Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “polygenic background”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2026

Large-scale multi-omics enhance risk prediction for type 2 diabetes.

BACKGROUND: Polygenic risk scores (PRS), metabolomics, and proteomics have each shown promise in improving type 2 diabetes risk prediction, but their combined utility beyond established clinical models remains unclear. We aimed to evaluate whether integrating multi-omics biomarkers enhances 10-year type 2 diabetes risk prediction beyond single-omics extensions and the clinical Cambridge Diabetes Risk Score (CDRS), which includes HbA1c measurements. METHODS: We analysed data from 42,840 UK Biobank participants without diagnosed diabetes at baseline. The study population was split into a derivation set (Phase 1 metabolomics release, N&#x2009;=&#x2009;23,108) to fit models and an independent validation set (Phase 2 release, N&#x2009;=&#x2009;19,732) to evaluate performance. Data for a PRS for type 2 diabetes, 11 metabolites, and 15 proteins were added to the CDRS to develop multi-omics prediction models. Model performance was evaluated using Harrell's C-index and the net reclassification index (NRI). RESULTS: During 10 years of follow-up, 1090 participants developed incident type 2 diabetes. Among individual omics layers, proteomics contributed the greatest improvement in predictive performance, increasing the C-index from 0.862 (clinical CDRS) to 0.884 (&#x394;C-index; + 0.022; P&#x2009;<&#x2009;0.001), with a continuous NRI of 42.0%. The full multi-omics model further significantly increased the C-index compared to a model combining the clinical CDRS with proteomics data (C-index, 0.891; &#x394;C-index; + 0.007; P&#x2009;<&#x2009;0.001). CONCLUSION: Integrating proteomics, metabolomics, and a diabetes-PRS into a clinical model substantially improves type 2 diabetes risk prediction beyond single-omics extensions. Several of the selected proteins and metabolites are on cardiovascular disease pathways, highlighting the link between diabetes and cardiovascular risk. However, the C-index difference between the proteomics extended and full multi-omics extended models is small, and the clinical models extended with proteomics data would be easier to translate into routine care because it needs only the measurement of 15 proteins. External validation and cost-effectiveness analyses are needed to support clinical adoption.

Humans↗
PubMed2002

Familial clustering of juvenile thyroid autoimmunity: higher risk is conferred by human leukocyte antigen DR3-DQ2 and thyroid peroxidase antibody status in fathers.

Thyroid autoimmunity is one of the most common immune disorders in females, and its polygenic background remains to be elucidated. The human leukocyte antigen (HLA) DQ region of chromosome 6 has been shown to confer susceptibility to thyroid autoimmune disease. The aim of our present investigation was to determine whether the transmission of high risk HLA DQ to patients with thyroid autoimmunity differs when transmission is from fathers as opposed to when transmission is from mothers. We studied 91 juvenile patients with chronic lymphocytic thyroiditis (68 females and 23 males; mean age, 10.5 +/- 3.9 yr), 12 patients with Graves' disease (all females; mean age, 8.8 +/- 4.0 yr), 53 healthy siblings, and their parents for thyroid function, antibodies, ultrasound, and DNA typing for HLA DQ susceptibility alleles. We observed an increased rate of transmission for the DQA1*0501-DQB1*0201 (DQ2) haplotype [35 of 53 transmitted (66%); P = 0.02]. This allele was preferentially transmitted by fathers [21 of 27 (78%); P < 0.004], whereas the maternal DQ2 haplotypes were not transmitted more often than expected. Subsequently, families were stratified as follows according to the parental thyroid peroxidase antibody (TPOAb) status: no parent, only mothers, only fathers, and both parents positive. There was no significant maternal transmission disequilibrium in any subset, but the paternal HLA DQ2 was preferentially transmitted [11 of 14 cases (79%); P = 0.03] in the group of TPOAb-positive mothers, and we observed a similar trend in the group of TPOAb- positive fathers (P = 0.08). Also, the portion of offspring affected by Graves' disease was significantly higher in TPOAb-positive than in TPOAb-negative fathers (P < 0.02). In conclusion, our findings demonstrate a significant effect of paternal HLA DQ alleles as well as antibody status on susceptibility to thyroid autoimmune disease in juvenile patients.

Adolescent↗
PubMed1997

Segregation analyses for presence of major genes affecting growth, backfat, and litter size in Dutch Meishan crossbreds.

Presence of major genes was investigated for two growth traits, backfat thickness, and two litter size traits in the F1 and F2 population of a cross between Meishan and European "White" pig lines. Segregation analyses were performed in a Bayesian setting, estimating the contribution of background polygenes and the contribution of a possible major gene to the expression of the traits considered. In a first analysis, F1 and F2 crossbred data were evaluated; different error variances were fitted for F1 and F2 observations. In the first analysis, significant contributions of major-gene variance were found for the two growth traits, backfat thickness, and litter size at first parity. In a second analysis, F2 data were evaluated to determine whether biases were introduced in the joint analysis of F1 and F2 data. In the second analysis, no major genes were found for growth traits. Major genes affecting backfat and litter size at first parity were confirmed. The gene identified to affect backfat is a dominant gene; the homozygous recessive genotype has approximately 6 mm of additional backfat. The gene identified to affect litter size at first parity also is a dominant gene; the homozygous recessive genotype produces five to six fewer pigs per litter.

Animals↗
PubMed1999

Influence of the three RN genotypes on chemical composition, enzyme activities, and myofiber characteristics of porcine skeletal muscle.

An experiment was conducted to evaluate the effects of the RN genotype on skeletal muscle characteristics in pigs sharing otherwise the same polygenic background. Animals were genotyped for RN on the basis of RTN (Rendement Technologique Napole) records using segregation analysis methods. Samples of longissimus (L) and semispinalis capitis (S) muscles were taken from 39 rn+/rn+, 38 RN-/rn+ and 37 RN-/RN- pigs slaughtered at 108 +/- 8.6 kg live weight. Activities of lactate dehydrogenase (LDH), citrate synthase (CS), and beta-hydroxy-acyl-coenzyme A dehydrogenase (HAD) were measured on both muscles to assess glycolytic, oxidative, and lipid beta-oxidation capacities, respectively. Histological examinations and chemical analyses were performed on L muscle. The energetic metabolism of the white L muscle was more oxidative in RN-/RN- than in rn+/rn+ pigs, as shown by increased CS and HAD activities (P < .001), decreased LDH activity (P < .001), larger cross-sectional area of IIA (P < .05) and IIB-red (P < .05) fibers, higher relative area of IIA fibers ( P < .05), and lower relative area of IIB-white fibers (P < .001). No significant difference was found between heterozygous and homozygous carriers of the RN- allele, except for CS activity, which was lower in RN-/rn+ than in RN-/RN- pigs. In L muscle, the RN- allele led to a large increase in glycolytic potential (+3.5 phenotypic SD between homozygotes) and lightness (+.7 SD), and a decrease in ultimate pH, dry matter, and protein contents (-1.7 to -2 phenotypic SD for these three traits), with an almost completely dominant effect. No differences were found between genotypes for intramuscular fat and hydroxyproline contents. In the red S muscle, the presence of RN- had no influence on enzyme activities. These results indicate that the RN genotype greatly influences compositional and histochemical traits and metabolic enzyme activities in a muscle type-dependent manner, with a completely or incompletely dominant effect of the RN- allele.

Alleles↗
PubMed1996

Genes and obesity.

Several twin and adoption studies as well as animal models have confirmed that obesity has a strong genetic component. It is apparent that obesity in humans has a complex polygenic background; that is, the phenotype is determined by an unknown number of genes together with environmental factors. However, there may well be single genes playing a major role within certain families, but the gene may vary from family to family. Two interesting gene candidates have been found in mouse experiments, the ob and the db gene, the products of which are probably a satiety hormone and its receptor, respectively, which regulate food intake. The recent cloning of the ob gene and its human homologue constitute a major breakthrough in this field. The 16-kD protein encoded by the ob gene is called leptin, and is well conserved among vertebrate species. The pig could be a valuable large animal model for human obesity. A fatness locus has been mapped to pig chromosome 4 and most probably a similar locus resides on human chromosome 1q. A more precise definition of the pig-human homology as regards this region is currently being investigated.

Animals↗
PubMedDate not supplied

[Genetic risk factors of neural tube defects].

Neural tube defects (NTDs) are a group of diseases caused by a failure of closure of the neural tube. Its aetiology contains both environmental and genetic factors. NTDs have a polygenic background. Genes, which are linked with NTDs occurrence, are both directly and indirectly connected with controlling the process of closure of the neural tube. Ones of those are genes of metabolism of folic acid as MTHFR, MTR, MTRR, CBS, MTHFD, folic acid receptors (FR) regulator genes from PAX family, T, PDGFRA and BRCA1 genes.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMedDate not supplied

[Mutations of MTHFR, MTR, MTRR genes as high risk factors for neural tube defects].

Neural tube defects (NTDs) have a polygenic background. There are numerous genes known to be high-risk genetic factors for NTDs. Ones of them are mutations of foliate metabolisms pathways genes. This paper shows the results of analysis of common mutations of MTHFR, MTR and MTRR genes. Results of screening mutations 2756A-->G and 66A-->G in MTR and MTRR genes respectively show that are might have an effect on NTDs incidence among the examined population. Analysis of data for the studied population does not prove the influence of mutations 677C-->T and 1298A-->C of MTHFR gene on NTDs.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1991

[Genetic eye defects in the dog].

Genetically determined disturbances of the normal function of the eye are distributed in high frequencies in several breeds of dogs. Two groups of these disturbances are discussed; disturbances resulting from the aims of breeding and defects caused by mutant genes. Disturbances such as ectropion, entropion and trichiasis may be regarded as the results of aims of breeding. They have a polygenic background and can be reduced by selection against the undesired traits and by modification of the breed standards. The frequencies of defects caused by mutant genes such as PRA, cataract and PHTVL/PHPV can be effectively reduced by veterinary practitioners. They are expected to be able to explain the consequences of breeding with animals carrying these genes to their clients when patients with these defects are presented.

Animals↗
PubMed1990

Multigenic human hypertension: evidence for subtypes and hope for haplotypes.

Hypertension that occurs before the age of 60 years is strongly aggregated in families, mostly due to genetic factors with weaker contributions from a shared family environment. Hypertension is probably a heterogeneous collection of overlapping subsets of pathophysiological mechanisms, such as dyslipidemia, obesity, hyperinsulinemia and cation metabolism. Highly heritable traits such as sodium-lithium countertransport, urinary kallikrein excretion and a body fat pattern index show evidence of major gene segregation in families with hypertension. They are thought to be intermediate phenotypes in the chain of pathophysiological events leading from specific genes to the distant phenotype of hypertension. They provide evidence of measurable contributions from single gene traits to the susceptibility to hypertension. Genetic linkage studies have suggested that other specific loci (e.g. histocompatibility leukocyte antigen, blood group MN and the haptoglobin protein) contribute to the susceptibility to hypertension. DNA sequencing has shown a point mutation for lipoprotein lipase that conveys susceptibility to lipid abnormalities, and possibly also hypertension, as seen in families with dyslipidemic hypertension. Further application of these approaches, especially in families that include multiple siblings with hypertension, shows promise of a true understanding of how the combined effects of a few specific genes, the polygenic background and selected environmental factors can lead to essential hypertension. This understanding should foster better tailored and more effective approaches to the prevention, diagnosis and treatment of hypertension.

Blood Pressure↗
PubMed1984

Comparisons of different sampling designs for the determination of genetic transmission mechanisms in quantitative traits.

The power provided by several sampling designs to detect segregation at a major locus was investigated in a simulation study using phenotypes constructed from a major-locus genotypic mean, a background polygenic effect, and an individual-specific environmental effect. Questions of which relatives, how many relatives, and how many independent pedigrees to collect were considered, using configurations ranging from nuclear families of size 5 to 4-generation pedigrees of size 45. Each configuration contained a single proband whose phenotype exceeded the 95th percentile in a population where 2.5% carry the disease susceptibility allele. Results suggest that, under the conditions simulated, when total sample size is fixed, samples composed of 3-generation pedigrees of intermediate size provide a greater magnitude of support for the presence of a major locus than do samples composed of nuclear families or 4-generation pedigrees. This study is the first to consider both the discriminatory power and estimation efficiency in comparing alternative sampling strategies for pedigree data.

Genetics, Medical↗
PubMed1984

Platelet monoamine oxidase (MAO) activity: evidence for a single major locus.

Monoamine oxidase (MAO), a mitochondrial enzyme involved in the degradation of biogenic amines, has been associated with psychiatric morbidity. Although twin and family studies have indicated that MAO activity is familial, the exact mode of transmission is unclear. We performed segregation analysis on 154 nuclear families containing 419 individuals using the mixed model, which allows for a single major locus with a polygenic background. We were able to reject a dominant and additive locus with or without a heritable background and a recessive locus without background. The acceptable models were: (1) a codominant model without background where the mean of the heterozygote distribution was 30% of the distance from the low to the high homozygote distributions, and (2) a recessive locus with heritable background. In both cases, the gene frequency for the high-MAO allele is approximately .25--at odds with suggestions that low-MAO represents a genetic marker for a disorder such as schizophrenia with a lifetime risk of only 0.85%. To ensure that results were not artifacts from a familial, skewed distribution, the data were also analyzed after power transformation. In addition, hypotheses were tested using both the joint and conditional likelihoods to examine for possible misspecification of the model with respect to intergenerational differences. Finally, we allowed for non-Mendelian transmission probabilities to provide another class of alternatives against which to test the hypothesis of a major locus. All these approaches provided additional confirmation for the presence of a major locus segregating within these families.

Alleles↗
PubMed1995

Genetic analysis of kifafa, a complex familial seizure disorder.

Kifafa is the Swahili name for an epileptic seizure disorder, first reported in the early 1960s, that is prevalent in the Wapogoro tribe of the Mahenge region of Tanzania in eastern Africa. A 1990 epidemiological survey of seizure disorders in this region reported a prevalence in the range of 19/1,000-36/1,000, with a mean age at onset of 11.6 years; 80% of those affected had onset prior to 20 years of age. A team of investigators returned to Tanzania in 1992 and collected data on > 1,600 relatives of 26 probands in 20 kifafa families. We have undertaken a genetic analysis of these data in order to detect the presence of familial clustering and whether such aggregation could be attributed to genetic factors. Of the 127 affected individuals in these pedigrees, 23 are first-degree relatives (parent, full sibling, or offspring) of the 26 probands; 20 are second-degree relatives (half-sibling, grandparent, uncle, or aunt). When corrected for age, the risk to first-degree relatives is .15; the risk to second-degree relatives is .063. These risks are significantly higher than would be expected if there were no familial clustering. Segregation analysis, using PAP (rev.4.0), was undertaken to clarify the mode of inheritance. Among the Mendelian single-locus models, an additive model was favored over either a dominant, recessive, or codominant model. The single-locus model could be rejected when compared with the mixed Mendelian model (inclusion of a polygenic background), although the major-gene component tends to be recessive.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1998

Genetic studies of polymorphisms in ten non-insulin-dependent diabetes mellitus candidate genes in Tamil Indians from Pondichery.

We report a study of 10 candidate genes presumably involved in diabetes or insulin resistance or obesity among Pondicherian Tamil Indians, an isolated population with a high prevalence of diabetes. Forty-nine families with at least two affected patients in the sibship (567 individuals) were selected and tested by PCR-RFLP techniques for reported mutations in 10 diabetes or obesity candidate genes: glucagon receptor, insulin receptor substrate 1, insulin receptor, human beta 3 adrenergic receptor, fatty acid binding protein 2, mitochondrial tRNA(Leu(UUR)), sulphonylurea receptor, human uncoupling protein and the glycogen-associated regulatory subunit of protein phosphatase-1. Glucokinase gene was also screened for mutations. No mutations were found in glucokinase, glucagon receptor and mitochondrial genes in any of the 49 probands. Frequencies of polymorphisms at other loci were similar to those reported in Caucasian populations, except for 4 of the loci at which a higher frequency of variants was observed: human beta 3 adrenergic receptor, human uncoupling type 1 protein, fatty acid binding protein 2 and the glycogen-associated regulatory subunit of protein phosphatase-1. However, no evidence of association between any of these gene variants and non-insulin-dependent diabetes mellitus (NIDDM) or quantitative traits related to NIDDM (including body mass index, waist/hip ratio, insulinaemia, glycaemia, triglycerides and total cholesterol) was found in our sample. These results suggest that none of these gene variants commonly found in the Pondicherian Tamil population of South India is a major NIDDM predisposing locus, although it cannot be excluded that they may contribute to the polygenic background of the metabolic syndrome in Pondichery.

Adult↗
PubMed2004

Apolipoprotein(a) size polymorphism is associated with coronary heart disease in polygenic hypercholesterolemia.

BACKGROUND AND AIM: In addition to high serum cholesterol levels, various cardiovascular risk factors may be involved in the development of coronary heart disease (CHD) in hypercholesterolemic subjects. As the levels of lipoprotein(a) [Lp(a)], an important and independent cardiovascular risk factor, are high in polygenic hypercholesterolemia (PH), we investigated plasma Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes in relation to occurrence of CHD events in PH patients. METHODS AND RESULTS: Lp(a) levels and apo(a) isoforms were determined in 191 PH patients, 83 normocholesterolemic subjects with CHD, and 94 normocholesterolemic controls without CHD. Lp(a) levels were similar in the hypercholesterolemic subjects with (n=100) or without CHD (n=91): 21.4 (range 6.6-59.23) vs 18.5 (range 5.25-57.25) mg/dL (p=NS). Low molecular weight apo(a) isoforms were more prevalent (55%) in the PH patients with CHD, whereas high molecular weight apo(a) isoforms were more prevalent (62.6%) in those without CHD: this difference was significant (p<0.05). A stepwise multiple-discriminant analysis made in order to determine the independence of common cardiovascular risk factors, Lp(a) levels and low molecular weight apo(a) isoforms in predicting CHD among hypercholesterolemic subjects showed that the presence of a positive family history of CHD, smoking, age, and the presence of at least one apo(a) isoform of low molecular weight were independently associated with CHD. CONCLUSIONS: Despite high Lp(a) levels, our findings do not support the hypothesis that Lp(a) plays an independent role in determining clinical CHD in PH subjects. However, the presence of at least one low molecular weight apo(a) isoform is an independent genetic predictor of CHD in hypercholesterolemic subjects. Together with other cardiovascular risk factors, apo(a) phenotypes should be assessed to evaluate the overall CHD risk status of all subjects with high serum cholesterol levels.

Adult↗
PubMed2000

Differing relationships of methylene tetrahydrofolate reductase genotypes with cardiovascular risk in familial and polygenic hypercholesterolaemia.

BACKGROUND: Plasma homocysteine and the methylene tetrahydrofolate reductase C677T polymorphism have been suggested as being risk factors for cardiovascular disease. OBJECTIVE: To determine whether plasma homocysteine and the methylene tetrahydrofolate reductase C677T polymorphism are risk factors for coronary heart disease in patients with heterozygous familial hypercholesterolaemia as compared with those with polygenic hyperlipidaemia. METHODS: Plasma homocysteine and the methylene tetrahydrofolate reductase polymorphism were assessed with other risk factors in 112 patients with familial hypercholesterolaemia and 72 patients with polygenic hyperlipidaemia, of whom 29 (25.8%) and 30 (41%) respectively had established cardiovascular disease and in 100 healthy normal subjects. RESULTS: Plasma homocysteine was not significantly elevated in patients with and without coronary heart disease with familial hypercholesterolaemia or polygenic hyperlipidaemia compared with controls. The allele frequencies for C677T were significantly different in patients with coronary heart disease and with polygenic hyperlipidaemia (0.35 versus 0.29) (P = 0.02) as opposed to those with coronary heart disease and familial hypercholesterolaemia (0.25 versus 0.30) (P = 0.63). Methylene tetrahydrofolate reductase genotype but not homocysteine had a weak association with coronary heart disease in logistic regression analysis in patients with polygenic hyperlipidaemia (P = 0.05) but neither methylene tetrahydrofolate reductase genotype or plasma homocysteine was a risk factor in patients with familial hypercholesterolaemia. CONCLUSION: Whilst methylene tetrahydrofolate reductase genotype may be a weak risk factor for coronary heart disease in polygenic hyperlipidaemia as opposed to familial hypercholesterolaemia, homocysteine does not seem to be an important risk factor for coronary heart disease in patients in southern UK.

Adult↗
PubMed2026

Hypertrophic cardiomyopathy: a genome-wide association meta-analysis and polygenic risk score.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a heritable trait with marked variability in expression and outcomes. Our aims were to discover new genetic loci associated with HCM and to test the effect of a new polygenic risk score (PRS) on incidence, phenotype and outcomes stratified by genotype status. METHODS: A discovery genome-wide association study (GWAS) was performed on 2284 HCM cases and 4525 controls. Two fixed-effects meta-analyses combined our discovery GWAS with single-trait and multi-trait results from a published study. Discovered loci underwent comprehensive bioinformatic analysis including functional and druggability annotations. A PRS using loci from the two meta-analyses was evaluated for association with HCM diagnosis in 411&#x2009;213 individuals from UK Biobank (UKBB); imaging phenotypes in individuals without HCM; a composite endpoint (including all-cause mortality and transplantation); and sudden cardiac death (SCD) in 1756 HCM cases. PRS analyses were stratified by genotype status. RESULTS: Three loci were found in the discovery GWAS (BAG3, FHOD3 and novel locus PPP1R3A). In the meta-analyses, 70 unique loci were identified, four novel (MYPN, YWHAE, NOS1AP and OBSCN). Bioinformatic analyses identified NOS1AP as a candidate HCM gene. A new PRS was significantly associated with HCM diagnosis (HR=3.19, 95%&#x2009;CI 2.46 to 4.14 for top 5% vs lower 95%; HR=1.88, 95%&#x2009;CI 1.72 to 2.06 per SD increase). Significant associations were found between PRS and greater left ventricular (LV) wall thickness and higher LV ejection fraction in UKBB participants without HCM. Genotype-negative HCM cases in the top 20% of the PRS distribution had an increased risk of SCD (HR=2.72, 95%&#x2009;CI 1.03 to 7.17). CONCLUSIONS: We report novel HCM loci. A new PRS predicted the risk of HCM development and associated imaging characteristics in the UKBB and outcomes in an HCM cohort.

Cardiomyopathies↗
PubMed2006

Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women.

Rheumatoid and juvenile idiopathic arthritis (RA, JIA) are chronic inflammatory arthropathies with polygenic autoimmune background. We analysed the IL-4 +33 C/T and IL-4R Q551R single nucleotide polymorphisms (SNPs) in 294 RA, 72 JIA and 165 controls from Northern Ireland. Analysis of the individual phenotypes (RA or JIA) showed that both the IL-4 +33 TT (P = 0.02; OR: 0.25, 95% CI: 0.07-0.87) and the IL-4R Q551R CC genotypes (P = 0.001; OR: 0.19, 95% CI: 0.06-0.56) were exclusively decreased in female RA patients compared to female controls. Similar non-significant trends were observed in female JIA patients (OR: 0.25, 95% CI: 0.03-2.11 and OR: 0.31, 95% CI: 0.07-1.47, respectively). Analysis of the common phenotype (inflammatory arthropathy; i.e. JIA and RA combined) corroborated the unique association of these polymorphisms with female inflammatory arthropathy (P = 0.013 and 0.002, respectively). This is the first demonstration of sex-specific association of the two foremost genes of the IL-4 signalling cascade with chronic inflammatory arthropathies.

Arginine↗