Changes in mdg1 and mdg2 location pattern at oppositely directed selection by a qualitative trait in an isogenic Drosophila melanogaster strain.
Explore the source record for details and available documents.
Animals↗
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.
Genetic relationships between systemic lupus erythematosus and a positive antinuclear antibody test in the absence of autoimmune disease.
OBJECTIVE: We defined the genetic factors associated with a positive ANA test (ANA+) in the absence of autoimmune disease and tested the association with SLE. METHODS: Using a case-control design, we performed a genome-wide association study (GWAS) in individuals of European ancestry without an autoimmune disease who had ANA tested as part of clinical care from DNA biobanks linked to de-identified electronic medical records: BioVU and Electronic Medical Records and Genomics. GWAS results were meta-analysed and single nucleotide polymorphism (SNP) heritability was calculated. A polygenic risk score (PRS) for ANA+ and for SLE was constructed and compared in patients with SLE, ANA+ and ANA negative (ANA-) individuals without autoimmune disease and general controls who never had ANA testing performed. RESULTS: A total of 7287 individuals of European ancestry were included in the meta-analyses (2169 ANA+ and 5118 ANA-); an SNP upstream of the TSBP1 in the HLA locus (rs1967688) was associated with ANA+ (p=4.84×10-8). SNP heritability for ANA+ was low (h2 SNP= 0.04), and the PRS for ANA+ was not significantly different in ANA+ and ANA- individuals. In contrast, the PRS for SLE was significantly higher in SLE compared with ANA+ individuals (p<2.2×10-16) but did not differ among ANA+, ANA- and general control groups (p=0.17). CONCLUSIONS: ANA+ occurring in the absence of autoimmune disease has a genetic association with the HLA region, but overall heritability is low. In addition, few SLE-associated SNPs were associated with ANA+, and the PRS for SLE was not associated with ANA+, indicating limited genetic overlap.
Humans↗
Of flies and man: Drosophila as a model for human complex traits.
Understanding the genetic and environmental factors affecting human complex genetic traits and diseases is a major challenge because of many interacting genes with individually small effects, whose expression is sensitive to the environment. Dissection of complex traits using the powerful genetic approaches available with Drosophila melanogaster has provided important lessons that should be considered when studying human complex traits. In Drosophila, large numbers of pleiotropic genes affect complex traits; quantitative trait locus alleles often have sex-, environment-, and genetic background-specific effects, and variants associated with different phenotypic are in noncoding as well as coding regions of candidate genes. Such insights, in conjunction with the strong evolutionary conservation of key genes and pathways between flies and humans, make Drosophila an excellent model system for elucidating the genetic mechanisms that affect clinically relevant human complex traits, such as alcohol dependence, sleep, and neurodegenerative diseases.
Animals↗
Organization of genes controlling disease resistance in the potato genome.
Nineteen single dominant genes (R genes) for resistance to viruses, nematodes, and fungi have been positioned on the molecular map of potato using DNA markers. Fourteen of those genes are located in five "hotspots" for resistance in the potato genome. Quantitative trait loci (QTL) for resistance to late blight caused by the oomycete Phytophthora infestans, to tuber rot caused by the bacterium Erwinia carotovora ssp. atroseptica, and to root cyst nematodes have been identified on all 12 potato chromosomes. Some QTL for resistance to different pathogens are linked to each other and/or to resistance hotspots. Based on the genetic clustering with R genes, we propose that some QTL for resistance have a molecular basis similar to single R genes. Mapping potato genes with sequence similarity to cloned R genes of other plants and other defense-related genes reveals linkage between candidate genes, R genes, and resistance QTL. To explain the molecular basis of polygenic resistance in potato we propose (a) genes having structural similarity with cloned R genes and (b) genes involved in the defense response. The "candidate gene approach" enables the identification of markers highly useful for marker-assisted selection in potato breeding.
Animals↗
Early onset albuminuria in Dahl rats is a polygenetic trait that is independent from salt loading.
The aim of the study was to characterize the genetic basis for the early onset of increased urinary albumin excretion (UAE) observed in the salt-sensitive Dahl rat (SS). We first characterized blood pressures and UAE values in adult SS compared with the spontaneously hypertensive rat (SHR) strain. Blood pressure measurements by radiotelemetry at 14 wk demonstrated similar spontaneous hypertension in both strains on a low-sodium diet containing 0.2% NaCl by weight, whereas UAE was markedly increased in SS compared with SHR (253.07 +/- 68.39 vs. 1.65 +/- 1.09 mg/24 h, P < 0.0001). Analysis of UAE in young animals of both strains fed a low-sodium diet demonstrated that UAE is elevated in SS as early as 4 wk of age (P < 0.0001), when ultrastructural evaluation of glomeruli by electron microscopy appears still normal. At 8 wk SS demonstrated a 280-fold elevated UAE compared with SHR (P < 0.0001). Consequently, to identify quantitative trait loci (QTLs) contributing to salt-independent early manifestation of increased UAE in the SS rat, we performed genome-wide linkage and QTL mapping analysis in a young F(2) population derived from the two contrasting strains. UAE was determined in 539 F(2) animals at 8 wk. We identified seven suggestive or significant UAE QTLs on rat chromosomes (RNO) RNO2, RNO6, RNO8, RNO9, RNO10, RNO11, and RNO19, accounting together for 34% of the overall variance of UAE in this F(2) population. Thus early onset albuminuria in the SS rat is under polygenetic influence and independent from salt loading.
Albuminuria↗
Physiological Genomics: Who we are and where we're going.
Explore the source record for details and available documents.
Animals↗
Evaluation of Multiple Breast Cancer Polygenic Risk Score Panels in Women of Latin American Heritage.
BACKGROUND: A substantial portion of the genetic predisposition for breast cancer is explained by multiple common genetic variants of relatively small effect. A subset of these variants, which have been identified mostly in individuals of European (EUR) and Asian ancestries, have been combined to construct a polygenic risk score (PRS) to predict breast cancer risk, but the prediction accuracy of existing PRSs in Hispanic/Latinx individuals (H/L) remain relatively low. We assessed the performance of several existing PRS panels with and without addition of H/L-specific variants among self-reported H/L women. METHODS: PRS performance was evaluated using multivariable logistic regression and the area under the ROC curve. RESULTS: Both EUR and Asian PRSs performed worse in H/L samples compared with original reports. The best EUR PRS performed better than the best Asian PRS in pooled H/L samples. EUR PRSs had decreased performance with increasing Indigenous American (IA) ancestry, while Asian PRSs had increased performance with increasing IA ancestry. The addition of two H/L SNPs increased performance for all PRSs, most notably in the samples with high IA ancestry, and did not impact the performance of PRSs in individuals with lower IA ancestry. CONCLUSIONS: A single PRS that incorporates risk variants relevant to the multiple ancestral components of individuals from Latin America, instead of a set of ancestry-specific panels, could be used in clinical practice. IMPACT: The results highlight the importance of population-specific discovery and suggest a straightforward approach to integrate ancestry-specific variants into PRSs for clinical application.
Adult↗
Population genomics in Sardinia: a novel approach to hunt for genomic combinations underlying complex traits and diseases.
The availability of highly polymorphic markers permits testing whether complex traits and diseases result from genomic interactions between nonallelic normal variants at separate loci. Such variants may be identified by deviations from the expected distributions of alleles at a high number of polymorphic loci, when individuals with the phenotype of interest are compared to normal controls of the same breeding unit, provided that both groups share the same remote ancestry and had no ancestors in common for the last three to four generations. The circumstances needed for such studies are ideally met on the island of Sardinia. The recurrent finding of the same type of association in separate breeding units between the phenotype of interest and a given genotype should allow a distinction between true genetic identity by descent and randomly occurring identities, as these will be obviously different in separate breeding units. The availability of several breeding units located in sharply different ecological environments will permit assessment of the role of nature/nurture factors in the degree of manifestation of each newly discovered genotype/phenotype association. A pilot study to evaluate the proposed strategy has been carried out in the Sardinian village of Carloforte, a community of about 8,000 individuals who have remained genetically homogeneous. Fifty-five control samples have been genotyped with six tetranucleotide microsatellites and with a subset of the 400 markers contained in the ABI PRISM linkage mapping panel, version 2. The allele frequencies for these microsatellite markers have been determined for these 55 individuals and compared to those from a random sampling of subsets of these 55 persons. For the six tetranucleotide microsatellites, a subset of as few as 20 people displayed the same allele frequency distributions as observed with the original 55 unrelated individuals. In conclusion, when samples are chosen from the same breeding unit, the number of individuals sufficient to draw the genomic profile of an isolated population can be relatively small. Likewise, the number of probands with the phenotype of interest can be even smaller when they are ascertained with the same genealogical criteria as the normal controls. By comparing the genomic profile of the probands to a fraction of the control samples within each of several separate breeding units of common remote ancestry, the search for genotype/phenotype association for mono- and multifactorial traits and diseases should be simplified and yield unequivocal results.
Aged↗
Heterogeneity for multiple disease loci in linkage analysis.
Many mendelian traits show heterogeneity; that is, the disease phenotype in different families may be caused by genes at different locations. In linkage analysis, this admixture type of heterogeneity (locus heterogeneity) has often been accommodated with one of the HOMOG programs, which thus far have been restricted to at most two disease gene locations. Here, an extension to an arbitrary number of disease locations is described. It has been implemented in a computer program, HOMOGM. This approach is also suitable as an approximation to the situation of complex traits, in which multiple disease genes may occur in the same family.
Algorithms↗
A novel approach to search for identity by descent in small samples of patients and controls from the same mendelian breeding unit: a pilot study on myopia.
Autosomal dominant high myopia, a genetic disorder already mapped to region 18p11.31, is common in Carloforte (Sardinia, Italy), an isolated village of 8,000 inhabitants descending from a founder group of 300 in the early 1700s. Fifteen myopic propositi and 36 normal controls were selected for not having ancestors in common at least up to the grandparental generation, although still descendants of the original founders. All subjects were genotyped for 14 markers located on autosome 18 at a resolution of about 10 cM. Allelic distributions were found to be similar at all tested loci in propositi and controls, except for the candidate marker D18S63 known to segregate in close linkage association with high myopia. In particular, the frequency of allele 85 among the propositi was almost double that of the controls (Fisher's exact test, p = 0.037). The association is more striking when the frequency of the genotype 85/85 in the two groups is compared (Fisher's exact test, p = 0.005). This conclusion was further evaluated through a bootstrap analysis by computing the overall probability of the observed data under the null hypothesis (i.e. no difference between the two groups in frequency distributions for the chromosome 18 markers). Again, marker D18S63 was found to have a sample probability lower than 0.004, which is significant at the 0.05 level after correcting for simultaneous testing of multiple loci. The study demonstrates the efficiency of our novel strategy to detect identity by descent (IBD) in small numbers of patients and controls when they are both part of well-defined Mendelian breeding units (MBUs). The iterative application of our strategy in separate MBUs is expected to become the method of choice to evaluate the ever-growing number of reported associations between candidate genes and multifactorial traits and diseases.
Adult↗
Prostate cancer and the problem of genotype phenotype correlation.
Explore the source record for details and available documents.
Genetic Linkage↗
Localising quantitative trait loci in the NOD mouse model of type 1 diabetes.
Explore the source record for details and available documents.
Animals↗
Susceptibility genes in rheumatoid arthritis.
Explore the source record for details and available documents.
Arthritis, Rheumatoid↗
Backward Haplotype Transmission Association (BHTA) algorithm - a fast multiple-marker screening method.
The mapping of complex traits is one of the most important and central areas of human genetics today. Recent attention has been focused on genome scans using a large number of marker loci. Because complex traits are typically caused by multiple genes, the common approaches of mapping them by testing markers one after another fail to capture the substantial information of interactions among disease loci. Here we propose a backward haplotype transmission association (BHTA) algorithm to address this problem. The algorithm can administer a screening on any disease model when case-parent trio data are available. It identifies the important subset of an original larger marker set by eliminating the markers of least significance, one at a time, after a complete evaluation of its importance. In contrast with the existing methods, three major advantages emerge from this approach. First, it can be applied flexibly to arbitrary markers, regardless of their locations. Second, it takes into account haplotype information; it is more powerful in detecting the multifactorial traits in the presence of haplotypic association. Finally, the proposed method can potentially prove to be more efficient in future genomewide scans, in terms of greater accuracy of gene detection and substantially reduced number of tests required in scans. We illustrate the performance of the algorithm with several examples, including one real data set with 31 markers for a study on the Gilles de la Tourette syndrome. Detailed theoretical justifications are also included, which explains why the algorithm is likely to select the 'correct' markers.
Algorithms↗
Genetic modifiers of hereditary hearing loss.
Explore the source record for details and available documents.
Animals↗
Two new recursive likelihood calculation methods for genetic analysis.
Recursive likelihood calculations for genetic analysis with ungenotyped pedigree data employ variations of the Elston-Stewart (ES) or the Lander-Green (LG) algorithms. With the ES algorithm, the number of loci may be limited but not the pedigree size. With the LG algorithm, the reverse is the case. We introduce two new algorithms for the computation of regressive likelihoods for pedigrees with multivariate traits. The first is an alternative formulation of our existing model, which leads to a simpler form in the binary trait, polygenic and mixed model cases. The second is an approximation model, which is computationally efficient. These methods apply to both continuous and binary traits, in the oligogenic and polygenic cases. Both methods coincide in the binary case. We considered these methods for cases in which all the traits are controlled by a single locus, with each trait controlled by one locus independent to the others. Simulation studies and analysis of a real data are presented for segregation analysis as illustrations. These methods can also be used in other model-based analyses. These methods are implemented in G.E.M.S., the genetic epidemiology models software.
Animals↗
Towards the genetic analysis of mulfactorial diseases: the estimation of allele frequency and epistasis.
OBJECTIVES: The general aim of this paper is to reactivate the original intention behind the Elston-Stewart algorithm: i.e. physiological characterisation of the effects of individual loci underlying quantitative variation. The specific aim is the estimation of allele frequency and epistasis in multifactorial genetic diseases. METHODS: In a general genetic model, the probability of disease is a sigmoid function of the number of disease alleles summed over all loci. This model has just 4 parameters: the number of loci; the population frequency of disease alleles; a threshold expressed as a proportion of disease alleles; and the slope of the sigmoid curve. Assuming 10 loci, the remaining parameters can be estimated from empirical data: population frequency of the disease, monozygotic twin concordance rates, and disease frequency in sibs of affected probands. RESULTS: For 10 typical multifactorial diseases, the estimates of allele frequency are generally high, of the order of 20%, with strong epistatic interactions between loci. It follows that the frequencies of subphenotypes specific for a single disease locus will also be high, and only about two-fold greater in affected individuals than in normal controls. CONCLUSIONS: Because of allelic heterogeneity, purely genomic approaches are unlikely to succeed in unravelling the genetics of multifactorial diseases; this will rather require articulation with physiology and the identification of biologically meaningful subphenotypes.
Diabetes Mellitus, Type 1↗