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PubMed1995

Toward fully automated genotyping: genotyping microsatellite markers by deconvolution.

Dense genetic linkage maps have been constructed for the human and mouse genomes, with average densities of 2.9 cM and 0.35 cM, respectively. These genetic maps are crucial for mapping both Mendelian and complex traits and are useful in clinical genetic diagnosis. Current maps are largely comprised of abundant, easily assayed, and highly polymorphic PCR-based microsatellite markers, primarily dinucleotide (CA)n repeats. One key limitation of these length polymorphisms is the PCR stutter (or slippage) artifact that introduces additional stutter bands. With two (or more) closely spaced alleles, the stutter bands overlap, and it is difficult to accurately determine the correct alleles; this stutter phenomenon has all but precluded full automation, since a human must visually inspect the allele data. We describe here novel deconvolution methods for accurate genotyping that mathematically remove PCR stutter artifact from microsatellite markers. These methods overcome the manual interpretation bottleneck and thereby enable full automation of genetic map construction and use. New functionalities, including the pooling of DNAs and the pooling of markers, are described that may greatly reduce the associated experimentation requirements.

Algorithms↗
PubMed1995

Mathematical limits of multilocus models: the genetic transmission of bipolar disorder.

We describe a simple, graphical method for determining plausible modes of inheritance for complex traits and apply this to bipolar disorder. The constraints that allele frequencies and penetrances lie in the interval 0-1 impose limits on recurrence risks, KR, in relatives of an affected proband for a given population prevalence, KP. We have investigated these limits for KR in three classes of relatives (MZ co-twin, sibling, and parent/offspring) for the general single-locus model and for two types of multilocus models: heterogeneity and multiplicative. In our models we have assumed Hardy-Weinberg equilibrium, an all-or-none trait, absence of nongenetic resemblance between relatives, and negligible mutation at the disease loci. Although the true values of KP and the KR's are only approximately known, observed population and family data for bipolar disorder are inconsistent with a single-locus model or with any heterogeneity model. In contrast, multiplicative models involving three or more loci are consistent with observed data and, thus, represent plausible models for the inheritance of bipolar disorders. Studies to determine the genetic basis of most bipolar disorder should use methods capable of detecting interacting oligogenes.

Alleles↗
PubMed1994

[Current studies on the identification of susceptibility genes for IDDM in NOD mice].

Until recently, localization of genes involved in multifactorial diseases, such as diabetes, was thought to be impracticable. The recent development of microsatellite genetic markers detected by PCR has facilitated detailed genetic analysis of complex traits. Microsatellite markers have been utilized for genetic analysis of NOD mice which spontaneously develop autoimmune IDDM similar to the human disease. There is evidence for ten distinct loci that affect the development of insulitis and diabetes in NOD mice. One of these loci, designated Idd-1, has been linked to the MHC on chromosome 17. Transgenic mouse experiments have shown that Idd-1 is composed of MHC class II genes I-A beta and I-E alpha.

Animals↗
PubMed1996

Parametric and nonparametric linkage analysis: a unified multipoint approach.

In complex disease studies, it is crucial to perform multipoint linkage analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of linkage analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint analysis of pedigree data to be performed rapidly in a single user-friendly environment.

Algorithms↗
PubMed1996

A variant of beta fibrinogen is a genetic risk factor for coronary artery disease and myocardial infarction.

BACKGROUND: Coronary artery disease is a complex trait caused by a number of genetic and environmental factors. Genes involved in hemostasis and coagulation are excellent candidate genes for CAD and its thrombotic complications, i.e., myocardial infarction (MI) and unstable angina. METHODS: We determined the frequency of beta-fibrinogen genotypes in a homogenous patient population with CAD undergoing coronary angioplasty and in a comparable group in the general population. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction mapping with Hha-1 and gel electrophoresis. Cases and controls were also genotyped for a G17382T polymorphism in the (beta-Myosin heavy chain) (beta-MyHC) gene, which is not a candidate gene for CAD. RESULTS: The distribution of beta-MyHC G/T genotypes and the frequency of alleles were similar in cases and controls. However, the beta-fibrinogen G/G genotype was present in 71% of patients with CAD as compared to 54% in the general population (p = 0.00001, OR: 2.1, 95% CI: 1.7-2.8). Seventy-one percent of patients with MI and 72% of patients with unstable angina had G/G genotype (p = 0.003, OR: 2.0, 95% CI: 1.3-3.3, and p = 0.005, OR: 2.1, 95% CI: 1.3-3.7, respectively). Sixty-nine percent of male and 82% of female patients with CAD had the G/G genotype as compared to 56% and 53% in in general population, respectively (p = 0.0381, and 0.0003, respectively). Multivariate regression analysis showed that the allele G was an independent predictor of case-control status or risk of MI in a codominant manner (F = 86.8 p < 0.0001). CONCLUSIONS: beta-fibrinogen G/G genotype is a genetic risk factor for predisposition to CAD and its thrombotic complications.

Adult↗
PubMed1996

Linkage of frontotemporal dementia to chromosome 17: clinical and neuropathological characterization of phenotype.

Frontotemporal dementia is a behavioral disorder of insidious onset and variable progression. Clinically, its early features reflect frontal lobe dysfunction characterized by personality change, deterioration in memory and executive functions, and stereotypical and perseverative behaviors. Pathologically, there is degeneration of the neocortex and subcortical nuclei, without distinctive features such as plaques, neurofibrillary tangles, or Pick or Lewy bodies. Within-family variation in neuropathology and clinical phenotype is observed. In cases where family aggregation is observed, it is inherited as an autosomal dominant, age-dependent disorder. Family studies recently have identified two dementia loci: chromosome 17 for disinhibition-dementia-parkinsonism-amyotrophic complex and pallido-ponto-nigral degeneration and chromosome 3 for familial nonspecific dementia. We describe a family (DUK1684) with clinically and neuropathologically confirmed, autosomal dominant, non-Alzheimer disease dementia. Linkage analysis of this family showed evidence for linkage to chromosome 17q21, with a multipoint location score (log10) of 5.52. A comparison of the clinical and pathological features in DUK1684 with those of the other chromosome 17-linked families, together with the linkage data, suggests that these families are allelic. These studies emphasize that genetic linkage analysis remains a useful tool for differentiating disease loci in clinically complex traits.

Age of Onset↗
PubMed1996

The Danish Twin Register.

BACKGROUND: Population based twin registers represent a valuable tool for genetic epidemiological research, since twin studies aim at separating the effect of genes and environment for complex traits. The Danish Twin Register's history, size, ascertainment and completeness of data, as well as data accessibility and availability are described. RESULTS: The Danish Twin Register comprises 14,051 twin pairs born 1870-1930, representing all twins surviving to age six years, and 20,888 twin pairs born 1953-1982, representing 75% of those born 1953-1967 and 95% of those born 1968-1982. The birth cohorts 1931-1952 og 1983-1993 are being ascertained at the moment. The register is available for research given certain conditions are fulfilled. CONCLUSION: This register will in a few years be the most comprehensive twin register in the world. It is a very valuable Danish research resource.

Child↗
PubMed1996

Genetic linkage studies for the identification of cancer-related genes.

The most commonly used method for genetic mapping of disease causing loci is the lod-score method, based on maximum likelihood estimation of the recombination fraction. This method is the most powerful one when the mode of inheritance of the disease is known, but is often used also for genetic mapping of complex traits, although in these cases alternative non parametric procedures are often preferable. In those families where cancer segregates as a Mendelian disease, mapping of the corresponding gene can be carried out as for any other genetic disorder. Modelling of the analysis should also consider the possible occurrence of reduced or age dependent penetrance, phenocopies, and genetic heterogeneity. The application of this method has already led to the identification of the genetic location and eventually to the cloning of several cancer-related genes, including FAP, BRCA1, NF1, and more recently AT. Understanding the molecular mechanisms leading to the disease in the Mendelian forms of cancer may prove helpful in unraveling the basis of the other more common forms of cancer.

Chromosome Mapping↗
PubMedDate not supplied

Francis Galton: his approach to polygenic disease.

Gregor Mendel is considered to be the founding father of modern genetics, and his laws of inheritance have led to the successful analysis of rare monogenic diseases such as cystic fibrosis, Duchenne muscular dystrophy, familial hypercholesterolaemia, and many others. Francis Galton chose multifactorial inheritance as his starting point, and his methods of analysis have withstood the test of time. He used detailed family records to study the inherited tendency of complex traits between parents and offspring, and between identical and non-identical twins to refine the analysis, and devised new statistics to attempt to measure the extent of inheritance. For all these reasons, he can be considered the founding father of quantitative genetics.

England↗
PubMed1998

The genetics of endometriosis.

Endometriosis is probably a complex trait, like diabetes, hypertension or asthma, which implies that the disease is caused by an interaction between multiple genes and the environment. This paper reviews the evidence, in both human and nonhuman primates, that supports the theory of a genetic basis to endometriosis. The OXEGENE study, which aims to identify susceptibility genes in endometriosis through linkage analysis, is also described. DNA is being collected from families containing at least two sisters with surgically confirmed revised American Fertility Society stage III and IV disease to carry out a genome-wide search for susceptibility genes. Candidate genes involved in galactose metabolism and dioxin detoxification are also being analyzed. The identification of genes conferring susceptibility to endometriosis may lead to a better understanding of disease etiology and, in time, improved therapeutic strategies and diagnostic methods.

Endometriosis↗
PubMed2005

Quantitative trait locus analysis of longitudinal quantitative trait data in complex pedigrees.

There is currently considerable interest in genetic analysis of quantitative traits such as blood pressure and body mass index. Despite the fact that these traits change throughout life they are commonly analyzed only at a single time point. The genetic basis of such traits can be better understood by collecting and effectively analyzing longitudinal data. Analyses of these data are complicated by the need to incorporate information from complex pedigree structures and genetic markers. We propose conducting longitudinal quantitative trait locus (QTL) analyses on such data sets by using a flexible random regression estimation technique. The relationship between genetic effects at different ages is efficiently modeled using covariance functions (CFs). Using simulated data we show that the change in genetic effects over time can be well characterized using CFs and that including parameters to model the change in effect with age can provide substantial increases in power to detect QTL compared with repeated measure or univariate techniques. The asymptotic distributions of the methods used are investigated and methods for overcoming the practical difficulties in fitting CFs are discussed. The CF-based techniques should allow efficient multivariate analyses of many data sets in human and natural population genetics.

Chromosome Mapping↗
PubMed1998

A mixture model approach to the mapping of quantitative trait loci in complex populations with an application to multiple cattle families.

A mixture model approach is presented for the mapping of one or more quantitative trait loci (QTLs) in complex populations. In order to exploit the full power of complete linkage maps the simultaneous likelihood of phenotype and a multilocus (all markers and putative QTLs) genotype is computed. Maximum likelihood estimation in our mixture models is implemented via an Expectation-Maximization algorithm: exact, stochastic or Monte Carlo EM by using a simple and flexible Gibbs sampler. Parameters include allele frequencies of markers and QTLs, discrete or normal effects of biallelic or multiallelic QTLs, and homogeneous or heterogeneous residual variances. As an illustration a dairy cattle data set consisting of twenty half-sib families has been reanalyzed. We discuss the potential which our and other approaches have for realistic multiple-QTL analyses in complex populations.

Animals↗
PubMed2001

The effect of pedigree complexity on quantitative trait linkage analysis.

Due to the computational difficulties of performing linkage analysis on large complex pedigrees, most investigators resort to simplifying such pedigrees by some ad hoc strategy. In this paper, we suggest an analytical method to compare the power of various pedigree simplification schemes by using the asymptotic distribution of the likelihood-ratio statistic. We applied the method to the large Hutterine pedigree. Our results indicate that the breaking and reduction of inbreeding loops can greatly diminish the power to localize quantitative trait loci. We also present an efficient Monte Carlo method for estimating identity-by-descent allele sharing in large complex pedigrees. This method is used to facilitate a linkage analysis of serum IgE levels in the Hutterites without simplifying the pedigree.

Adult↗
PubMed1995

Analysis of complex human genetic traits: an ordered-notation method and new tests for mode of inheritance.

A novel ordered notation is introduced that allows description and calculation of the probability of any nuclear-pedigree configuration of disease status and marker-allele information. Algorithms are given that allow for complex models of disease predisposition, a highly polymorphic or less polymorphic marker locus, gametic disequilibrium between the marker and disease loci (marker association with disease), recombination between the marker and disease loci, and different ascertainment schemes. The theoretical foundation is presented for a series of new tests to identify modes of inheritance and genetic heterogeneity. These use marker-locus data in nuclear families from four ascertainment schemes: simplex (S), multiplex parent-child (MPC), multiplex sibs (MS), and multiplex parent-sibs (MPS). The tests are (1) extension of the antigen-geno-type-frequencies-among-patients method to MPC, MS, and MPS pedigrees; (2) determination of the expected rates of transmission, or not, of marker alleles from parents to an affected child, for all pedigree types; (3) determination of expected identity by descent (IBD) values for affected sib pairs when a parent is affected (MPS pedigrees); and (4) determination of the expected marker-allele frequencies in affected-sib-pair IBD categories (MS and MPS pedigrees). A sampling strategy that includes the four pedigree types S, MPC, MS, and MPS is recommended for complex diseases once linkage and/or association of a marker with disease has been established. The full array of new and old tests that can be applied to these pedigrees provides a complementary suite of methods that can facilitate the mapping and characterization of complex human genetic traits.

Alleles↗
PubMed2005

Maize association population: a high-resolution platform for quantitative trait locus dissection.

Crop improvement and the dissection of complex genetic traits require germplasm diversity. Although this necessary phenotypic variability exists in diverse maize, most research is conducted using a small subset of inbred lines. An association population of 302 lines is now available--a valuable research tool that captures a large proportion of the alleles in cultivated maize. Provided that appropriate statistical models correcting for population structure are included, this tool can be used in association analyses to provide high-resolution evaluation of multiple alleles. This study describes the population structure of the 302 lines, and investigates the relationship between population structure and various measures of phenotypic and breeding value. On average, our estimates of population structure account for 9.3% of phenotypic variation, roughly equivalent to a major quantitative trait locus (QTL), with a high of 35%. Inclusion of population structure in association models is critical to meaningful analyses. This new association population has the potential to identify QTL with small effects, which will aid in dissecting complex traits and in planning future projects to exploit the rich diversity present in maize.

Chromosome Mapping↗
PubMed2000

Mapping quantitative trait loci in complex pedigrees: a two-step variance component approach.

There is a growing need for the development of statistical techniques capable of mapping quantitative trait loci (QTL) in general outbred animal populations. Presently used variance component methods, which correctly account for the complex relationships that may exist between individuals, are challenged by the difficulties incurred through unknown marker genotypes, inbred individuals, partially or unknown marker phases, and multigenerational data. In this article, a two-step variance component approach that enables practitioners to routinely map QTL in populations with the aforementioned difficulties is explored. The performance of the QTL mapping methodology is assessed via its application to simulated data. The capacity of the technique to accurately estimate parameters is examined for a range of scenarios.

Animals↗
PubMed1998

[Immunogenetic bases of systemic lupus erythematosus in humans].

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown pathogenesis. Familial studies and concordance rates among affected twins suggest that human SLE has a strong genetic basis. CURRENT KNOWLEDGE AND KEY POINTS: Recent studies have emphasized that SLE, like other autoimmune diseases, is a complex genetic trait with contributions of both major histocompatibility complex (MHC) associated genes and multiple non-MHC genes. Recent significant advances have been made in the genetic analysis of complex traits, which allow the identification of new candidate genes in SLE. Among the genes reviewed in this article, some polymorphisms of Fc gamma receptor genes and other genes or loci localized on the long arm of the human chromosome 1 appear to be very promising. FUTURE PROSPECTS AND PROJECTS: The identification of new susceptibility genes in SLE will certainly provide important insights into the breakdown of self-tolerance mechanisms leading to autoimmune diseases. To achieve this objective, the recruitment of a large number of genetic traits of multiplex families presenting with SLE is therefore essential. More than 125 multiplex families have been collected to date in France.

Animals↗
PubMed2002

The genetic epidemiology of spontaneous endometriosis in the rhesus monkey.

The etiology of endometriosis is uncertain, but there is increasing evidence that it is inherited as a complex genetic trait like diabetes or asthma. In such complex traits, multiple gene loci conferring susceptibility to the disease interact with each other and the environment to produce the phenotype. The study of such interactions in humans can be problematic. Thus, the availability of an animal model, which shares many aspects of anatomy and physiology with humans, is potentially a valuable tool for investigating the genetic epidemiology of the disease. Since endometriosis develops spontaneously in the rhesus monkey (Macaca mulatta) and the tissue is morphologically identical to its human counterpart, this population provides a unique opportunity to conduct such studies in this condition.

Animals↗