the current models of causation. Data from a large, representative study were available to the authors for secondary analysis. The epidemiology of dental caries as presented in the study indicates that the caries patterns in a free-living population were consistent with an infectious and nutrition model of causality. The genetic explanation, while represented in the data, was not as consistent with the findings as the infectious and nutritional explanations.

DMF Index↗
PubMed2026

Identification of OsCsLF6 Gene Responsible for Rice Seed Submergence Germination Through Genome-Wide Association Analysis.

Flooding stress is a primary environmental barrier that severely limits the widespread adoption of direct-seeded rice systems. Under submerged conditions, rapid coleoptile elongation serves as a vital morphological strategy that facilitates anaerobic germination and successful seedling establishment, yet its underlying molecular mechanisms remain poorly understood. Through a genome-wide association study, we identified a critical locus governing anaerobic coleoptile elongation, in which OsCsLF6, encoding a mixed-linkage glucan (MLG) synthase, was characterized as the causal gene. Genetic and biochemical analyses demonstrated that OsCsLF6 positively regulated coleoptile elongation by directly mediating MLG deposition into the primary cell wall. Mechanistically, we identified OsERF74, an AP2/ERF transcription factor, as an upstream master repressor that directly binds to a conserved core cis-element within the OsCsLF6 promoter. Under submergence, OsERF74 deficiency (oserf74 mutants) completely releases this transcriptional suppression, triggering a substantial upregulation of OsCsLF6 expression and subsequent hyper-accumulation of cell wall MLG. In contrast, constitutive overexpression of OsERF74 persistently blocks MLG biosynthesis. Crucially, a natural single-nucleotide polymorphism located within the OsERF74 binding element in the promoter defines two distinct haplotypes. The elite haplotype (Hap1) effectively disrupts OsERF74 binding affinity, which in turn attenuates transcriptional repression and sustains high OsCsLF6 expression, ultimately driving accelerated MLG synthesis and coleoptile elongation. Our findings establish a condition-specific OsERF74-OsCsLF6 regulatory module that serves as a central biochemical hub orchestrating cell wall remodelling during anaerobic germination. This module thus represents a promising molecular target and elite genetic resource for molecular breeding of flood-tolerant and direct-seeded rice varieties.

OsCsLF6↗
PubMed1998

Self-injurious behaviour as part of genetic syndromes.

BACKGROUND: The purpose of this paper is to review the association between genetic syndromes and self-injurious behaviour. METHOD: The information available from the literature on the subject of self-injurious behaviours and genetic syndromes was collated and presented with a critical appraisal. RESULTS: Self-injurious behaviours are associated with some genetic syndromes. However, the causal relationship between the genetic syndromes and the self-injurious behaviour remains far from clear. CONCLUSIONS: Although self-injurious behaviour has been shown to be the part of a broader phenotype in many genetic disorders, the specificity and sensitivity of these behaviours in this context remain unclear.

Brain Damage, Chronic↗
PubMed1997

The Swedish Centenarian Study: a multidisciplinary study of five consecutive cohorts at the age of 100.

UNLABELLED: Centenarians born 1887-91, who lived in southern Sweden were asked to participate in this multidisciplinary study (N = 164). Of the survivors (N = 143), 70 percent agreed (N = 100). The purpose was to describe the population from physical, social, and psychological points of view; to characterize centenarians with various health conditions and diverse degrees of autonomy and life satisfaction; and to identify factors at 100 years that predict future survival. RESULTS: Eighty-two percent were women, 25 percent lived in their own home, 37 percent in old age homes, and 38 percent in nursing homes. Socioeconomic status showed a similar distribution compared to nationally representative data. Fifty-two percent managed activities of daily living with or without minor assistance. The incidence of severe diseases was low. In 39 percent a disorder of the circulatory system was found. Thirty-nine percent (women) and 11 percent (men) had had at least one hip fracture. Twenty percent had good hearing and good vision. Twenty-seven percent were demented according to DSM III-R criteria. Means on cognitive tests (word-list, digit-span, learning, and memory) were lower compared to seventy to eighty year old groups. The variation in performance was extremely widespread. Personality profiles (MMPI) indicated that the centenarians were more responsible, capable, easygoing and less prone to anxiety than the population in general. Extensive neuropathological investigation revealed no major diseases or large lesions but mild through multiple changes. RESULTS suggest that centenarians are a special group genetically. A causal structure model emphasized body constitution, marital status, cognition and blood pressure as particularly important determinants for survival after 100 years.

Aged↗
PubMed1998

Molecular diseases and diseased molecules: ontological and epistemological dimensions.

In 1949, Linus Pauling and collaborators published in Science a paper provocatively titled: 'Sickle cell anemia, a molecular disease'. What was actually meant by 'molecular disease'? We interpret the concept of molecular disease in the frame of the traditional positions about the nature of diseases, the ontological and the physiological positions. We conclude that the physiological does not give an adequate account of what molecular diseases are. The ontological position, when correctly reinterpreted, leads to an understanding of molecular diseases where the macromolecule is seen as a symptom or as a part of a mechanism leading to the symptoms of the disease. We then show that the concept of molecular disease leads to a particular view of therapy, emphasizing eugenics as a way of eliminating disease. On the individual level, this concept leads to an increased power of diagnosis, and especially predictive diagnosis, but has little therapeutic consequence. Lastly, we examine how this concept of disease unifies two contemporary classifications of diseases, one based on the location of the diseases, the other on the cause of the diseases.

Anemia, Sickle Cell↗
PubMed2000

Predispositions, personality traits, and posttraumatic stress disorder.

This review suggests an explanation for the finding that trauma is a necessary but insufficient condition for the development of posttraumatic stress disorder. Predispositions affecting vulnerability to stress can help to account for discrepancies between traumatic exposure and pathological outcome. Such predispositions may be rooted in personality traits that shape the cognitive processing of stressful events, but they are also influenced by both prior life experiences and social supports. All of these observations are consistent with a biopsychosocial model of posttraumatic stress disorder.

Causality↗
PubMed2002

[Epidemiology and pathophysiology of spontaneous cervical artery dissection].

Spontaneous cervical artery dissections are produced by the penetration of circulating blood into the vessel wall of one or more cervical arteries, without a preceding major trauma. Dissection is one of the most frequent etiologies of ischemic stroke in young patients. Its annual incidence is about 3 per 100,000. Pathophysiology of cervical artery dissection remains misunderstood. Triggering factors such as minor trauma and infection have been identified. However, they are too trivial to explain alone the occurrence of a mural hematoma. Several abnormalities suggesting an underlying arteriopathy related to an extracellular matrix defect which could predispose to dissection have been reported: arterial redundancies, intracranial aneurysms, aortic root dilatation, common carotid artery distensibility increase, fibromuscular dysplasia, inherited connective tissue disorders, ultrastructural dermal connective tissue abnormalities. Other factors associated with dissection, such as migraine, hyperhomocysteinemia and alpha-1 antitrypsin deficiency, suggest arterial wall fragility secondary to hyperactivity of some proteases. If an underlying arteriopathy is likely, its nature remains unidentified to date and does not seem to be unique.

Aortic Dissection↗