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At least 433 records · Page 24Linked to original sources
PubMed2005

Finding fibrosis genes: the lung.

Many people are exposed to environmental risk factors for fibrosis, yet only a subset go on to develop disease. It is likely that a number of tissue-specific disease genes determine the path an individual will follow upon exposure to an environmental agent, and that individuals who carry certain combinations of these genes are most susceptible. Diseases which have multiple genetic and environmental determinants, known as "complex traits," present a formidable challenge for gene discovery as the combined influence of more than one gene and one or more environmental factors decrease power to isolate the effect of any single gene. Nevertheless, the identification of the genetic differences that underlie susceptibility to fibrotic disease is crucial to understanding the disease process and to the development of effective screening tests and treatments. No single strategy or method will likely be sufficient to link a candidate disease gene to a fibrosis phenotype. Therefore, we present techniques and resources that can be used in combination to dissect the genetics of complex traits and yield viable candidate genes. Testing of candidate genes and standards for formal proof of gene discovery are discussed.

Alleles↗
PubMed2005

Linkage analysis of alcohol dependence using MOD scores.

Alcohol dependence is a typical example of a complex trait that is governed by several genes and for which the mode of inheritance is unknown. We analyzed the microsatellite markers and the Affymetrix single-nucleotide polymorphisms (SNPs) for a subset of the Collaborative Study on the Genetics of Alcoholism family sample, 93 pedigrees of Caucasian ancestry comprising 919 persons, 390 of whom are affected according to DSM III-R and Feighner criteria. In particular, we performed parametric single-marker linkage analysis using MLINK of the LINKAGE package (for the microsatellite data), as well as multipoint MOD-score analysis with GENEHUNTER-MODSCORE (for the microsatellite and SNP data). By use of two liability classes, different penetrances were assigned to males and females. In order to investigate parent-of-origin effects, we calculated MOD scores under trait models with and without imprinting. In addition, for the microsatellite data, the MOD-score analysis was performed with sex-averaged as well as sex-specific maps. The highest linkage peaks were obtained on chromosomes 1, 2, 7, 10, 12, 13, 15, and 21. There was evidence for paternal imprinting at the loci on chromosomes 2, 10, 12, 13, 15, and 21. A tendency to maternal imprinting was observed at two loci on chromosome 7. Our findings underscore the fact that an adequate modeling of the genotype-phenotype relation is crucial for the genetic mapping of a complex trait.

Alcoholism↗
PubMed2005

A genome-wide set of congenic mouse strains derived from DBA/2J on a C57BL/6J background.

In the analysis of complex traits, congenic strains are powerful tools because they allow characterization of a single locus in the absence of genetic variation throughout the remainder of the genome. Here, we report the construction and initial characterization of a genome-wide panel of congenic strains derived from the donor strain DBA/2J on the background strain C57BL/6J. For many strains, we have carried out high-density SNP genotyping to precisely map the congenic interval and to identify any contaminating regions. Certain strains exhibit striking variation in litter size and in the ratio of females to males. We illustrate the utility of the set by "Mendelizing" the complex trait of myocardial calcification. These 65 strains cover more than 95% of the autosomal genome and should facilitate the analysis of the many genetic trait differences that have been reported between these parental strains.

Animals↗
PubMed2006

Genetic linkage of human height is confirmed to 9q22 and Xq24.

Human height is an important and heritable trait. Our previous two genome-wide linkage studies using 630 (WG1 study) and an extended sample of 1,816 Caucasians (WG2 study) identified 9q22 [maximum LOD score (MLS)=2.74 in the WG2 study] and preliminarily confirmed Xq24 (two-point LOD score=1.91 in the WG1 study, 2.64 in the WG2 study) linked to height. Here, with a much further extended large sample containing 3,726 Caucasians, we performed a new genome-wide linkage scan and confirmed, in high significance, the two regions' linkage to height. An MLS of 4.34 was detected on 9q22 and a two-point LOD score of 5.63 was attained for Xq24. In an independent sub-sample (i.e., the subjects not involved in the WG1 and WG2 studies), the two regions also achieved significant empirical P values (0.002 and 0.004, respectively) for "region-wise" linkage confirmation. Importantly, the two regions were replicated on a genotyping platform different from the WG1 and WG2 studies (i.e., a different set of markers and different genotyping instruments). Interestingly, 9q22 harbors the ROR2 gene, which is required for growth plate development, and Xq24 was linked to short stature. With the largest sample from a single population of the same ethnicity in the field of linkage studies for complex traits, our current study, together with two previous ones, provided overwhelming evidence substantiating 9q22 and Xq24 for height variation. In particular, our three consecutive whole genome studies are uniquely valuable as they represent the first practical (rather than simulated) example of how significant increase in sample size may improve linkage detection for human complex traits.

Adult↗
PubMed1999

Genetic basis of cerebrovascular accidents associated with hypertension.

Among hypertension-associated cardiovascular diseases, stroke represents one of the most common disorders. In fact, it significantly affects mortality and morbidity rates of all industrialized countries. Only recently, stroke has been considered as a complex trait and not as a mere consequence of hypertension. Indeed, it appears to be the result of an interaction among several genetic and environmental factors. The identification of the genetic determinants of stroke is a difficult task in humans, due to the genetic heterogeneity of human populations and the confounding presence of other risk factors. Thus, an experimental approach, through the use of a highly inbred animal model for stroke, offers a valuable alternative and additional support for a genetic dissection of cerebrovascular disease. In fact, the genetic analysis of stroke in the animal model of the stroke-prone spontaneously hypertensive rat provided clear evidence that stroke is a genetically determined complex trait, and that factors such as blood pressure and diet only play a permissive role. Finally, by using the experimental approach, we established that the gene encoding atrial natriuretic peptide, significantly linked to cerebrovascular disease in rats, is a genetic determinant of stroke in humans. The identification of the genetic basis of stroke represents an important step towards the institution of targeted preventive and therapeutic approaches to reduce the risks of cerebrovascular accidents. This article reviews the background, the experimental approach and the outcome of a strategy based on the use of the stroke-prone spontaneously hypertensive rat model, which aims at identifying the genetic basis of stroke.

Animals↗
PubMed2003

Genetic markers and their application in poultry breeding.

The current chicken genetic map contains at least 1,965 loci within 50 linkage groups, and it covers about 4,000 cM. About 235 of these loci have homology with known human or mammalian genes. The remaining loci are anonymous molecular DNA markers, including microsatellites, amplified fragment length polymorphism (AFLP), randomly amplified polymorphic DNA (RAPD), CR1 elements, and others. A third generation genetic map for human uses single nucleotide polymorphisms (SNP), which have allowed the mapping of complex traits by linkage disequilibrium. One advantage of SNP is that they are usually linked to the gene of interest, and association of the SNP with traits of economic importance can be analyzed using candidate gene approaches. With the tremendous advancements in characterizing chicken expressed sequence tags (EST), the identification of genetic polymorphisms such as SNP in chicken genes has become a reality. Our laboratory has undertaken an in silico analysis of the chicken EST at the University of Delaware by using a Phred/Phrap/Polyphred/Consed pipeline to identify candidate chicken SNP. Initial scanning of 23,427 chicken EST identified a total of 1,209 candidate SNP, with at least 182 non-synonymous SNP that result in an amino acid change observed. Validation of these candidate chicken SNP is ongoing. Placement of the SNP on the chicken genetic map will enhance marker density, thus allowing for mapping of complex traits through linkage analysis and linkage disequilibrium. Application of SNP to identify disease resistance genes in chickens is of special interest to our laboratory, especially in regards to Marek's disease and coccidiosis.

Animal Husbandry↗
PubMed2000

Genetic variation in coronary heart disease and myocardial infarction: methodological overview and clinical evidence.

The precise molecular mechanisrms that lead to coronary artery disease (CAD) and myocardial infarction (MI) are not understood, despite a wealth of knowledge on predisposing risk factors and pathomechanisms. CAD and MI are complex genetic diseases; neither the environment alone nor a single gene cause disease, but a mix of environmental and genetic factors lead to atherosclerosis of the coronary arteries and subsequent manifestation of clinical disease. The biological complexity of atherosclerotic disease results from unknown or unpredictable interactions of many genetic and environmental factors which, by themselves, have only been partially identified. According to current knowledge, genetic variations in causative or susceptihility genes form the basis of molecular mechanisms that, together with environmental impact, lead to CAD/MI and determine its clinical course. Linkage analysis, which follows 'disease' alleles in families, or genetic association in a population of unrelated individuals are tools used in the search for chromosomal loci and candidate genes that are involved in these complex diseases. Progress in sequencing and mapping of the human genorne and efforts to identify all of the expected one million single nucleotide polymorphisms (SNPs) expected to be present in mankind will allow new approaches such as genome-wide association studies. The contribution of the current state of knowledge on genetic variation in man towards the dissection of CAD/MI as complex traits is sobering. Raised expectations with regard to the power of molecular genetic studies as compared to the traditional pathophysiological experimental approaches, lack of precise clinical phenotyping, lack of functional characterisation of gene variants, and the vast number of yet undetected genes may provide some explanation. Except for certain polymorphisms in lipid genes (i.e., apolipoprotein E [apo E]) or rare genetic variations (i.e., LDL receptor), which have a causal effect on both the intermediate (LDL-cholesterol level in plasma) and the clinical phenotypes (CAD/MI), the role of most gene polymorphisms is controversial or unknown. Despite the enormous progress in sequencing the human genome and in molecular genetic and bioinformatic techniques during the past decade, the progress in mapping and identifying genes responsible for complex traits such as CAD/MI has been modest and presents a formidable challenge to medical research in the 21st century.

Coronary Disease↗
PubMed2001

Linkage and association: basic concepts.

Many investigators are turning their efforts to dissecting the etiology of complex traits. The primary tools for gene discovery, localization, and functional analysis are linkage and association studies. While the conceptual underpinnings of these approaches have long been known, advances in recent decades in molecular genetics, in the development of efficient computational algorithms, and in computing power have enabled the large-scale application of these methods. Here, we review the biological basis of linkage and association among loci and the common methods used to assess these relationships with respect to observed phenotypes. We further consider the two most common approaches--genome scans and candidate gene studies--especially their respective strengths, weaknesses, and resource requirements. Finally, we highlight some of the major challenges that arise from these investigative approaches and those that are inherent in the nature of complex traits. The chapters that follow elaborate on many of these topics.

Chromosome Mapping↗
PubMed2001

Linkage disequilibrium mapping: the role of population history, size, and structure.

Linkage disequilibrium mapping attempts to infer the location of a disease gene from observed associations between marker alleles and disease phenotype. This approach can be quite powerful when disease chromosomes are descended from a single founder mutation and the markers considered are tightly linked to the disease locus. The success of linkage disequilibrium map ping in fine-scale localization has led to the suggestion that genome-wide association testing might be useful in the detection of susceptibility genes for complex traits. Such studies would likely be performed in small, relatively isolated founder populations, where heterogeneity of the disease is less likely. To interpret the patterns of association observed in such populations, we need to understand the effect of population size, history, and structure on linkage disequilibrium. In this chapter, we first review measures of allelic association at a single locus. Measures of association between two loci are described, and some theoretical results are reviewed. We then consider some methods for inferring linkage between a marker and a rare disease, focusing on those that model the ancestry of the disease chromosomes. Next we discuss factors whose effect on disequilibrium are understood, and finally we describe the characteristics of some human populations that may be useful for disequilibrium mapping of complex traits.

Analysis of Variance↗
PubMed2003

Identifying loci for behavioral traits using genome-tagged mice.

Identification of behavioral loci through complex trait mapping remains a widely employed approach but suffers from poor gene localization and low replicability. Genome-tagged mice (GTMs) are overlapping sets of congenic strains spanning the whole genome and offer the possibilities of superior mapping power and reproducibility. In this study, three GTM strains each consisting of an average approximately 27 cM DBA/2J genomic intervals introgressed onto a C57BL/6J background were employed for localization of behavioral traits. These GTMs were chosen because the corresponding chromosomal regions had been previously identified as containing loci for learning and memory. Analysis of the GTMs allowed confirmation of the learning and memory loci, and one on chromosome 3 was in addition fine mapped to an 8.8-cM region of overlap between two of the GTMs. Moreover, loci for prepulse inhibition of the startle response, acoustic startle response, and spontaneous locomotor activity were also mapped. These results suggest that the GTMs should be a valuable resource for mapping and confirmation of loci contributing to complex behavioral traits in the mouse.

Animals↗
PubMed1998

Chromosomal linkage analysis of porphyria in mice induced by hexachlorobenzene-iron synergism: a model of sporadic porphyria cutanea tarda.

Genetic susceptibility to toxic chemicals is of major importance but most studies concentrate on candidate genes and searches for unknown susceptibility genes are uncommon. Human sporadic porphyria cutanea tarda is usually precipitated by alcohol, oestrogens, hepatitis viruses, HIV or haemodialysis. The mechanism is not known but there is a role for iron metabolism and an underlying genetic predisposition is suspected. A similar porphyria in humans has also been caused by hexachlorobenzene. These human porphyrias can be modelled in iron-loaded mice exposed to hexachlorobenzene, in which C57BL/10ScSn is a prototype susceptible strain whereas DBA/2 mice are extremely resistant. A search for susceptibility genes was undertaken using complex trait analysis with DNA microsatellite markers of 'high' and 'low' responders from an F2 intercross. Correlation of markers with susceptibility, defined as accumulation of uroporphyrin in the liver, was assessed by chi-squared test for the proportion of C57BL/10ScSn and DBA/2 alleles present. Susceptibility loci on chromosomes 12, 14 and 17 were identified. Further analysis of markers on chromosomes 14 and 17 by MAPMAKER/EXP and MAPMAKER/QTL gave LOD scores of 7.3 and 3.6, respectively. Typing of chromosome 12 for the Ahr gene, using a restriction fragment length polymorphism distinguishing between the b-1 and d alleles, gave significant but not perfect linkage. However, no strong association between alleles or expression of Cyp1a1/2 genes, regulated by Ahr, and susceptibility for porphyria was detected. The results demonstrate that the porphyria induced by hexachlorobenzene in C57BL/10ScSn mice is a complex trait determined by at least three genes, which may be of relevance to susceptibility in the development of sporadic porphyria cutanea tarda and unknown aspects of liver damage.

Animals↗
PubMed2003

Behavior genetics of canine aggression: behavioral phenotyping of golden retrievers by means of an aggression test.

Molecular genetic analysis of complex traits such as aggression strongly depends on careful phenotyping of individuals. When studying canine aggression, the information provided by the owners of the dogs is often not detailed and reliable enough for this purpose. Therefore we subjected 83 golden retrievers, both aggressive and nonaggressive individuals, to a behavioral test. These tests were analyzed with help of an ethogram, resulting in a behavioral profile for each of the dogs. In this article three methods are described of converting these profiles into a measure of behavioral phenotype. The usefulness of the methods is evaluated by comparing the test results with information provided by owners. Moreover, the hypothesis underlying all these methods, that a lowered threshold for aggressive behavior in general is present in the dogs, is also evaluated. Future research will need to reveal whether the methods meet the high standards that are necessary for studying complex traits.

Aggression↗
PubMed2004

Asthma genetics 2003.

The use of positional cloning for the identification of complex trait susceptibility genes has gained momentum with the completion of the human genome project. The approach involves the collection of well-phenotyped cohorts (either family-based or case-control designs), the generation of high-density single-nucleotide polymorphism linkage disequilibrium maps, and the application of powerful statistical methods to localize narrow regions of genetic association with disease. In 2003, two novel genes relating to asthma were identified using this approach, PHF11 and DPP10, neither of which had previously been implicated in the pathobiology of either asthma or allergy. In addition, further support for ADAM33 (the first asthma susceptibility gene identified by positional cloning) as an asthma gene was presented, although with mixed results. These discoveries open new avenues for research in asthma and allergy, and highlight the power (and limitations) of positional cloning for the identification of asthma genes, and complex trait genes in general.

ADAM Proteins↗
PubMed2003

Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q.

It is widely accepted that founder populations hold promise for mapping loci for complex traits. However, the outcome of these mapping efforts will most likely depend on the individual demographic characteristics and historical circumstances surrounding the founding of a given genetic isolate. The 'ideal' features of a founder population are currently unknown. The Micronesian islandic population of Kosrae, one of the four islands comprising the Federated States of Micronesia (FSM), was founded by a small number of settlers and went through a secondary genetic 'bottleneck' in the mid-19th century. The potential for reduced etiological (genetic and environmental) heterogeneity, as well as the opportunity to ascertain extended and statistically powerful pedigrees makes the Kosraen population attractive for mapping schizophrenia susceptibility genes. Our exhaustive case ascertainment from this islandic population identified 32 patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Three of these were siblings in one nuclear family, and 27 were from a single large and complex schizophrenia kindred that includes a total of 251 individuals. One of the most startling findings in our ascertained sample was the great difference in male and female disease rates. A genome-wide scan provided initial suggestive evidence for linkage to markers on chromosomes 1, 2, 3, 7, 13, 15, 19, and X. Follow-up multipoint analyses gave additional support for a region on 2q37 that includes a schizophrenia locus previously identified in another small genetic isolate, with a well-established recent genealogical history and a small number of founders, located on the eastern border of Finland. In addition to providing further support for a schizophrenia susceptibility locus at 2q37, our results highlight the analytic challenges associated with extremely large and complex pedigrees, as well as the limitations associated with genetic studies of complex traits in small islandic populations.

Adolescent↗
PubMed2005

Twin analyses of chronic fatigue in a Swedish national sample.

BACKGROUND: Chronic fatigue has infrequently been studied in twins. Data from twin studies can inform clinical and research approaches to the management and etiology of human complex traits. METHOD: The authors obtained telephone interview data on current chronic fatigue from 31406 individuals twins in the Swedish Twin Registry (aged 42-64 years, 75.68% response rate), from both members of 12407 pairs and from one member of 6592 pairs. Of the complete pairs, 3269 pairs were monozygotic, 9010 pairs dizygotic, and 128 pairs of unknown zygosity. Structural equation twin modeling was used to estimate the latent genetic architecture of varying definitions of fatiguing illness. RESULTS: Estimates of additive genetic effects, shared environmental effects, and individual-specific environmental effects were similar in males and females. No definition of current fatiguing illness (ranging from any fatigue to CFS-like illness) was strikingly distinctive. Individual-specific effects were the predominant source of variation, followed by modest genetic influences. We could not exclude a small but conceptually important contribution of shared environmental effects. CONCLUSIONS: Current fatiguing illness appears to be a complex trait resulting from both environmental and genetic sources of variation without pronounced differences by gender.

Adult↗
PubMed2004

Biologically meaningful expression profiling across species using heterologous hybridization to a cDNA microarray.

BACKGROUND: Unravelling the path from genotype to phenotype, as it is influenced by an organism's environment, is one of the central goals in biology. Gene expression profiling by means of microarrays has become very prominent in this endeavour, although resources exist only for relatively few model systems. As genomics has matured into a comparative research program, expression profiling now also provides a powerful tool for non-traditional model systems to elucidate the molecular basis of complex traits. RESULTS: Here we present a microarray constructed with approximately 4500 features, derived from a brain-specific cDNA library for the African cichlid fish Astatotilapia burtoni (Perciformes). Heterologous hybridization, targeting RNA to an array constructed for a different species, is used for eight different fish species. We quantified the concordance in gene expression profiles across these species (number of genes and fold-changes). Although most robust when target RNA is derived from closely related species (<10 MA divergence time), our results showed consistent profiles for other closely related taxa (approximately 65 MA divergence time) and, to a lesser extent, even very distantly related species (>200 MA divergence time). CONCLUSION: This strategy overcomes some of the restrictions imposed on model systems that are of importance for evolutionary and ecological studies, but for which only limited sequence information is available. Our work validates the use of expression profiling for functional genomics within a comparative framework and provides a foundation for the molecular and cellular analysis of complex traits in a wide range of organisms.

Animals↗
PubMed1998

Environmental factors can confound identification of a major gene effect: results from a segregation analysis of a simulated population of lung cancer families.

Proper control of environmental factors can be crucial to the identification of genes that influence susceptibility to a complex trait, especially for a trait such as lung cancer, for which the environmental factor (smoking) accounts for a significant etiologic fraction of the disease. An earlier segregation analysis of 337 Louisiana families, which incorporated direct measure of tobacco consumption, provided evidence for autosomal codominant inheritance of a major gene that influenced age at onset of lung cancer. Subsequent analyses were performed in which the families were stratified into two subsets based on birth cohort of the proband; results suggested the presence of heterogeneity that were postulated to reflect the influence of cohort trends in tobacco consumption. To evaluate this hypothesis further, we simulated a population of three-generation pedigrees in which an autosomal dominant mode of susceptibility to lung cancer was transmitted, but tobacco use varied across generations corresponding to published trends in smoking. A total of 200,000 individuals in families of various sizes, ages, and cigarette smoking habits were simulated from 1900 to 1980. From this population, 324 families (2,405 individuals) with 380 cases of lung cancer were ascertained through 328 lung cancer probands. Complex segregation analysis was performed using the REGTL program of S.A.G.E. in which pack-years of tobacco exposure were incorporated directly into the likelihood calculations. Although the no major gene, environmental, and Mendelian recessive hypotheses were rejected, both dominant and codominant transmission provided a good fit to the data. Thus in a population of simulated families with autosomal dominant susceptibility to lung cancer, intergenerational differences in tobacco consumption led to the detection of autosomal codominant transmission as an acceptable hypothesis. These results underscore the potential danger of segregation analysis of complex traits in which exposure to known environmental influences may differ across generations.

Computer Simulation↗
PubMed2005

Regulatory variation at glypican-3 underlies a major growth QTL in mice.

The genetic basis of variation in complex traits remains poorly understood, and few genes underlying variation have been identified. Previous work identified a quantitative trait locus (QTL) responsible for much of the response to selection on growth in mice, effecting a change in body mass of approximately 20%. By fine-mapping, we have resolved the location of this QTL to a 660-kb region containing only two genes of known function, Gpc3 and Gpc4, and two other putative genes of unknown function. There are no non-synonymous polymorphisms in any of these genes, indicating that the QTL affects gene regulation. Mice carrying the high-growth QTL allele have approximately 15% lower Gpc3 mRNA expression in kidney and liver, whereas expression differences at Gpc4 are non-significant. Expression profiles of the two other genes within the region are inconsistent with a factor responsible for a general effect on growth. Polymorphisms in the 3' untranslated region of Gpc3 are strong candidates for the causal sequence variation. Gpc3 loss-of-function mutations in humans and mice cause overgrowth and developmental abnormalities. However, no deleterious side-effects were detected in our mice, indicating that genes involved in Mendelian diseases also contribute to complex trait variation. Furthermore, these findings show that small changes in gene expression can have substantial phenotypic effects.

Aging↗