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PubMed2026

Investigating the causal role of smoking in gout: A triangulation approach combining NHANES data, genetic correlation, and Mendelian randomization.

The relationship between smoking and the development of gout is not well understood. To address this, we adopted a triangulation framework that integrates observational analysis, genetic correlation estimation, and two-sample Mendelian randomization (MR) to examine whether smoking confers a causal risk for gout. We first performed a cross-sectional analysis using information for 13,626 participants from the National Health and Nutrition Examination Survey between 2013 and 2018. The association of smoking with gout was subsequently assessed through logistic regression models. We next investigated the extent of shared genetic factors between smoking phenotypes and gout. We were able to demonstrate this using the linkage disequilibrium score regression applied to genome-wide association study data of European ancestry. Finally, to verify the causality of our relationship, we carried out a two-sample MR analysis. We selected the inverse-variance weighted (IVW) method and confirmed the consistency of using the IVW method with other statistical methods, including weighted median, weighted mode, and simple mode, as well as MR-Egger regression. We performed sensitivity analyses to investigate the heterogeneity of the hypothesis and stability of the data. Our findings based on National Health and Nutrition Examination Survey data reveal that there is a strong positive association between smoking and the risk of gout (odds ratio [OR]&#x2005;=&#x2005;1.94, 95% confidence interval [CI]&#x2005;=&#x2005;1.48-2.55, P&#x2005;<&#x2005;.001). This association persisted after confounding adjustments (OR&#x2005;=&#x2005;1.41, 95% CI&#x2005;=&#x2005;1.04-1.91, P&#x2005;=&#x2005;.027). In the subgroup analyses, former smokers and current smokers of 10 to 20 cigarettes per day had a substantially increased risk. Post-linkage disequilibrium score regression analysis revealed that the significantly positive genetic correlations of smoking initiation and lifetime smoking index with gout risk were both significantly positive. Additional evidence for causality is presented by MR. Genetic prediction of smoking initiation statistically increases gout risk (IVW OR&#x2005;=&#x2005;1.55, 95% CI&#x2005;=&#x2005;1.26-1.90, P&#x2005;=&#x2005;3.17&#x2005;&#xd7;&#x2005;10-5). A much stronger association is evident for lifetime smoking index (IVW OR&#x2005;=&#x2005;1.99, 95% CI&#x2005;=&#x2005;1.44-2.76, P&#x2005;=&#x2005;3.24&#x2005;&#xd7;&#x2005;10-5). These findings are the same with or without heterogeneity by sensitivity analysis. In light of our integrated analysis, smoking is a causative factor for gout. This suggests that public health interventions like anti-smoking campaigns might reduce gout incidence.

Humans↗
PubMed2003

Genetics and health disparities: fears and realities.

The development and testing of explanatory hypotheses about the underlying mechanisms that create health disparities among ethnic minorities will be crucial in identifying solutions for reducing the current differentials. This paper addresses the potential for using genetic information as a useful and necessary addition to approaches to measures of the "environment" in the study of the origins of health disparities. Approaches and theoretical perspectives on the integration of social science and genetic findings are discussed.

Causality↗
PubMed2005

Drosophila glutathione S-transferases.

The Drosophila glutathione S-transferases (GSTs; EC2.5.1.18) comprise a host of cytosolic proteins that are encoded by a gene superfamily and a homolog of the human microsomal GST. Biochemical studies of certain recombinant GSTs have linked their enzymatic functions to important substrates such as the pesticide DDT and 4-hydroxynonenal, a reactive lipid metabolite. Moreover, a correspondence has been observed between resistance to insecticide substrates-such as DDT-and elevated enzyme levels in resistant strains. Such significant, recurring connections suggest that these gst genes may feature in a model for the development of insecticide resistance. We have amassed substantial biochemical support for relating the overexpression of a particular gst gene to insecticide resistance but are still short of solid genetic evidence to affirm a causal relationship. With the Drosophila system, we have at our disposal genetic and molecular techniques such as p-element mutagenesis and excision, siRNA technology, and versatile transgenic techniques. We can use these methods to effect loss-of-function and gain-of-function conditions and, in these rendered contexts, study other potentially important functions of the gst gene superfamily. An immediate problem that comes to mind is the possible causal relationship between GST substrate specificity and chemical resistance phenotype(s). In this chapter, we present an analysis of selected strategies and laboratory methods that may be useful in pursuing a variety of interesting problems. We will cover three kinds of approaches-biochemistry, genetics, and genomics-as important instruments in a toolkit for studies of the Drosophila gst superfamily. We make the case that these approaches (biochemistry, genetics, and genomics) have helped us gain important insights and can continue to help the community gain a more complete understanding of the biological functions of GSTs. Such knowledge may be key in addressing questions about the detoxification of pesticides and how oxidative stresses affect life span. We hope that these techniques will prove fruitful in studying a host of other physiologic functions as well.

Amino Acid Sequence↗
PubMed1997

Opportunities for psychiatry from genetic findings.

BACKGROUND: The opportunities for psychiatry deriving from available or likely genetic advances are reviewed. METHOD: Clinical implications are considered in the context of both the misconceptions and benefits associated with relevant genetic findings. RESULTS: Misconceptions include that: heritability estimates have a 'true' fixed value; a high heritability means that environmental interventions will be ineffective; a high heritability within groups means that differences between groups will also be due to genes; genetic effects are determinative; 'genetic' means single abnormal genes; genes associated with disease must be bad and justify eugenic measures; gene therapy will be widely applicable; and genetic screening of the general population will be useful. The benefits include demonstrations that: both genes and environment have an ubiquitous influence; some prevailing diagnostic assumptions are mistaken; genes influence development; the effects of nature and nurture are not separate; and environmental effects tend to be person-specific. The potential value of molecular genetics lies in elucidation of causal processes as they apply to both brain systems and nature-nurture interplay; improving diagnosis and genetic counselling; and the development of improved pharmacological interventions. CONCLUSION: Advances in genetics will make a major impact on clinical psychiatry, and should bring practical benefits for both prevention and treatment.

Causality↗
PubMed1996

The implications for responsibility of possible genetic factors in the explanation of violence.

Genetic determinism is unlikely to be true of most human behaviour. The discovery of a genetically based disposition to violent behaviour would not automatically undermine a person's responsibility for such behaviour. The relevant question is not just whether the genetic disposition plays a causal role, but whether it is so strong as to be irresistible. This requires complex evaluation of different kinds of evidence. When genetic causes are combined with others, including environmental ones, the resulting picture of human behaviour may be a more determinist one than we are used to. Such a picture, if it came to be accepted, would not necessarily undermine responsibility. The everyday distinctions between what we can and cannot do would still survive. But understanding the full implications of such a picture would in some ways modify our attitudes and practices. Blame would take a different form, and retributive punishment might come to seen unacceptable.

Genes↗
PubMed2003

Phenotypic and behavioral genetic covariation between elemental cognitive components and scholastic measures.

The study subjected nine elementary cognitive task variables from the Cognitive Assessment Tasks (CAT) and three scholastic measures from the Metropolitan Achievement Test (MAT) to phenotypic and behavioral genetic structural equation modeling based on data for 277 pairs of same sex monozygotic (MZ) and dizygotic (DZ) twins from the Western Reserve Twin Project. Phenotypic and behavioral genetic covariation between certain elemental cognitive components and scholastic performance was examined to determine (a) whether these elemental cognitive components contribute substantially to the variance of scholastic performance; (b) whether such contributions vary across different domains of school knowledge or from specific domains to a general aptitude; (c) the behavioral genetic composition of the elemental cognitive components and the scholastic variables; and (d) how the association between the cognitive components and scholastic performance is genetically and environmentally mediated. The results of the study showed that as much as 30% of the phenotypic variance of scholastic performance was accounted for by the CAT general factor, which was presumably related to mental speed. A mainly genetic covariation was found between the mental speed component and scholastic performance, although each of the two variables was strongly influenced by both heritability and common family environment. The magnitude and etiology of the covariation were largely invariant whether mental speed was related to a common scholastic aptitude or to individual achievement measures covering different knowledge domains. Taken in conjunction with previous findings that mental speed has a substantial genetic correlation with psychometric g, and psychometric g has a mostly genetic covariation with scholastic achievement, the findings of the present study seems to point to a more global picture; namely, there is a causal sequence that starts from mental speed as the explanatory factor for both psychometric g and scholastic performance, and the etiology of the causal link is chiefly genetic.

Child↗
PubMed2000

Linking temperamental fearfulness and anxiety symptoms: a behavior-genetic perspective.

Research on mood and anxiety disorders has historically proceeded without sufficient reference to the growing body of work on the nature of typical emotional development and temperament. Reviewing data from several studies, we consider experiential, biological, and genetic factors as providing causal input to typical developmental variation in fearfulness and anxiety during infancy and early childhood. Longitudinal behavioral methods, psychophysiologic measures, and a behavior-genetic framework are used to approach these issues. Results from twin studies implicate moderately strong genetic influences on different facets of temperamental fearfulness, as well as childhood anxiety symptoms. Then, we consider the distinction between normal range temperament and overt anxiety symptoms from a quantitative genetic perspective. Biological correlates (cortisol, asymmetric frontal EEG activation, cardiac reactivity) of inhibited behavior are considered as related endophenotypes for anxiety. In a nongenetic analysis, we report the prediction of internalizing problems during kindergarten from earlier temperament and earlier basal cortisol measures. Our review highlights connections between behavioral indicators and various putative endophenotypes and the fuzzy boundary between normal-range temperament and anxiety disorders.

Anxiety↗
PubMedDate not supplied

Canine limbal melanoma: 30 cases (1992-2004). Part 1. Signalment, clinical and histological features and pedigree analysis.

OBJECTIVES: (1) To review the signalment, clinical, and histological features of canine limbal melanoma; (2) to perform pedigree analysis on breeds predisposed to limbal melanoma to establish if common ancestry exists; and (3) to investigate if any ancestral relationship exists between canine limbal melanoma and canine anterior uveal melanoma (CAUM). DESIGN: Retrospective study. ANIMALS STUDIED: Thirty dogs with limbal melanoma. METHODS: Medical records of patients were reviewed. Follow-up information was obtained by re-examination of patients or telecommunications with the referring veterinary surgeons or the owners. Pedigrees were analyzed for common ancestry amongst affected dogs. RESULTS The mean age (+/- SD) at diagnosis was 6.2 (+/- 2.75) years with a range from 1 to 11 years. There was a bimodal distribution of ages with a peak at 3-4 years and a peak at 7-10 years. There was no eye predilection or predisposition for sex or coat color. Twenty-five (83%) of the limbal melanomas occurred within a dorsal arc from the dorsomedial to the ventrolateral limbus. Golden retrievers were four times more common in the melanoma group compared to the Animal Health Trust population (P < 0.0001). Labrador retrievers were three times more common in the melanoma group (P=0.01). Pedigree analysis on eight Golden retrievers [limbal melanoma (n=5), CAUM (n=2) and diffuse ocular melanosis (n=1)], revealed a pattern of inter-relatedness consistent with the condition(s) being caused, at least in part, by a genetic mutation(s). A similar level of inter relatedness was evident in six Labrador retrievers (limbal melanoma (n=2) and CAUM (n=4)). In 5/22 cases (23%), histological features suggestive of malignancy were present including intratumor necrosis in 4/22 cases (18%) and cellular atypia in 1/22 cases (5%). CONCLUSIONS: In Golden and Labrador retrievers there is evidence that limbal melanomas, CAUM and ocular melanosis are at least in part heritable and that the same genetic mutation(s) may be causally associated with melanocytic disease at different ocular sites. The same genetic mutation(s) may be present in these two breeds. Histology should be performed on all cases to identify those with greater malignant potential.

Age Factors↗
PubMed2026

Dissecting the shared genetic architecture between migraine subtypes and cardiovascular diseases: a multi-layered genomic analysis.

BACKGROUND: Epidemiological studies have linked migraine to an increased risk of cardiovascular disease (CVD); however, the shared genetic basis and putative causal relationships between migraine subtypes and cardiovascular traits remain poorly understood. METHODS: Leveraging large-scale GWAS summary statistics for migraine phenotypes (overall migraine, migraine with aura [MA], and migraine without aura [MO]) from FinnGen R12, along with seven cardiovascular diseases from publicly available consortia, we conducted a multi-layered genetic analysis. This integrative framework encompassed genetic correlation [linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL)], cross-trait meta-analysis (CPASSOC and PLACO), Bayesian colocalization, summary-data-based Mendelian randomization (SMR) using GTEx v8 eQTL data, and bidirectional two-sample Mendelian randomization (MR). RESULTS: Significant genetic correlations were identified between migraine and multiple cardiovascular traits, with hypertension and coronary artery disease (CAD) showing the most robust associations. MA exhibited broader genetic overlap with cardiovascular diseases than MO, including a notably stronger correlation with ischemic stroke, whereas MO demonstrated a stronger correlation with hypertension. Cross-trait meta-analysis identified 160 pleiotropic loci across 17 of 21 trait pairs. Colocalization analysis confirmed 32 loci harboring shared causal variants, mapped to 13 candidate genes, of which 7 (PHACTR1, LRP1, SOX7, ABO, FHOD3, MEI1, XKR6) were further validated by SMR as exhibiting tissue-specific regulatory effects. Among these, PHACTR1 displayed the broadest pleiotropic profile across migraine phenotypes and vascular diseases. After MR-PRESSO outlier removal, bidirectional MR identified 10 MR-supported associations, two of which (genetic liability to hypertension on overall migraine, and CAD on MA) survived Bonferroni correction, all free of detectable horizontal pleiotropy. Genetic liability to hypertension was associated with increased migraine risk (OR&#x2009;=&#x2009;1.90, 95% CI 1.25-2.90, P&#x2009;=&#x2009;2.64&#x2009;&#xd7;&#x2009;10&#x207b;&#xb3;), atherosclerotic diseases showed subtype-specific effects (inverse for MO, positive for MA), and, in the reverse direction, migraine was associated with increased ischemic stroke risk. CONCLUSIONS: This study provides a comprehensive and systematic characterization of the shared genetic architecture between migraine subtypes and cardiovascular diseases. By identifying pleiotropic genes and bidirectional putative causal relationships with subtype-specific patterns, our findings carry implications for the development of targeted therapeutics and subtype-specific cardiovascular risk stratification.

Humans↗
PubMed1999

Human retinoic X receptor beta: complete genomic sequence and mutation search for ossification of posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by ectopic bone formation in the ligament. OPLL is a very common disorder, in fact it constitutes the leading cause of myelopathy among Japanese. In the previous report, we provided the genetic linkage evidence that the genetic susceptibility of OPLL mapped to HLA complex of chromosome 6. As a candidate gene approach, retinoic X receptor beta (RXR beta), assigned to chromosome 6p21.3 adjacent to HLA class II, was analyzed for a possible causality. To start screening for the molecular variants of RXR beta in OPLL subjects, we first obtained P1 phage genomic clones containing the entire human RXR beta and elucidated the genomic organization of the gene. The human RXR beta is composed of 10 exons spanning over 6.2 kb of genomic DNA. Sequence analysis of the promoter region revealed a GC-rich sequence without TATA motif. We have identified three distinct molecular variants, one was in exon 10 and two were in the intergenic region between RXR beta and collagen 11A2 (COL11A2). Two variants in the intergenic region, 3' end + 140 and 3' end + 561, exhibit statistically significant associations with OPLL in case-control study (p = 0.0028 for 3' end + 140 and p = 0.034 for 3' end + 561). These results indicate that the genetic causality of OPLL lies within or close to the RXR beta/COL11A2 locus.

Adult↗
PubMed2005

The general public's information needs and perceptions regarding hereditary cancer: an application of the Integrated Change Model.

The Integrated Change Model (the I-Change Model) was used to analyse the general public's need and perceptions concerning receiving information on the role of hereditary factors with regard to cancer. The results from a study in 457 Dutch adults showed that 25% correctly indicated the types of cancer where hereditary factors can play a role. Respondents, however, overestimated the role of hereditary factors causing breast cancer. Recognition of warning signs was low, as was the recognition of inheritance patterns. Participants wanted to know the types of cancer with hereditary aspects, how to recognise hereditary cancer in the family, personal risks and the steps to be taken when hereditary predisposition is suspected. The most popular information channels mentioned were leaflets, the general practitioner, and the Internet. Respondents interested in receiving information on heredity and cancer were more often female, had had experiences with hereditary diseases, had more knowledge, perceived more advantages, encountered more social support in seeking information, and had higher levels of self-efficacy. Education should outline the most important facts about hereditary cancer, how to get support, and create realistic expectations of the impact of genetic factors.

Adolescent↗
PubMed2006

Utilization of a whole genome SNP panel for efficient genetic mapping in the mouse.

Phenotype-driven genetics can be used to create mouse models of human disease and birth defects. However, the utility of these mutant models is limited without identification of the causal gene. To facilitate genetic mapping, we developed a fixed single nucleotide polymorphism (SNP) panel of 394 SNPs as an alternative to analyses using simple sequence length polymorphism (SSLP) marker mapping. With the SNP panel, chromosomal locations for 22 monogenic mutants were identified. The average number of affected progeny genotyped for mapped monogenic mutations is nine. Map locations for several mutants have been obtained with as few as four affected progeny. The average size of genetic intervals obtained for these mutants is 43 Mb, with a range of 17-83 Mb. Thus, our SNP panel allows for identification of moderate resolution map position with small numbers of mice in a high-throughput manner. Importantly, the panel is suitable for mapping crosses from many inbred and wild-derived inbred strain combinations. The chromosomal localizations obtained with the SNP panel allow one to quickly distinguish between potentially novel loci or remutations in known genes, and facilitates fine mapping and positional cloning. By using this approach, we identified DNA sequence changes in two ethylnitrosourea-induced mutants.

Animals↗
PubMedDate not supplied

New insights into the genetics of multiple sclerosis.

Tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develop in genetically susceptible individuals after exposure to a causal agent that is yet undefined. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, posttranscriptional regulatory mechanisms, and significant environmental influences. Equally significant is that genetic heterogeneity also likely exists, meaning that specific genes influence susceptibility and pathogenesis in some affecteds but not in others. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen significant progress in the developments of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and to define the pathological basis of demyelination. These developments have set the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. The identification and characterization of the genes are likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.

Female↗
PubMedDate not supplied

Genetics: changing health care in the 21st century.

Advances in human genetics are rapidly changing the scope of information and care that can be provided to health care consumers. By the year 2005 it is expected that the entire human genome will be mapped and all 70,000-100,000 genes will be identified. Currently, there are more than 5,000 known single-gene disorders. With the movement of specialized health services into the primary care setting, nurses increasingly will need to be knowledgeable about genetic disorders, screening/diagnostic tests, and implications for health care. In addition, the management of genetic information raises issues of informed consent, privacy and confidentiality, truth telling and disclosure, and nondiscrimination.

Causality↗
PubMed2026

Multiple metabolic factors and kidney dysfunction: Causal evidence and translational insights from a mendelian randomization study.

Chronic kidney disease is a major global public health burden. This study investigated the causal effects of systolic blood pressure (SBP), apolipoprotein B (ApoB), and serum urate on renal function and albuminuria, and explored potential mechanistic implications. Two-sample Mendelian randomization (MR) analyses were conducted using large-scale genome-wide association study summary statistics from European populations. Univariable MR estimated total causal effects on estimated glomerular filtration rate (eGFR) and albuminuria. Multivariable MR assessed independent effects of correlated exposures, and 2-step MR evaluated albuminuria as a mediator. Cis-MR analyses were performed to explore target-proximal genetic evidence for lipid-related drug targets. Genetically predicted SBP was causally associated with reduced eGFR, while ApoB was inversely associated with albuminuria risk. serum urate showed no significant causal effects. Multivariable and mediation analyses supported distinct roles of SBP and ApoB, with albuminuria partially mediating the SBP-eGFR association. Cis-MR analyses indicated heterogeneous renal effects of lipid-lowering targets. These findings provide genetic evidence linking SBP to renal dysfunction, suggest that albuminuria may partially mediate the association between SBP and renal function, and highlight the complex renal relevance of lipid-related pathways.

Mendelian Randomization Analysis↗