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Transgenic and null mutant animals for psychosomatic research.

OBJECTIVE: Progress in the use of genetically altered animals for psychosomatic research is reviewed. METHOD: Analysis of the strengths and weaknesses of these models, particularly from a developmental and behavioral prospective is used to assess the validity of these models. RESULTS: Genetically altered animals can be used to create models of the estimated 5000 human diseases in which genetic predispositions play a role, as well as models for diseases that do not involve gene defects, such as human immunodeficiency virus (HIV) infection. In addition, these models have already contributed immensely to our understanding of basic biology and the biology of behavior. Replication of human gene defects in mice has provided direct models of human disease, but there are various factors that sometimes prevent the gene defect from producing the human disease in mice. However, even in this case, the models can contribute to understanding the basic biology of the disease. CONCLUSIONS: While genetically altered animals have revolutionized the understanding of single gene disorders, their promise has not yet been fulfilled for multigenic behavioral disorders. Newer techniques to allow control of the tissue and stage of development at which a gene is expressed are likely to enhance the usefulness of these models for psychosomatic research. New models of disease for testing psychological impacts on illness and specific ways altering neurotransmitter function will be discovered. While these models will be extremely useful to psychosomatic medicine, the nature of this discipline of necessity involves emphasis on individual experience, and thus will never be amenable to exclusively genetic analysis.

Animals↗

Engineering a genetic transformation system for Colletotrichum acutatum, the causal fungus of lime anthracnose and postbloom fruit drop of citrus.

Postbloom fruit drop (PFD) of citrus is caused by Colletotrichum acutatum. PFD isolates infect flower petals, induce abscission of small fruit and can cause severe yield loss on most citrus cultivars. Isolates from Key lime anthracnose (KLA) cause that disease on the Mexican lime, but also cause PFD on sweet orange. Both PFD and KLA isolates exhibited resistance to the common selection agents including hygromycin, bialaphos, benomyl and geneticin/G418. A genetic transformation system was developed for C. acutatum to confer resistance to sulfonylurea (chlorimuron ethyl) by expressing an acetolactate synthase gene (sur) cassette from Magnaporthe grisea. The protocol was tested on 11 different KLA and PFD isolates. The transformation frequencies were highly variable among isolates and among experiments (0-17.9 per microg circular DNA using 10(7) protoplasts). Southern blot analysis of transformants indicated that the plasmid vector was randomly integrated in multiple copies into the genome of C. acutatum. Addition of restriction enzymes or use of a vector with homologous sequences did not change the transformation frequencies, but tended to reduce the number integrated. Over 97% of the transformants retained the sulfonylurea resistance phenotype under non-selective conditions. Of 300 transformants tested, three were unable to cause necrotic lesions on detached Key lime leaves. The transformation method opens up opportunities for the genetic manipulation of C. acutatum.

Blotting, Southern↗

Mapping quantitative effects of oligogenes by allelic association.

Regression analysis of a quantitative trait as a function of a single diallelic polymorphism has been extended to allelic association by composite likelihood under the Malecot model for multiple markers. We applied the method to 10 single nucleotide polymorphisms (SNPs) spanning 27 kb of the angiotensin-I converting enzyme (ACE) gene in British families, localising a causal SNP between G2530A and 4656(CT)3/2 in the 3' region, at a distance of 21.6+/-0.9 kb from the most proximal SNP T-5491C. Neither they nor the I/D polymorphism is causal. To clarify genetic parameters we applied combined segregation, linkage and association analysis. Stronger evidence for the 3' region was obtained, with significant evidence of a lesser 5' effect as reported in French and Nigerian families. However, rigorous confirmation requires that the causal SNPs be identified. Both Malecot and parametric analysis appear to have high power by comparison with alternative methods for localizing oligogenes and their causal polymorphisms.

Chromosome Mapping↗

Concordant contralateral lambdoidal synostosis in dizygotic twins.

Twin studies have been widely used to investigate genetic versus environmental causality of malformations. While there are numerous reports of concordant sutural fusions in syndromic twins, there are few cases in siblings with nonsyndromic single suture synostosis. Lambdoidal synostosis has no clear genetic etiology. Discordant synostosis has been reported in one monozygotic twin; there is also an unsubstantiated report of concordance in dizygotic twins. We describe dizygotic twins concordant for contralateral lambdoidal synostosis. Mutational analysis for FGFR 1,2,3 was negative. Given the low incidence, absence of reported inheritability, and lack of documented concordance in monozygotic twins, the pathogenesis of isolated lambdoidal fusion can only be ascribed to stochastic influences.

Craniosynostoses↗

[Familial recurrent laryngeal nerve paralysis, a genetically fixed syndrome -- additional remark on linkage of deficiency gene and HLA (author's transl)].

Hereditary laryngeal paralysis has been rarely reported. Some authors describe additional neurological signs in connection with the cranial nerve, or mental retardation. It has been assumed that there is a causal connection with genetic deficiency. Familial studies, presented with this article, showed abductor and adductor paralysis in the mother and in the son, aged 13, abductor paralysis in the daughters, who were 11 and 5 years old, respectively, and normal laryngeal function in the father and in one 10-year old daughter. There were no neurological signs or mental deficits in any member of the family. Genetic analysis of blood-group and HLA systems confirmed linkage of the HLA system and vocal cord disorder, as suggested by Mace et al. (5). Hence, further observations and investigations will be necessary to prove this statement.

Adolescent↗

Integrative analyses of mendelian randomization and bioinformatics reveal casual relationship and genetic links between COVID-19 and knee osteoarthritis.

BACKGROUND: Clinical and epidemiological analyses have found an association between coronavirus disease 2019 (COVID-19) and knee osteoarthritis (KOA). Infection with COVID-19 may increase the risk of developing KOA. OBJECTIVES: This study aimed to investigate the potential causal relationship between COVID-19 and KOA using Mendelian randomization (MR) and to explore the underlying mechanisms through a systematic bioinformatics approach. METHODS: Our investigation focused on exploring the potential causal relationship between COVID-19, acute upper respiratory tract infection (URTI) and KOA utilizing a bidirectional MR approach. Additionally, we conducted differential gene expression analysis using public datasets related to these three conditions. Subsequent analyses, including transcriptional regulation analysis, immune cell infiltration analysis, single-cell analysis, and druggability evaluation, were performed to explore potential mechanisms and prioritize therapeutic targets. RESULTS: The results indicate that COVID-19 has a one-way impact on KOA, while URTI does not play a causal role in this association. Ribosomal dysfunction may serve as an intermediate factor connecting COVID-19 with KOA. Specifically, COVID-19 has the potential to influence the metabolic processes of the extracellular matrix, potentially impacting the joint homeostasis. A specific group of genes (COL10A1, BGN, COL3A1, COMP, ACAN, THBS2, COL5A1, COL16A1, COL5A2) has been identified as a shared transcriptomic signature in response to KOA with COVID-19. Imatinib, Adiponectin, Myricetin, Tranexamic acid, and Chenodeoxycholic acid are potential drugs for the treatment of KOA patients with COVID-19. CONCLUSIONS: This study uniquely combines Mendelian randomization and bioinformatics tools to explore the possibility of a causal relationship and genetic association between COVID-19 and KOA. These findings are expected to provide novel perspectives on the underlying biological mechanisms that link COVID-19 and KOA.

Humans↗

Semantic relations asserting the etiology of genetic diseases.

Considerable research is being directed at extracting molecular biology information from text. Particularly challenging in this regard is to identify relations between entities, such as protein-protein interactions or molecular pathways. In this paper we present a natural language processing method for extracting causal relations between genetic phenomena and diseases. After presenting the results of preliminary evaluation, we suggest the use of a graphical display application for viewing the semantic predications produced by the system.

Computer Graphics↗

Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans.

Genetic variants that increase the risk for complex diseases persist in human populations, despite adverse effects on health and longevity. Life-history theory predicts that such alleles can be maintained by trade-offs arising from pleiotropy, yet direct genomic evidence has been limited. We asked whether disease-associated variants persist because they enhance reproduction, despite costs to health and lifespan. By analysing genome-wide data across 62 diseases, longevity and fertility, we show that disease-risk alleles are, on average, associated with reduced longevity and increased fertility. Moreover, the subset of alleles that increase both fertility and disease risk appear to have been favoured by natural selection over the past 50,000 years. Using Mendelian randomization, we detect a causal effect of genetic liability to disease on longevity, but no robust evidence for a causal effect on fertility; importantly, these estimates remain stable after adjusting for socioeconomic factors. At the individual level, we compared offspring numbers between affected and unaffected individuals with high polygenic disease risk. For most diseases, affected individuals had more children than unaffected ones. But for early-onset diseases, the pattern reverses, indicating reproductive costs of early morbidity. Together, these results support antagonistic pleiotropy and help explain the persistence of disease-risk alleles in human populations.

Humans↗

Relevance of metabolic polymorphisms to human carcinogenesis: evaluation of epidemiologic evidence.

Genetic modulation of environmental exposures associated with common malignancies (lung and bladder) is an attractive mechanism to explain differential susceptibility to tobacco or occupation related carcinogens in the population. Epidemiologic studies to test the hypothesis of such associations and to evaluate evidence for a causal role for genetic factors in the etiology of chemically-induced tumors are challenging and require the close collaboration of epidemiologists, clinicians and laboratory investigators. In this work we review the evidence for an association of three polymorphisms of drug or xenobiotic metabolism with human cancers. Methodologic considerations and data relevant to evaluating a causal role for each polymorphism are considered. Fair to good support for both an association of the acetylation phenotype with occupationally-related bladder cancer and for an association of the debrisoquine metabolic phenotype and lung cancer is found, although in neither case is the evidence completely convincing. Epidemiologic evidence for the association of aryl hydrocarbon hydroxylase and lung cancer is presently problematic because of difficulties in the assay and subsequent confounding factors. DNA based assays are at various stages of development for each of the genotypes and promise to simplify future studies while introducing new methodologic pitfalls. Further studies in all three areas are warranted as each has important implications for the understanding of the carcinogenic process, etiology and the public health aspects of common malignancies.

Age Factors↗

Tilting at Twindmills: rethinking sociological responses to behavioral genetics.

While we commend Horwitz et al. (2003) for speaking to core issues in behavioral genetics, we disagree with many particulars of their article. We are skeptical of their claims regarding the particular contribution offered by both their methods and data. We believe also that the findings they present as challenging the equal environments assumption are, upon closer examination, not persuasive. Most fundamentally, we worry that the way in which Horwitz et al. conceptualize the relationship between genes and environments is not the best means of doing so for sociologists interested in engaging behavioral genetics.

Adolescent↗

Population genetic structure of Pyrenophora teres Drechs. the causal agent of net blotch in Sardinian landraces of barley (Hordeum vulgare L.).

Monoconidial cultures of Pyrenophora teres, the causal agent of barley net blotch, were isolated from leaves collected from six populations of the barley landrace "S'orgiu sardu" growing in five agro-ecological areas of Sardinia, Italy, and genotyped using AFLPs. The 150 isolates were from lesions of either the "net form" (P. teres f. sp. teres) or the "spot form" (P. teres f. sp. maculata) of the disease. Of 121 AFLP markers, 42%, were polymorphic. Cluster analysis resolved the isolates into two strongly divergent groups (F(ST) = 0.79), corresponding to the net (45% of the isolates) and the spot (55% of the isolates) forms (designated the NFR and SFR groups, respectively). The absence of intermediate genotypes and the low number of shared markers between the two groups indicated that hybridization between the two formae is rare or absent under the field condition of Sardinia. Five of the barley populations hosted both forms but in different proportions. The SFR populations were similar in overall polymorphism to the NFR populations. However, compared to the SFR form, the NFR occurred in all fields sampled and showed a higher population divergence (F(ST) = 0.43 versus F(ST) = 0.09 with all isolates; F(ST) = 0.37 versus F(ST) = 0.06 with clone corrected samples) probably due to a lower migration rate. AFLP fingerprints resolved 117 distinct genotypes among the 150 isolates sampled (78%), 87% in SFR and 68% in NFR isolates. Although the absolute numbers may be a function of the number of AFLP markers assayed, the relative difference suggests that clonality is more prevalent among the NFR isolates (with 11 of 46 haplotypes observed more than once), compared with SFR isolates (7 of 71 haplotypes). Both digenic and multilocus linkage disequilibrium analyses suggested that sexual reproduction occurs at significant levels within the NFR and SFR populations, and that the relative contribution of sexual and asexual reproduction varies among different environments.

Fungi↗

[Aortic aneurysms excluding Marfan's syndrome].

The causal factors of aneurysm are not the same in the ascending and abdominal aorta. Atheroma is the dominant lesion in the abdominal aorta and genetic abnormalities predisposing to "mediacystic necrosis" are more frequently observed in ascending aortic aneurysms. The causal genetic abnormalities are multiple: abnormalities of fibrillin type I in Marfan's syndrome, collagen abnormalities in the Ehlers-Danlos syndrome, abnormalities of microfibrils, possible metallo-proteases, with many gene candidates. Finally, some ascending aortic aneurysms are associated with bicuspid aortic valves, some of which are familial. Familial factors are less evident in abdominal aortic aneurysms: genes favoring atheroma may be responsible but the factors which predispose to dilatation and non stenosis are not well known: they would seem to be general factors because the tendency to arterial dilatation is diffuse. In all cases, because of the high risk of disease in a close relative, a familial enquiry would seem to be justified with echocardiography for close relatives of affected subjects, especially when young and female.

Aortic Aneurysm↗

Causal effects of cholelithiasis on hepatopancreatobiliary diseases: a multi-cohort Mendelian randomization study.

BACKGROUND: Cholelithiasis is commonly associated with multiple hepatopancreatobiliary diseases, yet whether these relationships reflect causal mechanisms or shared risk factors remains unclear. METHODS: We performed a phenome-oriented two-sample Mendelian randomization (MR) analysis to evaluate the causal impact of genetic liability to cholelithiasis across hepatopancreatobiliary outcomes. Independent genome-wide significant variants were selected as instrumental variables. Primary analyses used inverse variance weighting, complemented by sensitivity analyses, reverse MR, and multivariable MR adjusting for body mass index (BMI). RESULTS: Genetic predisposition to cholelithiasis was associated with increased risk of acute pancreatitis and extrahepatic cholangiocarcinoma (eCCA), with consistent directionality across datasets.The association with acute pancreatitis was interpreted as a positive control, whereas the null association with alcohol-induced acute pancreatitis served as a negative control. No causal association was observed for portal vein thrombosis. Sensitivity analyses, including MR-PRESSO and MR Steiger filtering, supported the robustness and directionality of the causal estimates. Reverse MR analyses showed no consistent evidence supporting reverse causality. Multivariable MR indicated that observed effects were not fully explained by BMI-related pathways. CONCLUSION: These findings suggest that cholelithiasis susceptibility may contribute to the broader hepatopancreatobiliary disease network, extending its clinical relevance beyond a localized biliary disorder.

Mendelian Randomization Analysis↗

Experimental demonstration of a causal relationship between heterogeneity of selection and genetic differentiation in quantitative traits.

Comparisons of estimates of genetic differentiation at molecular markers (F(ST)) and at quantitative traits (Q(ST)) are a means of inferring the level and heterogeneity of selection in natural populations. However, such comparisons are questionable because they require that the influence of drift and selection on Q(ST) be detectable over possible background influences of environmental or nonadditive genetic effects on Q(ST)-values. Here we test this using an experimental evolution approach in metapopulations of Arabidopsis thaliana experiencing different levels of drift and selection heterogeneity. We estimated the intensity and heterogeneity of selection on morphological and phenological traits via selection differentials. We demonstrate that Q(ST)-values increased with increasing selection heterogeneity when genetic drift was limited. The effect of selection on Q(ST) was thus detectable despite significant genotype-by-environment interactions that most probably biased the estimates of genetic differentiation. Although they cannot be used as a direct validation of the conclusions of prior studies, our results strongly support both the relevance of Q(ST) as an estimator of genetic differentiation and the role of local selection in shaping the genetic differentiation of natural populations.

Analysis of Variance↗

[Genetics of dilated cardiomyopathy].

Dilated cardiomyopathy is one of the leading causes of heart failure and a primary cause for heart transplantation in patients below the age of 40 years. Despite major advances in diagnostic procedures such as examination of myocardial biopsies, the etiology remains unknown in many patients. Chronic inflammation or myocarditis and chronic alcohol abuse are considered two main etiologic factors in dilated cardiomyopathy. A third causal factor, namely genetic transmission of the disease, is at least as common as myocardial inflammation or toxic damage. Several prospective studies of relatives of patients with dilated cardiomyopathy proved that about 25-30% of all cases are of familial etiology. The most common mode of inheritance is autosomal dominant. Less frequently is the disease inherited as an X-chromosomal trait. Autosomal recessive and mitochondrial transmission is rare. The penetrance is highly variable and age dependent. Many relatives of patients with DCM show only minor cardiac abnormalities and it is unknown whether they progress to full cardiomyopathy in later life. Examination of families has identified so far eight disease genes, namely the dystrophin, tafazzin, cardiac actin, desmin, lamin A/C, delta- sarcoglycan, cardiac beta-myosin heavy chain, and cardiac troponin T gene. Certain mutations in lamin A/C cause conduction system disease and dilated cardiomyopathy, whereas other mutations cause in addition skeletal muscle myopathy. Dystrophin mutations are the cause of the rare X-linked dilated cardiomyopathy without skeletal muscle involvement and a progressive course in young men. Other mutations in the dystrophin gene, mainly deletions, are the cause of the muscular dystrophy Becker and Duchenne which also present with dilated cardiomyopathy. Mutations of the desmin, delta-sarcoglycan, the cardiac actin and beta-myosin heavy chain as well as the troponin T gene are known to cause autosomal dominant-dilated cardiomyopathy without other abnormalities. The infantile X-linked DCM is caused by mutations of the tafazzin gene. The onset of the disease is typically within the first year of life and death occurs usually in childhood. Most patients may in addition be characterized by skeletal myopathy, short stature, neutropenia and abnormal mitochondria, also referred to as Barth syndrome. Knowledge of the DCM disease genes led to the new hypothesis that dilated cardiomyopathy is a disease of the myocardial force generation or force transmission. Many more disease loci are known but the responsible disease genes are not yet identified. Better understanding of the expression and function of disease genes may eventually result in new diagnostic and therapeutic tools in order to improve the prognosis of this severe disorder.

Actins↗

The relationship between major depression, attention-deficit hyperactivity disorder and coronary artery disease: A two-sample Mendelian randomization analysis.

Coronary artery disease (CAD) constitutes a principal cause of global morbidity and mortality. Studies imply a connection between mental health disorders, especially major depression (MD) and attention-deficit hyperactivity disorder (ADHD), and the risk of CAD. To investigate the causal influence of genetic susceptibility to MD and attention-deficit/hyperactivity disorder (ADHD) on the risk of CAD, summary-level data from genome-wide association studies involving individuals of European descent were utilized. This analysis identified 11 single-nucleotide polymorphisms (SNPs) associated with MD, 60 SNPs linked to ADHD, and 10 SNPs related to CAD as instrumental variables. The inverse variance weighted method was employed for causal estimation, complemented by sensitivity analyses using MR-Egger regression and the weighted median estimator. A positive causal relationship was identified between MD, attention-deficit/hyperactivity disorder (ADHD), and the risk of CAD [MD: Odds Ratio (OR): 42.66, 95% Confidence Interval (CI): 7.55-241.2; ADHD: OR: 1.055, 95% CI: 1.006-1.106]. No significant causal association was observed between obesity and ADHD. In the multivariable Mendelian randomization (MVMR) analysis, the causal effect of ADHD on CAD was found to be diminished (OR: 1.005, 95% CI: 0.998-1.020), while the impact of body mass index on CAD remained stable (OR: 1.557, 95% CI: 1.459-1.661). This Mendelian randomization study reveals the lack of a consistent association among MD, ADHD, and CAD, suggesting a causal relationship and bidirectional effects between ADHD and obesity.

Humans↗