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Results for “Mendelian Randomization Analysis”

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PubMed1996

Segregation analysis of two lung function indices in a random sample of young families: the Humboldt Family Study.

The Humboldt Family Study was conducted in the town of Humboldt, Saskatchewan, in 1993. Familial correlations and segregation analyses of lung function were carried out in 799 individuals in 214 nuclear families that included 214 fathers, 214 mothers, and 371 children. Forced expiratory volume in 1 second (FEV1) and maximal mid-expiratory flow rate (MMFR) were first regressed on age, height, weight, and their quadratic and cubic terms as well as on smoking status in four groups separately (mothers, fathers, daughters, and sons), with terms significant at the 0.10 level being retained. Residual phenotypes were standardized within the four groups. Class D regressive models were used to perform familial correlations and segregation analyses. For both FEV1 and MMFR, father-mother correlations were not significantly different from zero, and mother-offspring, father-offspring, and sibling-sibling correlations showed no statistically significant difference from each other. Based on the "polygenic" models, the estimated intraclass correlation is 0.132 (+/- 0.035) for FEV1 and 0.171 (+/- 0.039) for MMFR, and the narrow-sense heritability is 0.264 for FEV1 and 0.342 for MMFR. Segregation analysis shows that the "mixed" model with both single locus and polygenic components had a better fit for FEV1 than single-locus or polygenic only models. However, the model which included a nontransmitted environmental factor [tau(AA) = tau(AB) = tau(BB) = qA] and polygenic loci had a better fit than the Mendelian model [tau(AA) = 1, tau(AB) = 1/2, tau(BB) = 0] [Akaike's information criterion (AIC) = 2219.47 vs. AIC = 2222.14]. For MMFR, the Mendelian "mixed" model gave a nonsignificant improvement in loge likelihood compared to the simple polygenic model. Comparison of the single-locus model and Mendelian "mixed" model shows no difference in fitting the data. This study suggests that FEV1 and MMFR are controlled by many loci with no major effects and/or common environmental factors.

Adolescent↗

PubMed2001

Meiotic pairing of sex chromosome fragments and its relation to atypical transmission of a sex-linked marker in Ephestia kuehniella (Insecta: Lepidoptera).

The physical basis of non-Mendelian segregation of a sex-linked marker was studied in sex- chromosome mutant females of eight ASF ('abnormal segregating females') lines in the flour moth, Ephestia kuehniella. Electron microscopical analysis of microspread synaptonemal complexes revealed that in one line, the Z chromosome segment that contained the dz+ allele was translocated onto an autosome. The resulting quadrivalent visible in early female meiosis was 'corrected' into two bivalents in later stages. This explains autosomal inheritance of the sex chromosome marker in this strain. In the other seven ASF lines, the type of meiotic pairing of an additional fragment (Zdz+) of the Z chromosome was responsible for abnormal segregation of the marker gene. In several of these lines, Zdz+ contained a piece of the W chromosome in addition to the Z segment, as was confirmed by comparative genomic hybridization (CGH). Zdz+ formed three alternative pairing configurations with the original sex chromosomes: (i) a WZZdz+ trivalent, (ii) a WZ bivalent and a Zdz+ univalent or (iii) a ZZdz+ bivalent and a W univalent. In the most frequent WZZdz+ configuration, Zdz+ synapsed with Z and, consequently, segregated with W, simulating W linkage. This explains the predominant occurrence of the parental phenotypes in the progeny. Zdz+ univalents or W univalents, on the other hand, segregated randomly, resulting in both parental and nonparental phenotypes. In two of these lines, the Zdz+ was transmitted only to females. The results suggest that the W chromosome segment in Zdz+ of these lines contains a male-killing factor which makes it incompatible with male development. Our data provide direct evidence for the regular transmission of radiation-induced fragments from lepidopteran chromosomes through more than 50 generations. This is facilitated by the holokinetic nature of lepidopteran chromosomes. We conclude that Zdz+ fragments may persist as long as they possess active kinetochore elements.

Animals↗

PubMed2000

Familial Aggregation and Segregation Analysis of Snoring and Symptoms of Obstructive Sleep Apnea.

To investigate possible modes of inheritance that would explain familial aggregation in obstructive sleep apnea (OSA), familial correlation and segregation analyses were performed on data derived from 584 pedigrees with 2019 cases enrolled in the Tucson Epidemiologic Study of Obstructive Airways Disease (TESOAD) who were at least 10 years of age and who had information pertaining to snoring and daytime sleepiness. Data were obtained from the 9th (May 1984 to October 1985) and 12th (February 1990 to October 1992) surveys of the TESOAD, which is a random, stratified sample of the non-Hispanic Caucasian population of Tucson, Arizona. A snoring phenotype was considered present if it occurred on at least some nights. A "sleep apnea" phenotype was constructed if participants snored and experienced daytime sleepiness. Familial correlations for snoring showed significant mother-child and sibling correlations but not father-child correlations. For sleep apnea, significant parent-daughter but not parent-son or sibling correlations were observed. Segregation analyses for snoring with regressive familial effects and sibling, age, and obesity covariates showed no evidence for mendelian transmission. However, additional familial effects were present that suggested phenotype aggregation from polygenic or environmental factors, or both. For the sleep apnea phenotype, similar segregation analyses indicated that mendelian dominant or codominant models were possible. However, the analyses also suggested that a nongenetic model fit the data as well. In addition, consistent with the familial correlations, specific maternal- and sibling-related effects remained even after inclusion of age, gender, and obesity covariates. These data support the concept that inheritable or shared environmental factors contribute to the development of OSA and that maternal components may be more important than paternal ones.

Journal Article↗

PubMed2003

The hairless (hr) gene is involved in the congenital hypotrichosis of Valle del Belice sheep.

Congenital hypotrichosis in mammalian species consists of partial or complete absence of hair at birth. The hairless gene is often responsible for this disorder in men, mice and rats. Recent experimental data on Valle del Belice sheep reared in Sicily for milk production, support the genetic control of the ovine hypotrichosis as a Mendelian recessive trait. The ovine hairless gene was chosen as the candidate gene involved in this disorder. Blood samples were collected from Valle del Belice sheep with the normal and hypotrichotic phenotypes. Almost the entire hairless gene was successfully amplified using the long PCR technique. Unrelated sheep with differing phenotypes were randomly chosen for sequencing the amplified products. Different mutations related to the hypotrichotic phenotype were found in exon 3. In fact, sequencing revealed an A/T transversion at position 739, a G/A transition at position 823, and a C/T transition at position 1312. From these nucleotide exchanges, three substitutions of the processed mature protein were deduced at the amino acid positions 247 (Thr/Ser), 275 (Ala/Thr), and 438 (Gln/Stop). A PCR-SSCP based test was developed in order to detect the last mutation, which is responsible for the hypotrichotic phenotype.

Animals↗

PubMed1984

The bingo model of survivorship. II: statistical aspects of the bingo model of multiplicity 1 with application to hereditary polyposis of the colon.

Some Mendelian disorders (Huntington chorea, hereditary polyposis coli) are not manifest at birth but show a distribution in the age of onset. Patients at risk fall into three groups. In type I, they are affected when first examined. In type II, they are not affected at one visit, but are at a later visit. Those of type III (who comprise an indistinguishable mixture of those who have, and those who have not, inherited the gene) are never found to be affected. This paper posits a model that the age of onset is logistic. (It is a degenerate bingo model in which competing causes of death may be ignored.) The statistical properties of maximum likelihood estimation (MLE) are explored by Monte Carlo simulation of this logistic function with known arbitrary parameters. Two schemes are used: point-prevalence (or synchronic) data of types I and III, and piecewise longitudinal (diachronic) data; this allows all three types to be included. Samples of various sizes between 25 and 100 are used. While estimates of the parameters are positively biased (especially with small samples), the estimate of the mean appears to be consistent, almost unbiased, and fairly precise, though somewhat larger than the estimates from the lower bound (a fact that calls for some caution in interpreting actual data). The MLE was applied to 109 patients with the Gardner syndrome (GS); measures of variability found by applying MLE to four random subsets of 25 each were compared against the asymptotic estimates. The analysis was also applied to 36 persons with familial polyposis coli (FPC). The mean age of onset in GS and FPC was similar, and since they are rather earlier than is currently believed, it is recommended that regular supervision be started at not later than 10 years of age.

Adolescent↗

PubMed1992

Commingling and complex segregation analysis of fasting plasma glucose in the Lipid Research Clinics family study.

Commingling and segregation patterns of fasting plasma glucose (GL) were examined in family data from 5 clinics (Cincinnati, Stanford, Iowa, Minnesota, and Oklahoma) of the Lipid Research Clinics (LRC) family study. In addition to the primary question of whether there was a major gene for GL, a secondary purpose was to investigate the possibility of genetic heterogeneity among the 5 clinics. No statistical support was found for heterogeneity among clinics, either in the commingling of distributions or in the segregation patterns. For the combined clinics sample, both a major effect and a multifactorial component were significant. However, the major effect (accounting for 73% of the variance) was not found to be consistent with a major gene, as the hypothesis of Mendelian transmission was rejected. The most parsimonious model involved equal transmission probabilities, which suggests that the major effect is not transmitted from parents to offspring. Possible sources of this major non-Mendelian effect were explored. The multifactorial component accounted for 10% of the variance in GL levels, and no generational differences were noted. Although our study was unable to provide evidence in favor of a major gene effect, it should be noted that a major gene cannot be firmly refuted. For example, a variety of interactions, such as genotype-dependent age effects, could have masked the transmission probabilities.

Adolescent↗

PubMed2026

Bidirectional causal relationships between plasma proteins, neuroimaging metrics and risk of Alzheimer's disease.

BACKGROUND: Changes in neuroimaging metrics are among the first detectable pathophysiological alterations in Alzheimer's disease (AD). Proteins are closely linked to fluctuations in neuroimaging metrics. Therefore, the analysis of the proteomic signature associated with neuroimaging metrics holds significant promise for uncovering therapeutic targets that contribute to AD. METHODS: GWAS data concerning the Brain Imaging Data Structure (BIDs). The AD cohort comprised a total of 401,661 individuals diagnosed with AD, alongside 10,520 control participants. For a bidirectional MR analysis involving neuroimaging metrics, proteomics, and AD, the methods utilized included inverse variance weighted (IVW), MR Egger, weighted median, weighted mode, and the Wald ratio approaches. RESULTS: We identified 12 neuroimaging metrics that demonstrate significant relevance to AD (thickness of the left total hemisphere, volume of the right thalamus, and et al.). These metrics are structural magnetic resonance imaging (MRI) biomarkers that remain stable throughout the entire course of AD, from the preclinical stage through mild cognitive impairment (MCI) to dementia. Additionally, we found a substantial number of 1633 proteins that also show a noteworthy causal relationship with AD. Functional enrichment analysis indicated that these proteins were predominantly focused within various pathways linked to AD, encompassing those involved in the synaptic vesicle cycle, synaptic membranes, neurotransmitter release, and the activity of GABA receptors. In addition, our research indicates that the significant relationships observed between the identified proteins and AD are influenced by neuroimaging metrics. Notably, we found that these neuroimaging metrics play a crucial role in mediating a substantial 67% of the inverse relationship that exists between PTPRC and the phenotypic characteristics associated with AD. CONCLUSIONS: This study successfully establishes a connection between proteomic and neuroimaging metrics, as well as the AD that influence them. By creating this relationship, the research offers important information that aids in comprehending the intricate mechanisms involved in AD.

Alzheimer Disease↗

PubMed1999

Cigarette smoking as a triggering factor of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa is a chronic inflammatory skin disease involving the axillary, inguinal and anogenital regions and sometimes, in addition, the submammary or sacral areas. The etiology of this condition is unknown. OBJECTIVE: A matched-pair case-control study was performed to evaluate the influence of smoking habits on the manifestation of this disease. METHODS: Patients who had received surgical treatment for hidradenitis suppurativa in two dermatological centers completed a questionnaire dealing with family history, course of the disease and smoking habits. To form a randomized matched-pair control group, an equal number of patients admitted for various other skin diseases such as atopic dermatitis, varicose veins, skin tattoos, alopecia areata or melanoma was matched for sex and age and evaluated for smoking habits. Statistical analysis was performed by use of several chi2 tests in a cross-table setting. Moreover, a comparison to the expected smoking prevalence in Germany based on national statistics was performed. RESULTS: Out of 84 patients treated for hidradenitis suppurativa, 63 subjects (27 men, 36 women) completed the questionnaire. The rate of active cigarette smokers was 88.9% (56 patients), whereas 4 subjects (6.4%) had never smoked. 3 patients (4.8%) stated to be ex-smokers, but 2 of these had quit smoking only recently and after onset of the disease. The rate of smokers in the matched-pair control group was 46%. The significantly higher proportion of active smokers among patients with hidradenitis suppurativa can be expressed by an odds ratio of 9.4, the calculated 95% confidence interval was 3.7-23.7 (p < 0.001). The expected smoking prevalence in Germany was 26.7% according to national statistics. 73% of our patients had no family history of hidradenitis suppurativa whereas 27% reported at least one affected first-degree relative. CONCLUSION: From the exceedingly high rate of smokers among patients with this condition we conclude that cigarette smoking is a major triggering factor of hidradenitis suppurativa. Remarkably, the disease can be categorized as a smoking sequel that is neither of vascular nor neoplastic nature. Because familial occurrence was rather rarely reported, and because an environmental factor in the form of cigarette smoking appears to be of crucial importance to trigger the disease, we assume that the genetic basis of hidradenitis suppurativa is polygenic rather than mendelian. Smoking cessation should be encouraged particularly in patients with hidradenitis suppurativa although it is unknown whether this improves the course of the disease.

Adolescent↗

PubMed2006

Accounting for heterogeneous variances in multitrait evaluation of Jersey type traits.

The multitrait genetic evaluation system for type traits was modified to estimate adjustments for heterogeneous variance (HV) simultaneously with estimated breeding values (EBV) for final score and 14 linear traits. Each variance within herd, year, and parity was regressed toward a predicted variance, which was determined by fitting a model with fixed effects of the mean final score for herd, size of the contemporary group, appraisal month, and year-season and a random effect for herd-appraisal date. Herd-appraisal date was included as a random effect to regress the observed heterogeneity for a given herd-appraisal date toward the fixed effects. Method R was used to estimate variances for the heterogeneity model in each EBV iteration. To evaluate the effect of the adjustment, parent averages were calculated from evaluations with recent appraisals removed. The adjustment slightly improved correlations within birth year between those parent averages and EBV from current data on bulls for most traits, but did not improve correlations for final score, strength, dairy form, teat length, or foot angle. Annual trends for EBV were lower with HV adjustment than for unadjusted EBV for all traits except final score and rump angle for cows and rump width for bulls, which were essentially unchanged. Standard deviations of Mendelian sampling (evaluation minus mean of parent evaluations) declined less over time for HV-adjusted than for unadjusted evaluations. The slope at year 2000 of Mendelian-sampling standard deviations from HV-adjusted evaluations ranged from 10.0% for udder depth to 42.7% for teat length compared with the slope for unadjusted evaluations. This HV adjustment, which was implemented for USDA evaluations in May 2001 for Jerseys and in 2002 for other breeds, improves the accuracy of evaluations, particularly comparisons over time, by accounting for the change in variation.

Animals↗

PubMed2026

Genetic architecture of endometriosis: risk factors, comorbidities and clinical implications.

BACKGROUND: In 1999, Dr Susan Treloar and colleagues conducted a landmark twin study in Australia and reported their estimate of 51% for the heritability of endometriosis. This important result led several groups to begin mapping genetic factors contributing to increased endometriosis risk. Despite early challenges, advances in genome-wide association studies (GWAS) have identified multiple genetic risk factors and some target genes implicated in follow-up studies on genetic regulation of transcription. Access to large publicly available genetic datasets and analysis with endometriosis GWAS results is also providing new opportunities to answer important questions about comorbid conditions associated with endometriosis and their implications for clinical practice. OBJECTIVE AND RATIONALE: The objective of the review is to summarize the last 25 years of genetic studies in endometriosis, outline contributions to our understanding of the disease, and suggest future directions to accelerate biological insights from genetic studies to improve clinical outcomes. SEARCH METHODS: A comprehensive review of scientific literature on the genetics of endometriosis was conducted through searches in PubMed and Google Scholar up to June 2026. Search terms included "endometriosis AND (genetics OR GWAS OR genetic risk factors)", For studies addressing the functional characterization of genetic risk loci, additional searches employed the terms "endometriosis AND (genotype-phenotype associations OR colocalization OR eQTL OR mQTL OR multi omics methods)". To identify studies examining shared genetic risk between endometriosis and comorbid conditions, the search strategy included "endometriosis AND (genetic correlation OR colocalization OR Mendelian randomisation)". Publications reporting discoveries related to genetic risk factors for endometriosis and studies interpreting their biological and clinical significance were critically evaluated, and 144 publications were discussed in the review. OUTCOMES: Discovery of genetic risk factors started slowly and has accelerated in recent years with developments in technology and international collaborations to combine data and increase statistical power. GWAS have mapped 80 genetic risk factors that implicate gene regulation of hormonal targets, development of the reproductive tract, regulation of cell proliferation, and regulation of epithelial cell differentiation. In common with most other complex diseases, effects of individual common genetic risk factors are small. However, several examples demonstrate that small effect sizes are not a good predictor for the impact of drugs developed against genetically validated targets. Genetic risk factors implicate five genes regulating gonadotrophin release and oestrogen action, the major target pathway of current drugs for treatment of endometriosis demonstrating proof-of-principal for biologically meaningful results. Genetic correlation and Mendelian Randomization studies highlight important causal relationships between endometriosis and comorbid conditions including a possible role for testosterone during development and shared genetic risk factors for gynaecological, gastrointestinal, pain, psychiatric, and inflammatory conditions. Understanding causal relationships between endometriosis and related conditions will aid clinical management and more personalized treatments. WIDER IMPLICATIONS: Genetic studies provide novel insights into endometriosis pathogenesis and associations with related comorbid conditions. Genetic factors modifying gene regulation and disease risk likely act in specific cell types, and access to datasets from genetically informed cell-based models, single-cell and spatial omics data are needed to accelerate progress. Future studies should address critical questions of heterogeneity and disease subtypes, expand the search for genetic risk factors to non-European populations, evaluate the role of rare and structural variants, and better integrate data from functional, genomics, genetics, and clinical studies to reduce diagnostic delay, develop novel treatment strategies, and translate discoveries into personalized management strategies for affected individuals. REGISTRATION NUMBER: N/A.

comorbid conditions↗

PubMed2026

Multi-Omics Genome-Wide to Explore the Formation and Development Targets for Intracranial Aneurysms.

Intracranial aneurysms (IAs) represent a significant and potentially life-threatening category of disease, and there is currently a lack of effective treatment options aimed at preventing the progression of the disease. Accordingly, this study is dedicated to exploring and identifying effective drug targets that can help in the prevention of both the formation and rupture of IAs, along with a detailed examination of the underlying potential mechanisms involved in these processes. The data related to IAs for this research was obtained from the ISGC Biobank and UK Biobank. Then, we investigated the possible biological functions and unintended consequences of targeting the specific genes that were highlighted in IAs by using mediation analysis, virtual knockout experiments, and PW-MR studies. A total of 5 unique potential drug targets for IAs (FKTN, MAP3K1, PSMA4, SLC22A4, ADAM17), 4 unique potential drug targets for SAH (PSMA4, ADAM17, GPR160, SLC22A4), and 2 unique potential drug targets for UIA (SLC22A4, PRCP) were identified across brain or blood samples. Among the various candidates identified, SLC22A4 has emerged as a promising potential drug target, showing significant expression levels in both blood and brain tissues. Additionally, phenome-wide MR of SLC22A4 across 32 selected phenotypes did not identify statistically significant adverse associations after FDR correction. Virtual knockout (KO) experiments on SLC22A4 revealed that SLC22A4 KO disrupted 81 genes, all of which are involved in IAs-related pathways. Besides, we recognized BRD-K85337334 as potential candidates for targeting SLC22A4. This research indicates that an increase in SLC22A4 gene expression within the blood or brain is directly linked to a heightened risk of IAs rupture, which will aid in prioritizing the development of drugs for IAs.

Humans↗

PubMed2002

Intrafamilial correlation of clinical manifestations in neurofibromatosis 2 (NF2).

Measuring correlation in clinical traits among relatives is important to our understanding of the causes of variable expressivity in Mendelian diseases. Random effects models are widely used to estimate intrafamilial correlations, but such models have limitations. We incorporated survival techniques into a random effects model so that it can be used to estimate intrafamilial correlations in continuous variables with right censoring, such as age at onset. We also describe a negative-binomial gamma mixture model to determine intrafamilial correlations of discrete (e.g., count) data. We demonstrate the utility of these methods by analyzing intrafamilial correlations among patients with neurofibromatosis 2 (NF2), an autosomal-dominant disease caused by mutations of the NF2 tumor-suppressor gene. We estimated intrafamilial correlations in age at first symptom of NF2, age at onset of hearing loss, and number of intracranial meningiomas in 390 NF2 nonprobands from 153 unrelated families. A significant intrafamilial correlation was observed for each of the three features: age at onset (0.35; 95% confidence interval (CI) 0.23-0.47), age at onset of hearing loss (0.51; 95% CI, 0.35-0.64), and number of meninginomas (0.29; 95% CI, 0.15-0.43). Significant correlations were also observed for age at first symptom within NF2 families with truncating mutations (0.41; 95% CI, 0.06-0.68) or splice-site mutations (0.29; 95% CI, 0.03-0.51), for age at onset of hearing loss within families with missense mutations (0.67; 95% CI, 0.18-0.89), and for number of meningiomas within families with splice-site mutations (0.39; 95% CI, 0.13-0.66). Our findings are consistent with effects of both allelic and nonallelic familial factors on the clinical variability of NF2.

Adolescent↗

PubMed2004

Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas.

Clear-cut inherited Mendelian traits, such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, account for <4% of colorectal cancers. Another 20% of all colorectal cancers are thought to occur in individuals with a significant inherited multifactorial susceptibility to colorectal cancer that is not obviously familial. Incompletely penetrant, comparatively rare missense variants in the adenomatous polyposis coli gene, which is responsible for familial adenomatous polyposis, have been described in patients with multiple colorectal adenomas. These variants represent a category of variation that has been suggested, quite generally, to account for a substantial fraction of such multifactorial inherited susceptibility. The aim of this study was to explore this rare variant hypothesis for multifactorial inheritance by using multiple colorectal adenomas as the model. Patients with multiple adenomas were screened for germ-line variants in a panel of candidate genes. Germ-line DNA was obtained from 124 patients with between 3 and 100 histologically proven synchronous or metachronous adenomatous polyps. All patients were tested for the adenomatous polyposis coli variants I1307K and E1317Q, and variants were also sought in AXIN1 (axin), CTNNB1 (beta-catenin), and the mismatch repair genes hMLH1 and hMSH2. The control group consisted of 483 random controls. Thirty of 124 (24.9%) patients carried potentially pathogenic germ-line variants as compared with 55 ( approximately 12%) of the controls. This overall difference is highly significant, suggesting that many rare variants collectively contribute to the inherited susceptibility to colorectal adenomas.

Adenoma↗

PubMed2026

Proteomic pathways mediating low socioeconomic status and cardiovascular events in older adults in CHS and ARIC.

BACKGROUND AND AIMS: Many studies have linked socioeconomic status (SES) and cardiovascular outcomes, yet the biologic mechanisms mediating these associations are only partially understood. The objective of this study was to identify molecular mediators of the association of low SES with coronary heart disease (CHD) and stroke. METHODS: This research was conducted in 2942 Black and White adults in the Cardiovascular Health Study (mean age 76.2 years) and 10,689 Black and White adults in the Atherosclerosis Risk in Communities Study (mean age 60.0 years). We used factor analysis to create a composite measure of low educational attainment, low-income, and blue-collar occupation. Approximately 5000 proteins were measured with an aptamer-based method, and CHD and stroke events were adjudicated. Results were stratified by race, which was conceptualized as a social factor. RESULTS: Low SES was associated with 44 and 262 proteins, in Black and White adults, respectively. No protein met the Bonferroni adjusted threshold for statistically significantly mediation among Black participants. Among White participants, 23 proteins mediated the association between SES adversity and CHD and 5 mediated the association between SES adversity and stroke. The strongest mediating associations for CHD included PTPRS, SCG3, and MMP12. The strongest mediating associations for stroke included NCAN, FAM20B, and APLP1. SPARCL1 and CDCP1 remained the strongest mediators of the association between SES adversity and CHD, after adjusting for potential confounders and traditional cardiovascular risk factors. CONCLUSION: We identified several biomarkers that characterize the biologic risk of SES adversity on CHD and stroke.

Aged↗

PubMed1987

Classification principles and genetics of chronic gastritis.

Two family samples, (i) a sample considered to represent the population at large (431 subjects) and (ii) a sample of first-degree relatives of index subjects (IS) with overt pernicious anaemia (183 subjects) were analyzed in order to evaluate the onset and course of chronic gastritis (CG) and the pathogenetic factors involved with special reference to the effects of genetic variation. The analysis was based on data obtained from two generations: first generation (sibs of the IS) and second (children of the IS). Formulae derived from Poisson process were used for age-correction of the gastritic changes. Otherwise, conventional statistical methods were used in the genetic analysis and the calculation of prevalences of CG. This approach enabled us to achieve a classification of gastritis into more specific subgroups and to evaluate the natural course of the disease. The progression of gastritis in the second generation (children; mean age 35 years) was roughly similar in antrum and body, indicating that gastritis starts as a diffuse process affecting both areas of the stomach to a rather similar degree. The start of CG and its progression is at least to some degree influenced by genetic factors and probably regulated by the male sex. Thus nearly all children of male IS's with a non-atrophic mucosa (normal mucosa or superficial gastritis) showed a normal mucosa suggesting the existence of a particular sex-bound, genetic mechanisms. These mechanisms may prevent or delay the progression of gastritis up to middle age, when a change in dynamics occurs leading to formation of more specific subtypes of CG. In the first generation (mean age 60 years) CG dispersed into more specific subtypes (corresponding to types A and B of Strickland and McKay and type AB of Glass) and to more advanced stages, which were connected with a higher than expected prevalence of advanced stages also in the relatives. The families of IS's with type A atrophic gastritis (AG) (severe AG in the body but no AG in antrum), type B (AG in antrum but no AG in body) and type AB AG (AG in both antrum and body) showed typical dynamic patterns of the age-specific prevalences of AG. Genetic calculations showed that the type A of AG found in pernicious anaemia patients and their relatives is inherited by a simple dominant gene, while this type of inheritance is statistically unlikely in the type B of AG. The type B, on the other hand, exhibited characteristics that indicate a recessive Mendelian inheritance.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed2026

Schizophrenia and bipolar disorder: a comparative analysis of genetic and brain network connectivity.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions with overlapping clinical presentations, genetic risk factors, and brain network dysfunction. Whether alterations in large-scale intrinsic brain networks reflect shared or disorder-specific genetic influences remains poorly understood. Clarifying this distinction is essential for refining etiological models and improving diagnostic precision. METHODS: Genome-wide inferred statistics (GWIS) were applied to decompose the genetic architecture of SCZ and BD into shared and unique components. Using resting-state network (RSN) data from the UK Biobank, functional connectivity (FC) and structural connectivity (SC) were extracted as neuroimaging phenotypes. Causal inference approaches were subsequently employed to infer potential directional relationships between brain network connectivity and each disorder. RESULTS: Analyses revealed both common and distinct patterns of brain network connectivity associated with SCZ and BD. Notably, SC within the default mode network (DMN) exhibited opposing effects across the two disorders, suggesting divergent structural underpinnings despite clinical overlap. Additionally, SC within the limbic network (LN) and frontotemporal control network demonstrated potential causal relationships with both conditions, implicating these circuits astransdiagnostic neural substrates. CONCLUSION: These findings illuminate the shared and disorder-specific genetic and neural architecture underlying SCZ and BD. Integrating genome-wide genetic methods with large-scale neuroimaging data offers a powerful framework for disentangling psychiatric comorbidity and may inform more targeted diagnostic criteria and individualized treatment strategies.

Humans↗