PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Multifactorial Inheritance”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 811 records · Page 45Linked to original sources

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↗

Imputation methods for missing data for polygenic models.

Methods to handle missing data have been an area of statistical research for many years. Little has been done within the context of pedigree analysis. In this paper we present two methods for imputing missing data for polygenic models using family data. The imputation schemes take into account familial relationships and use the observed familial information for the imputation. A traditional multiple imputation approach and multiple imputation or data augmentation approach within a Gibbs sampler for the handling of missing data for a polygenic model are presented.We used both the Genetic Analysis Workshop 13 simulated missing phenotype and the complete phenotype data sets as the means to illustrate the two methods. We looked at the phenotypic trait systolic blood pressure and the covariate gender at time point 11 (1970) for Cohort 1 and time point 1 (1971) for Cohort 2. Comparing the results for three replicates of complete and missing data incorporating multiple imputation, we find that multiple imputation via a Gibbs sampler produces more accurate results. Thus, we recommend the Gibbs sampler for imputation purposes because of the ease with which it can be extended to more complicated models, the consistency of the results, and the accountability of the variation due to imputation.

Adult Children↗

Transmission ratio distortion in families from the Framingham Heart Study.

BACKGROUND: One implicit assumption in most linkage analysis is that live-born siblings unselected for a phenotype do not share alleles greater than the Mendelian expectation at any particular locus. However, since most families are recruited for genetic studies because of the presence of disease, there is little data available to confirm that this is the case. We hypothesized that loci that behave in a non-Mendelian fashion could be identified using genotype data from the Framingham Heart Study families. We tested the hypothesis that live-born sibs, either stratified by or irrespective of gender, demonstrate excess sharing of alleles on the autosomes, i.e., transmission ratio distortion. Multipoint linkage analysis of siblings either according to gender or not was performed using an allele-sharing method. Such observations may have implications for the mapping of loci for complex disease and quantitative traits in human pedigrees. RESULTS: No results that reached genome-wide significance were observed. However, four regions demonstrated excess sharing of alleles at p < 0.002 when sibships were stratified by gender-three of which were present in males. Of note, a female-specific locus co-localized with region that is linked to mean systolic blood pressure in the same families. In addition, three other regions demonstrated excess sharing of alleles in sibships irrespective of gender, including a region on chromosome 10p14-p15 (p = 7.5 x 10(-4)). CONCLUSION: Although no loci meeting genome-wide significance were detected to demonstrate transmission ratio distortion, loci with suggestive evidence for linkage were detected. These may have implications for the mapping of susceptibility loci for complex disease in human pedigrees.

Adolescent↗

Adjusting for covariates on a slippery slope: linkage analysis of change over time.

BACKGROUND: We analyzed the Genetic Analysis Workshop 13 (GAW13) simulated data to contrast and compare different methods for the genetic linkage analysis of hypertension and change in blood pressure over time. We also examined methods for incorporating covariates into the linkage analysis. We used methods for quantitative trait loci (QTL) linkage analysis with and without covariates and affected sib-pair (ASP) analysis of hypertension followed by ordered subset analysis (OSA), using variables associated with change in blood pressure over time. RESULTS: Four of the five baseline genes and one of the three slope genes were not detected by any method using conventional criteria. OSA detected baseline gene b35 on chromosome 13 when using the slope in blood pressure to adjust for change over time. Slope gene s10 was detected by the ASP analysis and slope gene s11 was detected by QTL linkage analysis as well as by OSA analysis. Analysis of null chromosomes, i.e., chromosomes without genes, did not reveal significant increases in type I error. However, there were a number of genes indirectly related to blood pressure detected by a variety of methods. CONCLUSIONS: We noted that there is no obvious first choice of analysis software for analyzing a complicated model, such as the one underlying the GAW13 simulated data. Inclusion of covariates and longitudinal data can improve localization of genes for complex traits but it is not always clear how best to do this. It remains a worthwhile task to apply several different approaches since one method is not always the best.

Blood Pressure↗

Evidence for bivariate linkage of obesity and HDL-C levels in the Framingham Heart Study.

BACKGROUND: Epidemiological studies have indicated that obesity and low high-density lipoprotein (HDL) levels are strong cardiovascular risk factors, and that these traits are inversely correlated. Despite the belief that these traits are correlated in part due to pleiotropy, knowledge on specific genes commonly affecting obesity and dyslipidemia is very limited. To address this issue, we first conducted univariate multipoint linkage analysis for body mass index (BMI) and HDL-C to identify loci influencing variation in these phenotypes using Framingham Heart Study data relating to 1702 subjects distributed across 330 pedigrees. Subsequently, we performed bivariate multipoint linkage analysis to detect common loci influencing covariation between these two traits. RESULTS: We scanned the genome and identified a major locus near marker D6S1009 influencing variation in BMI (LOD = 3.9) using the program SOLAR. We also identified a major locus for HDL-C near marker D2S1334 on chromosome 2 (LOD = 3.5) and another region near marker D6S1009 on chromosome 6 with suggestive evidence for linkage (LOD = 2.7). Since these two phenotypes have been independently mapped to the same region on chromosome 6q, we used the bivariate multipoint linkage approach using SOLAR. The bivariate linkage analysis of BMI and HDL-C implicated the genetic region near marker D6S1009 as harboring a major gene commonly influencing these phenotypes (bivariate LOD = 6.2; LODeq = 5.5) and appears to improve power to map the correlated traits to a region, precisely. CONCLUSIONS: We found substantial evidence for a quantitative trait locus with pleiotropic effects, which appears to influence both BMI and HDL-C phenotypes in the Framingham data.

Adult↗

Multivariate variance-components analysis of longitudinal blood pressure measurements from the Framingham Heart Study.

Multivariate variance-components analysis provides several advantages over univariate analysis when studying correlated traits. It can test for pleiotropy or (in the longitudinal context) gene x age interaction. It can also have more power than univariate analyses to detect a quantitative trait locus influencing several traits. We apply multivariate variance components to longitudinal systolic blood pressure data from the Framingham Heart Study. We find evidence for a polygenic influence on blood pressure (heritabilities at different ages range from 27% to 38%). Tests based on a factor-analytic parameterization of the polygenic variance find significant (p < 2 x 10(-3)) evidence that different genes affect blood pressure at different ages. Still, estimates for the proportion of polygenic variance due to shared genes ran as high as 85% for some trait pairs. Univariate and multivariate linkage analyses replicate previous linkage results on chromosome 17 (maximum LOD scores of 2.2 and 2.4, respectively). In this study, multivariate analysis provides no increase in power; this is likely due to the strong positive correlation in systolic blood pressure measured at different ages.

Adult↗

Similarity by state/descent and genetic vector spaces: analysis of a longitudinal family study.

Using the genome-wide screening data of the Framingham Heart Study (394 nuclear families, 1328 genotyped subjects, 397 marker loci) we have quantified the underlying genetic diversity through high-dimensional genetic feature vectors and constructed a genetic vector space for the analysis of population substructure. Adaptive clustering procedures led to three major subgroups that were regarded as being related to "biological" ethnicity and that included more than 70% of the subjects. Based on these subgroups we addressed the question of ethnicity-related and ethnicity-independent risk factors for coronary heart disease (CHD). To this end, we relied upon hypertension as an endophenotype of CHD and applied a multivariate sib-pair method in order to search for oligogenic marker configurations for which the sib-sib similarities deviated from the parent-offspring similarities. Indeed, the latter similarities are always "0.5" irrespective of the affection status of parents and offspring. Loci with significant contributions to the oligogenic marker configuration constituted a CHD-specific genetic vector space. We found several ethnicity-independent signals. One signal on chromosome 8 may relate to the CYP11B1/CYP11B2 genes.

Adult Children↗

Mapping complex traits using Random Forests.

Random Forest is a prediction technique based on growing trees on bootstrap samples of data, in conjunction with a random selection of explanatory variables to define the best split at each node. In the case of a quantitative outcome, the tree predictor takes on a numerical value. We applied Random Forest to the first replicate of the Genetic Analysis Workshop 13 simulated data set, with the sibling pairs as our units of analysis and identity by descent (IBD) at selected loci as our explanatory variables. With the knowledge of the true model, we performed two sets of analyses on three phenotypes: HDL, triglycerides, and glucose. The goal was to approach the mapping of complex traits from a multivariate perspective. The first set of analyses mimics a candidate gene approach with a high proportion of true genes among the predictors while the second set represents a genome scan analysis using microsatellite markers. Random Forest was able to identify a few of the major genes influencing the phenotypes, such as baseline HDL and triglycerides, but failed to identify the major genes regulating baseline glucose levels.

Chromosome Mapping↗

Approaches to mapping genetically correlated complex traits.

Our Markov chain Monte Carlo (MCMC) methods were used in linkage analyses of the Framingham Heart Study data using all available pedigrees. Our goal was to detect and map loci associated with covariate-adjusted traits log triglyceride (lnTG) and high-density lipoprotein cholesterol (HDL) using multipoint LOD score analysis, Bayesian oligogenic linkage analysis and identity-by-descent (IBD) scoring methods. Each method used all marker data for all markers on a chromosome. Bayesian linkage analysis detected a linkage signal on chromosome 7 for lnTG and HDL, corroborating previously published results. However, these results were not replicated in a classical linkage analysis of the data or by using IBD scoring methods.We conclude that Bayesian linkage analysis provides a powerful paradigm for mapping trait loci but interpretation of the Bayesian linkage signals is subjective. In the absence of a LOD score method accommodating genetically complex traits and linkage heterogeneity, validation of these signals remains elusive.

Cholesterol, HDL↗

HLA DR phenotypic frequencies and genetic risk of Type 1 diabetes in west region of Algeria, Tlemcen.

BACKGROUND: The main genomic region controlling the predisposition to type 1 diabetes is the Human Leukocyte Antigens (HLA) class II of the major histocompatibility complex. Association with different HLA types depends also on the studied populations. In our investigation, we tried to measure the phenotypic HLA class II association frequencies of DR3 and/or DR4 antigens, using a serologic method called microlymphocytotoxicity analysis, in diabetic and nondiabetic (ND) subjects originating from the west-Algerian region of Tlemcen. The aim of the present study was to determine which HLA DR antigens represent a high susceptibility to develop the disease in this area. Using a case-control retrospective study design, we randomly recruited ninety-one related subjects, 39 type 1 diabetics and 52 ND as controls, at the Internal Medicine Board of Medical Centre University of Tlemcen. RESULTS: DR3 antigen frequencies were comparable between the type 1 diabetics and the ND subjects and showed no association with the disease (p = 1.000, OR = 0.95), whereas DR4 and DR3DR4 antigens were associated with susceptibility to develop type 1 diabetes (DR4; OR = 2.10, DR3DR4; OR = 1.30). Also, no incidence for DR3 (p = 0.2646) or DR3DR4 (p = 0.0699) antigen frequencies was related to the sex ratio. However, significant differences in HLA DR4 frequencies between type 1 diabetics and ND were found to be related to sex (p = 0.0085). CONCLUSION: Taken together, our investigation showed that the strongest association with type 1 diabetes was noticed in the presence of HLA DR4 antigens followed by DR3DR4 antigens. This study highlighted a characteristic of Tlemcen population; a history of consanguineous marriages. Association studies between the disease and genetic polymorphisms should be undertaken in a population where consanguinity is more limited to reduce confounding in result interpretations.

Adolescent↗

Extension of multifactor dimensionality reduction for identifying multilocus effects in the GAW14 simulated data.

The multifactor dimensionality reduction (MDR) is a model-free approach that can identify gene x gene or gene x environment effects in a case-control study. Here we explore several modifications of the MDR method. We extended MDR to provide model selection without crossvalidation, and use a chi-square statistic as an alternative to prediction error (PE). We also modified the permutation test to provide different levels of stringency. The extended MDR (EMDR) includes three permutation tests (fixed, non-fixed, and omnibus) to obtain p-values of multilocus models. The goal of this study was to compare the different approaches implemented in the EMDR method and evaluate the ability to identify genetic effects in the Genetic Analysis Workshop 14 simulated data. We used three replicates from the simulated family data, generating matched pairs from family triads. The results showed: 1) chi-square and PE statistics give nearly consistent results; 2) results of EMDR without cross-validation matched that of EMDR with 10-fold cross-validation; 3) the fixed permutation test reports false-positive results in data from loci unrelated to the disease, but the non-fixed and omnibus permutation tests perform well in preventing false positives, with the omnibus test being the most conservative. We conclude that the non-cross-validation test can provide accurate results with the advantage of high efficiency compared to 10-cross-validation, and the non-fixed permutation test provides a good compromise between power and false-positive rate.

Computer Simulation↗

Multifactor-dimensionality reduction versus family-based association tests in detecting susceptibility loci in discordant sib-pair studies.

Complex diseases are generally thought to be under the influence of multiple, and possibly interacting, genes. Many association methods have been developed to identify susceptibility genes assuming a single-gene disease model, referred to as single-locus methods. Multilocus methods consider joint effects of multiple genes and environmental factors. One commonly used method for family-based association analysis is implemented in FBAT. The multifactor-dimensionality reduction method (MDR) is a multilocus method, which identifies multiple genetic loci associated with the occurrence of complex disease. Many studies of late onset complex diseases employ a discordant sib pairs design. We compared the FBAT and MDR in their ability to detect susceptibility loci using a discordant sib-pair dataset generated from the simulated data made available to participants in the Genetic Analysis Workshop 14. Using FBAT, we were able to identify the effect of one susceptibility locus. However, the finding was not statistically significant. We were not able to detect any of the interactions using this method. This is probably because the FBAT test is designed to find loci with major effects, not interactions. Using MDR, the best result we obtained identified two interactions. However, neither of these reached a level of statistical significance. This is mainly due to the heterogeneity of the disease trait and noise in the data.

Chromosome Mapping↗

GeneLink: a database to facilitate genetic studies of complex traits.

BACKGROUND: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. RESULTS: GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. CONCLUSIONS: GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at http://research.nhgri.nih.gov/genelink.

Alleles↗

Genomic regulation of natural variation in cortical and noncortical brain volume.

BACKGROUND: The relative growth of the neocortex parallels the emergence of complex cognitive functions across species. To determine the regions of the mammalian genome responsible for natural variations in cortical volume, we conducted a complex trait analysis using 34 strains of recombinant inbred (Rl) strains of mice (BXD), as well as their two parental strains (C57BL/6J and DBA/2J). We measured both neocortical volume and total brain volume in 155 coronally sectioned mouse brains that were Nissl stained and embedded in celloidin. After correction for shrinkage, the measured cortical and noncortical brain volumes were entered into a multiple regression analysis, which removed the effects of body size and age from the measurements. Marker regression and interval mapping were computed using WebQTL. RESULTS: An ANOVA revealed that more than half of the variance of these regressed phenotypes is genetically determined. We then identified the regions of the genome regulating this heritability. We located genomic regions in which a linkage disequilibrium was present using WebQTL as both a mapping engine and genomic database. For neocortex, we found a genome-wide significant quantitative trait locus (QTL) on chromosome 11 (marker D11Mit19), as well as a suggestive QTL on chromosome 16 (marker D16Mit100). In contrast, for noncortex the effect of chromosome 11 was markedly reduced, and a significant QTL appeared on chromosome 19 (D19Mit22). CONCLUSION: This classic pattern of double dissociation argues strongly for different genetic factors regulating relative cortical size, as opposed to brain volume more generally. It is likely, however, that the effects of proximal chromosome 11 extend beyond the neocortex strictly defined. An analysis of single nucleotide polymorphisms in these regions indicated that ciliary neurotrophic factor (Cntf) is quite possibly the gene underlying the noncortical QTL. Evidence for a candidate gene modulating neocortical volume was much weaker, but Otx1 deserves further consideration.

Animals↗

Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths.

BACKGROUND: Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie? RESULTS: We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered. CONCLUSION: The genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment.

Attention Deficit Disorder with Hyperactivity↗

Divergent autoimmune genetic landscapes in diabetic and non-diabetic individuals.

BACKGROUND: Type 2 diabetes (T2D) and autoimmune diseases are complex disorders shaped by genetic, immunological, and environmental factors. However, differences in genetic susceptibility to autoimmune disorders between diabetic and non-diabetic individuals remain poorly understood, particularly within the Indian population. This study aimed to compare polygenic susceptibility to multiple autoimmune diseases between individuals with and without T2D from Gujarat, India. RESULTS: Polygenic risk scores were evaluated for eleven autoimmune diseases in 474 individuals, including 99 diabetics and 375 non-diabetics. Significant differences were observed for systemic lupus erythematosus and rheumatoid arthritis. Individuals with diabetes showed a higher genetic risk for systemic lupus erythematosus, whereas non-diabetic individuals exhibited a higher genetic risk for rheumatoid arthritis. Pathway enrichment analysis of disease-associated genetic variants revealed significant involvement of immune-related pathways, including antigen processing and presentation, T-helper cell differentiation, and immune responses to viral infections. CONCLUSIONS: The findings reveal disease-specific differences in genetic susceptibility to autoimmune disorders between diabetic and non-diabetic individuals. These results highlight the complex immunogenetic relationship between type 2 diabetes and autoimmune diseases and provide insight into shared and distinct immune pathways within an Indian population. Such information may support future efforts in risk stratification and precision medicine approaches for immune-related comorbidities in diabetes.

Humans↗

Enhancing detection of polygenic adaptation: a comparative study of machine learning and statistical approaches using simulated evolve-and-resequence data.

BACKGROUND: Detecting signals of polygenic adaptation remains a significant challenge in population genomics, as traditional methods often struggle to identify the associated subtle, multi-locus allele-frequency shifts. Here, we introduced and tested several novel approaches combining machine learning techniques with traditional statistical tests to detect polygenic adaptation patterns in time-series of allele frequency changes from whole genome data. We implemented a Naive Bayesian Classifier (NBC) and One-Class Support Vector Machines (OCSVM), and compared their performance against the classical Fisher's Exact Test (FET). Furthermore, we combined machine learning and statistical models (OCSVM-FET and NBC-FET), resulting in 5 competing approaches. The framework is mainly designed and validated for evolve-and-resequence (EaR) experimental designs, where defined selection pressures and temporal sampling are feasible, but might be applicable for certain natural experiments as well. RESULTS: Using a simulated dataset based on empirical C. riparius Pool-Seq data, we evaluated methods across evolutionary scenarios varying in generation, selection strength, and number of loci under selection. Our results demonstrate that the combined OCSVM-FET approach consistently outperformed competing methods, achieving the lowest false positive rate, highest area under the curve, and high accuracy. The performance peak aligned with what we term the 'late dynamic phase' of adaptation - the period after initial selection has occurred but before fixation - highlighting the method's sensitivity to ongoing selective processes. CONCLUSIONS: Furthermore, we emphasize the critical role of parameter tuning, balancing biological assumptions with methodological rigor. While broader applicability remains an important direction for future work, the present benchmarking is intentionally scoped to EaR experimental contexts.

Machine Learning↗