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PubMed1989

Immune response to BCG-Moreau (Rio de Janeiro) strain. Spectrum of delayed hypersensitivity in genetically defined mice.

Generation of delayed hypersensitivity (DTH) in genetically defined mice immunized with Mycobacterium bovis BCG of the Moreau (Rio de Janeiro) strain was studied. This vaccine strain has been reported as the most virulent and able to induce strong tuberculin sensitivity. Mice were selected by the expression of Bcg gene trait, by responsiveness to mycobacterial antigens and H2 haplotype. DTH was evaluated by the ear-swelling test of mice immunized subcutaneously with live BCG at doses ranging from 1 microgram to 1000 micrograms. A survey of inbred strains of mice showed H2b and H2q mice as high responders, H2d as an intermediate responder, H2k as a low responder and H2a as a non-responder. Study of H2-congenic pairs of high and non-responder strains showed significant DTH in all mice independently of the genetic background and H2 haplotype. A mouse strain expressing Bcg (r) trait displayed DTH superior to a Bcg (s) strain. Comparison of DTH response of strains expressing Bcg (r) or (s) trait showed no relationship between the Bcg locus and DTH to mycobacteria. These data suggest DTH is under polygenic control including the major histocompatibility complex but excluding the Bcg locus.

Animals↗
PubMed2004

Killer cell inhibitory receptors involved in graft-versus-host disease and graft-versus-leukemia effect in allogeneic hematopoietic stem cell transplantation - review.

Killer cell inhibitory receptors (KIR) are members of the immunoglobulin superfamily (Ig-SF) and transmembrane molecules type I expressed on human natural killer cells and some T lymphocytes. They are ligands for HLA class I antigens. According to the "missing-self" hypothesis, KIR deliver inhibitory signals that prevent target-cell lysis upon binding to the self MHC class I antigens. KIR regulates NK cell function concerned with the control graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (HSCT). The KIR repertoire is substantially influenced by the polymorphic and polygeneic nature of the KIR gene family, and there exist the polymorphism of KIR ligands mainly HLA-C molecule. So it is difficult to achieve the beneficial effect of NK cells on the outcome of partly HLA-mismatched hematopoietic cell transplantation. This review aims to provide background and previous observations on the KIRs which are thought to influence the outcome of HSCT.

Animals↗
PubMed2005

Recurring challenges from a necrotrophic fungal plant pathogen: a case study with Leptosphaeria maculans (causal agent of blackleg disease in brassicas) in Western Australia.

BACKGROUND: Blackleg disease of Brassica napus, caused by the necrotrophic fungus Leptosphaeria maculans, causes severe yield losses in Australia, Europe and Canada. In Western Australia, it nearly destroyed the oilseed rape industry in 1972 when host genotypes and conducive environmental conditions favoured severe epidemics. The introduction of cultivars with polygenic resistance and the adoption of sound cultural practices two decades later helped to manage the disease. These were abandoned by many farmers in recent years in favour of the effective but ephemeral resistance conferred by the single dominant gene-based resistance derived from B. rapa ssp. sylvestris. Recently, several cultivars carrying this gene have collapsed widely within a period of 3 years after their commercial release. An environment conducive to the disease and the association of the pathogen with susceptible hosts in Western Australia for over 80 years together have led to the proliferation of L. maculans races, amounting to half of all races delineated to date from Europe, including the United Kingdom, Canada and Australia. SCOPE: This review demonstrates the problems that emerge when traditional cultural practices employed, along with cultivars containing polygenic resistance to a serious necrotrophic pathogen, are discarded in preference to the exclusive deployment of effective but ephemeral single dominant gene-based resistance to the disease across Southern Australia. CONCLUSIONS: Single dominant gene-based resistance currently available, on its own, will not confer durable resistance to blackleg disease in oilseed rape. Return to earlier management practices, including reliance upon polygenic resistance and induced resistance, may be the best currently available options to maintain production in regions across Southern Australia predisposed to severe epidemics.

Ascomycota↗
PubMed2004

The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis.

Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130F759/F759 mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130F759/F759 mice, including lymphoadenopathy, splenomegaly, hyper-gamma-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC(bright) CD11c+ population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6-/-/gp130F759/F759/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130F759/F759/pX-Tg is a unique mouse model for RA.

Animals↗
PubMed2003

Strategy and model building in the fourth dimension: a null model for genotype x age interaction as a Gaussian stationary stochastic process.

BACKGROUND: Using univariate and multivariate variance components linkage analysis methods, we studied possible genotype x age interaction in cardiovascular phenotypes related to the aging process from the Framingham Heart Study. RESULTS: We found evidence for genotype x age interaction for fasting glucose and systolic blood pressure. CONCLUSIONS: There is polygenic genotype x age interaction for fasting glucose and systolic blood pressure and quantitative trait locus x age interaction for a linkage signal for systolic blood pressure phenotypes located on chromosome 17 at 67 cM.

Adult↗
PubMed1992

Polygenic nature of spontaneous diabetes in the rat. Permissive MHC haplotype and presence of the lymphopenic trait of the BB rat are not sufficient to produce susceptibility.

We describe the phenotypic characteristics of animals in the fifth backcross-intercross generation of a breeding program in which the RT1 u haplotype and the phenotypic trait responsible for the T-lymphopenia of BB rats have been transferred to the ACI background. In this generation of animals, 24% were lymphopenic with decreased numbers of PBL expressing CD5, TCR alpha, and RT6. The PBL of the lymphopenic animals had a decreased mitogenic response to ConA. All of the nonlymphopenic animals were homozygous for RT6.2. Phenotypic analysis of intestinal IEL revealed that this was also the case for the lymphopenic animals. Moreover, IEL of the lymphopenic animals exhibited a pattern of staining (increased numbers of TCR alpha beta+CD4+CD8+ and decreased numbers of TCR alpha beta+CD4-CD8+) similar to that of BB DP animals. The ACI.1U(BB)-lymphopenic animals, although having two of the genetic traits associated with the expression of spontaneous diabetes mellitus, uniformly fail to develop diabetes. Breeding studies in which these animals were crossed with BB and hBB rats suggest that other genes are necessary for development of overt diabetes.

Animals↗
PubMed1995

Familial hypercholesterolemia: molecular, biochemical, and clinical characterization of a French-Canadian pediatric population.

BACKGROUND: Familial hypercholesterolemia (FH) is a dominantly-inherited disorder attributable to a defect in the low-density lipoprotein (LDL) receptor gene. Five mutations at this locus have been identified in French-Canadians. In children, it may be difficult to clinically distinguish FH from other forms of polygenic or monogenic hyperlipidemia. Therefore, our objectives were to define the molecular basis of our subjects' hypercholesterolemia, to characterize their biochemical phenotype in relation to the underlying molecular defect, and to assess their response to chronic dietary therapy. METHODS: We studied 88 unrelated French-Canadian children with a persistent increase in LDL cholesterol and a parental history of hyperlipidemia. Baseline and end-of-diet lipid and apolipoprotein levels were measured. Mutational analysis at the LDL receptor gene locus was performed. RESULTS: Heterozygosity for the common French-Canadian LDL receptor gene > 10-kb deletion was found in 57% of subjects (group 1), 14% carried one of the other four previously characterized LDL receptor gene mutations (group 2), and none of the five molecular defects tested was detected in 29% (group 3). Total cholesterol, LDL cholesterol, and apolipoprotein B baseline levels were similar among these three groups but significantly higher than in control subjects. However, there was wide interindividual variability even among those carrying the same mutation. Significantly lower baseline levels of high-density lipoprotein cholesterol and apolipoprotein A1 were found in group 1 compared with group 3 and the controls. The response to diet was similar among the three groups with an average reduction in the mean level of total cholesterol of 4.4%. CONCLUSIONS: The frequency of proven FH heterozygotes (71%) was remarkable in the pediatric population studied. Our data suggest that, in children, a persistent primary increase in LDL cholesterol associated with a parental history of hyperlipidemia is a good predictor of an underlying monogenic disorder as opposed to a polygenic disorder, at least in French-Canadians. Only molecular analysis allowed us to unequivocally define the cause of our patients' hypercholesterolemia. Most children with familial hyperlipidemia did not reach desirable plasma lipid levels solely under diet therapy.

Adolescent↗
PubMed1989

The genetics of diabetes susceptibility in mice.

The factors associated with a diabetes-susceptible genotype in mice exhibiting various forms of heritable glucose intolerance syndromes are discussed. Genetic models of insulin-dependent and non-insulin-dependent diabetes in mice are described. Although single gene mutations can be defined for each model that are major contributors to diabetogenic stress, polygenic interactions are required for the expression of a diabetic phenotype, and environmental factors are also contributory. Several strongly penetrant single gene mutations are capable of affecting obesity and insulin-resistant states. Analysis of inbred strain genomic interactions with one of these recessive obesity-producing genes, diabetes (db), suggests that development of a diabetic phenotype is dependent on the strength of an interaction between the db gene and sulfotransferase enzymes. Specifically, diabetes-susceptible vs. resistant inbred strain backgrounds can be distinguished by the extent to which the db mutation elicits an accelerated sequestration by sulfoconjugation of tissue estrogens while androgens remain free. In a male gender- (and Y chromosome-)associated model of transient glucose intolerance, stress as well as a requirement for both adrenal and testicular secretions are each components of the susceptibility background. In the obesity-associated diabetes models, autoimmunity, when it occurs, is a secondary reflection of pancreatic beta cell destruction. The nonobese diabetic (NOD) mouse, in contrast, represents a model in which autoimmunity against beta cells is a primary event in the development of insulin-dependent diabetes. In NOD mice, a gene that is either the unique class II gene in the major histocompatibility complex or is in linkage disequilibrium with this complex makes a major (recessivelike) contribution to diabetes susceptibility. However, diabetogenesis can be mediated only through a multifactorial interaction among this susceptibility locus and multiple unlinked genetic loci regulating immune responsiveness. In addition, the NOD mouse represents one of the best models of diabetes available for demonstrating a critical interaction between heredity and environmental factors. The polygenic nature of the various heritable forms of glucose intolerance syndromes in mice points to a comparable or even greater genetic heterogeneity underlying the major types of diabetes in humans.

Animals↗
PubMed1999

The R576 IL-4 receptor alpha allele correlates with asthma severity.

BACKGROUND: Atopic disorders, including asthma, are very prevalent, affecting up to 40% of populations, and their incidence is on the rise. Although environmental factors are important in the development of atopy, there is a strong genetic predisposition. Several genes and chromosomal regions have been linked to atopy and asthma, supporting the polygenic nature of these disorders. IL-4 and IL-13 are T(H)2 cytokines with numerous activities that contribute to allergic inflammation and asthma. Both IL-4 and IL-13 use the IL-4 receptor alpha chain (IL-4Ralpha) as a component of their respective receptor systems. Allelic variants of IL-4Ralpha have been reported, and the R576IL-4Ralpha allele was recently shown to be a risk factor for atopy. OBJECTIVE: We sought to determine whether the R576 allele was associated with the prevalence or clinical severity of asthma. METHODS: We developed a rapid, reliable, PCR-based assay to screen individuals for the R576IL-4Ralpha allele and used this assay to genotype prospectively recruited individuals with asthma (n = 149) and control subjects (n = 57). RESULTS: There was a strong association of R576IL-4Ralpha with the prevalence and clinical severity of asthma. In a prospective cohort, homozygosity for R576 was significantly increased in individuals with asthma (n = 149, P =.03; relative risk 8.2) compared with controls (n = 57). Furthermore, 1 or 2 copies R576IL-4Ralpha correlated with asthma severity establishing a genotype-phenotype relationship and suggesting a gene dosage effect. CONCLUSIONS: Thus R576IL-4Ralpha acts as an allergic asthma susceptibility and disease-modifying gene and may serve as a clinically useful marker of asthma severity.

Adult↗
PubMed1995

A general method for identifying major hybrid male sterility genes in Drosophila.

The genes responsible for hybrid male sterility in species crosses are usually identified by introgressing chromosome segments, monitored by visible markers, between closely related species by continuous backcrosses. This commonly used method, however, suffers from two problems. First, it relies on the availability of markers to monitor the introgressed regions and so the portion of the genome examined is limited to the marked regions. Secondly, the introgressed regions are usually large and it is impossible to tell if the effects of the introgressed regions are the result of single (or few) major genes or many minor genes (polygenes). Here we introduce a simple and general method for identifying putative major hybrid male sterility genes which is free of these problems. In this method, the actual hybrid male sterility genes (rather than markers), or tightly linked gene complexes with large effects, are selectively introgressed from one species into the background of another species by repeated backcrosses. This is performed by selectively backcrossing heterozygous (for hybrid male sterility gene or genes) females producing fertile and sterile sons in roughly equal proportions to males of either parental species. As no marker gene is required for this procedure, this method can be used with any species pairs that produce unisexual sterility. With the application of this method, a small X chromosome region of Drosophila mauritiana which produces complete hybrid male sterility (aspermic testes) in the background of D. simulans was identified. Recombination analysis reveals that this region contains a second major hybrid male sterility gene linked to the forked locus located at either 62.7 +/- 0.66 map units or at the centromere region of the X chromosome of D. mauritiana.

Animals↗
PubMed1990

Hybrid dysgenesis-induced quantitative variation on the X chromosome of Drosophila melanogaster.

To determine the ability of the P-M hybrid dysgenesis system of Drosophila melanogaster to generate mutations affecting quantitative traits, X chromosome lines were constructed in which replicates of isogenic M and P strain X chromosomes were exposed to a dysgenic cross, a nondysgenic cross, or a control cross, and recovered in common autosomal backgrounds. Mutational heritabilities of abdominal and sternopleural bristle score were in general exceptionally high-of the same magnitude as heritabilities of these traits in natural populations. P strain chromosomes were eight times more mutable than M strain chromosomes, and dysgenic crosses three times more effective than nondysgenic crosses in inducing polygenic variation. However, mutational heritabilities of the bristle traits were appreciable for P strain chromosomes passed through one nondysgenic cross, and for M strain chromosomes backcrossed for seven generations to inbred P strain females, a result consistent with previous observations on mutations affecting quantitative traits arising from nondysgenic crosses. The new variation resulting from one generation of mutagenesis was caused by a few lines with large effects on bristle score, and all mutations reduced bristle number.

Animals↗
PubMed2004

Differential hepatic gene expression in a polygenic mouse model with insulin resistance and hyperglycemia: evidence for a combined transcriptional dysregulation of gluconeogenesis and fatty acid synthesis.

New Zealand obese (NZO) mice exhibit severe insulin resistance of hepatic glucose metabolism. In order to define its biochemical basis, we studied the differential expression of genes involved in hepatic glucose and lipid metabolism by microarray analysis. NZOxF1 (SJLxNZO) backcross mice were generated in order to obtain populations with heterogeneous metabolism but comparable genetic background. In these backcross mice, groups of controls (normoglycemic/normoinsulinemic), insulin-resistant (normoglycemic/hyperinsulinemic) and diabetic (hyperglycemic/hypoinsulinemic) mice were identified. At 22 weeks, mRNA was isolated from liver, converted to cDNA, and used for screening of two types of cDNA arrays (high-density filter arrays and Affymetrix oligonucleotide microarrays). Differential gene expression was ascertained and assessed by Northern blotting. The data indicate that hyperinsulinemia in the NZO mouse is associated with: (i) increased mRNA levels of enzymes involved in lipid synthesis (fatty acid synthase, malic enzyme, stearoyl-CoA desaturase) or fatty acid oxidation (cytochrome P450 4A14, ketoacyl-CoA thiolase, acyl-CoA oxidase), (ii) induction of the key glycolytic enzyme pyruvate kinase, and (iii) increased mRNA levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects were enhanced by a high-fat diet. In conclusion, the pattern of gene expression in insulin-resistant NZO mice appears to reflect a dissociation of the effects of insulin on genes involved in glucose and lipid metabolism. The data are consistent with a hypothetical scenario in which an insulin-resistant hepatic glucose production produces hyperinsulinemia, and an enhanced insulin- and substrate-driven lipogenesis further aggravates the deleterious insulin resistance of glucose metabolism.

Animals↗
PubMed2000

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

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

Cross-Cultural Comparison↗
PubMed1996

Immunosusceptibility genes in rheumatoid arthritis.

The polygenic predisposition to RA is conferred particularly by disease susceptibility sequences in the HVR3 of HLA DRB1 present in those subtypes of DR4 and DR1 that are associated with RA. The aim of this study was to examine predisposing interactions between genes encoding HLA and immunoglobulin molecules. Accordingly, we compared the genetic background of 114 Australian patients with RA with that of Australian controls of similar ethnic background. We identified HLA-A, B, and DR phenotypes serologically, HLA-DR, DQ alleles, and subtypes of DR4 by DNA typing, and Gm allogenotypes and immunoglobulin switch region polymorphisms by RFLP. For the subjects with RA, we confirmed previously reported observations that included an excess of females, 71%, a high frequency of HLA types DR4 or DR1 of 77% versus controls 47%, and a high frequency of the HVR3 susceptibility sequences of 76%, with 24% homozygous, and 52% heterozygous for the sequences. We observed other genetic correlations in RA that included increases in frequencies of DR4 in males, DR1 in females, the class I specificity HLA-B27 overall but more particularly in females, 24% in females, versus 5% of controls, HLA-DQB1*0302 (DQ8) in DR4*0401-positive patients, and the Gm allogenotype 1,2,3;23 +/- ; 5,10, 15% of patients versus 4% of controls. Examination of switch region genes gave no evidence of differences in the polymorphisms distributions. Thus, the major genetic risks for RA that are conferred by female gender and the HVR3 of HLA DRB1 are modulated by interactions between gender and HLA class I and class II alleles, and the Gm allogenotype.

Adult↗
PubMed2026

Genetic heterogeneity affects the risk of incident depression, comorbidity, and response to environment: A prospective trajectory study.

BACKGROUND: Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored. METHODS: First, depression risk loci from a large-scale genome-wide meta-analysis were annotated to Gene Ontology (GO) terms by functional enrichment. GO-based polygenic risk scores (GO-PRS) were then calculated for individuals in the UK Biobank. Principal component analysis (PCA) was applied for dimensionality reduction, followed by cluster analysis to identify genetic subtypes of depression. Multistate models were applied to assess the impact of genetic patterns on the trajectory from healthy status to incident depression, and depression to 26 subsequent diseases, as well as the associations between environmental factors and disease trajectories across genetic subtypes. RESULTS: Participants were categorized into three genetic subtypes: immune-dominant, neuro-dominant, and comprehensive-risk. Significant differences in risk of depression and subsequent diseases, and susceptibility to environmental factors were observed across subtypes. Comprehensive-risk subtype showed higher risks of depression compared to immune-dominant (HR: 1.10, 95% CI: 1.05-1.15) and neuro-dominant subtype (HR: 1.12, 95% CI: 1.08-1.16). Comprehensive-risk subtype exhibited higher risks of transition from depression to subsequent diseases, such as anemia compared to immune-dominant subtype, and diseases of the digestive system compared to neuro-dominant subtype. Environmental factors were more strongly associated with the transition from depression to subsequent diseases in immune-dominant and comprehensive-risk subtypes, including cardiovascular, respiratory, and metabolic diseases. CONCLUSIONS: Our findings highlight the genetic heterogeneity of depression and comorbidities, and shed light on how genetic components modulate responses to environmental factors.

Humans↗
PubMed2005

Allele-specific CAPS markers based on point mutations in resistance alleles at the pvr1 locus encoding eIF4E in Capsicum.

Marker-assisted selection has been widely implemented in crop breeding and can be especially useful in cases where the traits of interest show recessive or polygenic inheritance and/or are difficult or impossible to select directly. Most indirect selection is based on DNA polymorphism linked to the target trait, resulting in error when the polymorphism recombines away from the mutation responsible for the trait and/or when the linkage between the mutation and the polymorphism is not conserved in all relevant genetic backgrounds. In this paper, we report the generation and use of molecular markers that define loci for selection using cleaved amplified polymorphic sequences (CAPS). These CAPS markers are based on nucleotide polymorphisms in the resistance gene that are perfectly correlated with disease resistance, the trait of interest. As a consequence, the possibility that the marker will not be linked to the trait in all backgrounds or that the marker will recombine away from the trait is eliminated. We have generated CAPS markers for three recessive viral resistance alleles used widely in pepper breeding, pvr1, pvr1 (1), and pvr1 (2). These markers are based on single nucleotide polymorphisms (SNPs) within the coding region of the pvr1 locus encoding an eIF4E homolog on chromosome 3. These three markers define a system of indirect selection for potyvirus resistance in Capsicum based on genomic sequence. We demonstrate the utility of this marker system using commercially significant germplasm representing two Capsicum species. Application of these markers to Capsicum improvement is discussed.

Alleles↗
PubMed2026

Joint effects of childhood adversity and genetic risk for psychosis on psychopathology in the UK Biobank.

BACKGROUND: The individual effects of genetic factors and adverse childhood experiences (ACEs) on risk of psychosis, including schizophrenia (SCZ) and bipolar disorder (BIP), have been widely acknowledged, but their interaction effects on individual psychopathological symptoms remain unclear. METHODS: Based on data from 163,704 individuals in the UK Biobank, we investigated the joint effects of polygenic risk scores (PRSs) of SCZ and BIP and ACEs on psychopathology. ACEs status and 55 psychopathological symptoms from seven domains were measured retrospectively using an online mental health questionnaire in 2016. Recent genome-wide association studies for SCZ and BIP were combined with genotype data to generate PRSs. Logistic regression analyses were then conducted to explore univariate and joint main effects of PRSs and ACEs on psychopathological symptoms, as well as their additive and multiplicative interaction effects. RESULTS: The interaction mechanisms for PRSs and ACEs varied across symptom domains: additive interactions were observed on the depression (RERIBIP-ACEs = 0.20-0.25), anxiety (RERISCZ-ACEs = 0.20; RERIBIP-ACEs = 0.22-0.26), help-seeking (RERISCZ-ACEs = 0.24; RERIBIP-ACEs = 0.23), and cognition domains (RERISCZ-ACEs = -0.23 to -0.17), whereas multiplicative interactions were only detected on the psychotic (betaSCZ-ACEs = -0.543; betaBIP-ACEs = -0.181), mania (betaBIP-ACEs = -0.195), self-harm or suicide (betaSCZ-ACEs = -0.118), and cognitive domains (betaSCZ-ACEs = -0.204 to -0.157). CONCLUSIONS: The interplay mechanisms for genetic liability to SCZ and BIP and ACEs vary across symptom domains. This study reveals heterogeneity in gene-ACEs interaction mechanisms underlying psychosis and may provide personalized guidance for psychological care after ACEs.

Humans↗
PubMed2005

Segregation of urine calcium excretion in families ascertained for nephrolithiasis: evidence for a major gene.

BACKGROUND: The quantitative genetics of urine calcium excretion has not been established. It is a trait of interest because hypercalciuria is commonly found in subjects with nephrolithiasis. The aim of this study was to model the segregation of this trait in a sample of French-Canadian families ascertained through a stone former. METHODS: Major gene, polygenic, and mixed models were fit to 24-hour urine calcium excretion from 567 individuals in 221 nuclear families, while simultaneously taking into account gender, age at examination, body mass index (BMI), and the use of thiazide drugs. The nuclear families were extracted from 154 pedigrees, some of which were four generations, with at least two siblings with a history of calcium stones. RESULTS: All the proposed genetic models fit the data significantly better than the null model. The most parsimonious model was the mixed codominant/polygenic model but it was statistically indistinguishable from the single-gene codominant model. In both of these models the heritability attributable to the major gene was estimated to be 0.58. CONCLUSION: Our results suggest that a major gene with a relatively large effect on variation in urine calcium excretion is segregating in French-Canadian families with stone formers. This implies that the power of quantitative trait segregation analysis of urine calcium excretion may be increased in these families, and results indicate that it should be feasible to genetically map the quantitative trait locus.

Adult↗