SEARCH · Search PubMed

Results for “complex trait”

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

SourceResearch connectionFrom yearThrough year

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

At least 415 records · Page 23Linked to original sources

PubMed2000

The genetics of multiple sclerosis.

Epidemiological studies implicate an interplay between genetic and environmental factors in the aetiology of multiple sclerosis. The classical genetic observations suggest that multiple sclerosis is a complex trait in which susceptibility is determined by several genes acting independently or epistatically. The main dividend from understanding the genetic basis of susceptibility in multiple sclerosis will be an improved understanding of the pathogenesis. To date, candidate gene approaches have proved relatively unrewarding other than in establishing the association with alleles of the major histocompatibility complex (MHC). In common with most other complex traits, no major susceptibility gene has been identified through full genome screens but regions of interest have provisionally been identified. An important part of future studies in the genetics of multiple sclerosis will be to resolve the question of disease heterogeneity.

Genetic Predisposition to Disease↗

PubMed2004

Statistical tests for admixture mapping with case-control and cases-only data.

Admixture mapping is a promising new tool for discovering genes that contribute to complex traits. This mapping approach uses samples from recently admixed populations to detect susceptibility loci at which the risk alleles have different frequencies in the original contributing populations. Although the idea for admixture mapping has been around for more than a decade, the genomic tools are only now becoming available to make this a feasible and attractive option for complex-trait mapping. In this article, we describe new statistical methods for analyzing multipoint data from admixture-mapping studies to detect "ancestry association." The new test statistics do not assume a particular disease model; instead, they are based simply on the extent to which the sample's ancestry proportions at a locus deviate from the genome average. Our power calculations show that, for loci at which the underlying risk-allele frequencies are substantially different in the ancestral populations, the power of admixture mapping can be comparable to that of association mapping but with a far smaller number of markers. We also show that, although "ancestry informative markers" (AIMs) are superior to random single-nucleotide polymorphisms (SNPs), random SNPs can perform quite well when AIMs are not available. Hence, researchers who study admixed populations in which AIMs are not available can perform admixture mapping with the use of modestly higher densities of random markers. Software to perform the gene-mapping calculations, "MALDsoft," is freely available on the Pritchard Lab Web site.

Chromosome Mapping↗

PubMed2004

Geographic stratification of linkage disequilibrium: a worldwide population study in a region of chromosome 22.

Recent studies of haplotype diversity in a number of genomic regions have suggested that long stretches of DNA are preserved in the same chromosome, with little evidence of recombination events. The knowledge of the extent and strength of these haplotypes could become a powerful tool for future genetic analysis of complex traits. Different patterns of linkage disequilibrium (LD) have been found when comparing individuals of African and European descent, but there is scarce knowledge about the worldwide population stratification. Thus, the study of haplotype composition and the pattern of LD from a global perspective are relevant for elucidating their geographical stratification, as it may have implications in the future analysis of complex traits. We have typed 12 single nucleotide polymorphisms in a chromosome 22 region--previously described as having high LD levels in European populations--in 39 different world populations. Haplotype structure has a clear continental structure with marked heterogeneity within some continents (Africa, America). The pattern of LD among neighbouring markers exhibits a strong clustering of all East Asian populations on the one hand and of Western Eurasian populations (including Europe) on the other, revealing only two major LD patterns, but with some very specific outliers due to specific demographic histories. Moreover, it should be taken into account that African populations are highly heterogeneous. The present results support the existence of a wide (but not total) communality in LD patterns in human populations from different continental regions, despite differences in their demographic histories, as population factors seem to be less relevant compared with genomic forces in shaping the patterns of LD.

Asia↗

PubMed2005

Linkage disequilibrium and association studies in higher plants: present status and future prospects.

During the last two decades, DNA-based molecular markers have been extensively utilized for a variety of studies in both plant and animal systems. One of the major uses of these markers is the construction of genome-wide molecular maps and the genetic analysis of simple and complex traits. However, these studies are generally based on linkage analysis in mapping populations, thus placing serious limitations in using molecular markers for genetic analysis in a variety of plant systems. Therefore, alternative approaches have been suggested, and one of these approaches makes use of linkage disequilibrium (LD)-based association analysis. Although this approach of association analysis has already been used for studies on genetics of complex traits (including different diseases) in humans, its use in plants has just started. In the present review, we first define and distinguish between LD and association mapping, and then briefly describe various measures of LD and the two methods of its depiction. We then give a list of different factors that affect LD without discussing them, and also discuss the current issues of LD research in plants. Later, we also describe the various uses of LD in plant genomics research and summarize the present status of LD research in different plant genomes. In the end, we discuss briefly the future prospects of LD research in plants, and give a list of softwares that are useful in LD research, which is available as electronic supplementary material (ESM).

Chromosome Mapping↗

PubMed2002

Behavioural and physiological characterization of inbred mouse strains: prospects for elucidating the molecular mechanisms of mammalian learning and memory.

With the advent of recombinant DNA methodology, it has become possible to dissect the molecular mechanisms of complex traits, including brain function and behaviour. The increasing amount of available information on the genomes of mammalian organisms, including our own, has facilitated this research. The present review focuses on a somewhat neglected area of genetics, one that involves the study of inbred mouse strains. It is argued that the use of inbred mice is complementary to transgenic approaches in the analysis of molecular mechanisms of complex traits. Whereas transgenic technology allows one to manipulate a single gene and investigate the in vivo effects of highly specific, artificially induced mutations, the study of inbred mouse strains should shed light on the roles of naturally occurring allelic variants in brain function and behaviour. Systematic characterization of the behavioural, electrophysiological, neurochemical, and neuroanatomical properties of a large number of inbred strains is required to elucidate mechanisms of mammalian brain function and behaviour. In essence, a 'mouse phenome' project is needed, entailing the construction of databases to investigate possible causal relationships amongst the phenotypical characteristics. This review focuses on electrophysiological and behavioural characterization of mouse strains. Nevertheless, it is emphasized that the full potential of the analysis of inbred mouse strains may be attained if techniques of numerous disciplines, including gene expression profiling, biochemical analysis, and quantitative trait loci (QTL) mapping, to name but a few, are also included.

Animals↗

PubMedDate not supplied

Canavan disease: a monogenic trait with complex genomic interaction.

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.

Amidohydrolases↗

PubMed2002

The genetics of variation in gene expression.

The genetic basis of variation in gene expression lends itself to investigation by microarrays. For genetic analysis, we view the expression level of a gene as a quantitative or 'complex' trait, analogous to an individual's height or cholesterol level, and, therefore, as an inherited phenotype. Several genetic analyses of 'gene expression phenotypes' have been carried out in experimental organisms, and initial steps have been taken toward similar studies in humans--although these present challenging technical and statistical problems. Further advances in the genetic analysis of variation in gene expression will contribute to our understanding of transcriptional regulation and will provide models for studying other quantitative and complex traits.

Animals↗

PubMed2001

Exploring haplotype sharing methods in general and isolated populations to detect gene(s) of a complex genetic trait.

We applied a new haplotype sharing method to the simulated Genetic Analysis Workshop 12 data for both isolated and general populations without knowledge of the disease model, using affection status as phenotype and three different sample sizes. The highest peak for the mean sharing of the haplotypes was found in the isolated population for the markers D06G034 and D06G035, which flank the candidate genes located on chromosome 6, with -log10(p) values of 2.9 and 7.0 in the moderate and large study samples, respectively. The whole genome screen detected three further loci with -log10(p) values of 3.0, which turned out to be false positives. None of the true gene loci were detected in the general population even in the largest sample. The test of linkage disequilibrium based on excess haplotype sharing over the linkage equilibrium expectation revealed z-values one order of magnitude higher in the isolated than in the general population. This approach appears to be promising for mapping genes of complex diseases depending on population characteristics.

Chromosome Mapping↗

PubMed1980

[Relationship between personality traits and complex therapy of chronic alcoholic patients].

The paper is concerned with results of complex psychotherapy attained in the course of the treatment of 103 patients with chronic alcoholism. The perception of ones own disease in patients with chronic alcoholism is discussed. The psychotherapeutic approach and the content of work, in order to achieve the sobering aim in individual and group psychotherapy in a vigilant state are described. The paper also discusses questions of adaptation to the environment on a sobering level, as well as problems of differentiated psychotherapy depending upon the typological personality traits.

Adult↗

PubMed2004

[The genetics HIV cohort of the Swiss HIV Cohort Study--facing the new challenges in medicine].

Host genetic factors determine the individual natural course of HIV infection and influence the response to therapy and the occurrence of adverse events to treatment. Variants of multiple genes are associated with faster but also slower development of severe immunodeficiency. However, only very rarely the variant of one single gene explains a specific clinical phenotype. But multiple genetic marker form a complex trait, which is difficult to analyse biostatistically. Research in this rapidly evolving field asks for structures in which hypotheses can be generated and evaluated and which combine basic and diagnostic and therapeutic research. The large amount of prospective information on HIV disease natural history and treatment response of the Swiss HIV Cohort Study will make of the Genetics project an excellent test-setting for some of the immediate difficulties in this research field: validation of new markers and modelling of complex traits.

Anti-HIV Agents↗

PubMed2023

Pervasive correlations between causal disease effects of proximal SNPs vary with functional annotations and implicate stabilizing selection.

The genetic architecture of human diseases and complex traits has been extensively studied, but little is known about the relationship of causal disease effect sizes between proximal SNPs, which have largely been assumed to be independent. We introduce a new method, LD SNP-pair effect correlation regression (LDSPEC), to estimate the correlation of causal disease effect sizes of derived alleles between proximal SNPs, depending on their allele frequencies, LD, and functional annotations; LDSPEC produced robust estimates in simulations across various genetic architectures. We applied LDSPEC to 70 diseases and complex traits from the UK Biobank (average N=306K), meta-analyzing results across diseases/traits. We detected significantly nonzero effect correlations for proximal SNP pairs (e.g., -0.37±0.09 for low-frequency positive-LD 0-100bp SNP pairs) that decayed with distance (e.g., -0.07±0.01 for low-frequency positive-LD 1-10kb), varied with allele frequency (e.g., -0.15±0.04 for common positive-LD 0-100bp), and varied with LD between SNPs (e.g., +0.12±0.05 for common negative-LD 0-100bp) (because we consider derived alleles, positive-LD and negative-LD SNP pairs may yield very different results). We further determined that SNP pairs with shared functions had stronger effect correlations that spanned longer genomic distances, e.g., -0.37±0.08 for low-frequency positive-LD same-gene promoter SNP pairs (average genomic distance of 47kb (due to alternative splicing)) and -0.32±0.04 for low-frequency positive-LD H3K27ac 0-1kb SNP pairs. Consequently, SNP-heritability estimates were substantially smaller than estimates of the sum of causal effect size variances across all SNPs (ratio of 0.87±0.02 across diseases/traits), particularly for certain functional annotations (e.g., 0.78±0.01 for common Super enhancer SNPs)-even though these quantities are widely assumed to be equal. We recapitulated our findings via forward simulations with an evolutionary model involving stabilizing selection, implicating the action of linkage masking, whereby haplotypes containing linked SNPs with opposite effects on disease have reduced effects on fitness and escape negative selection.

Journal Article↗

PubMed2003

Genetics of macular dystrophies and implications for age-related macular degeneration.

Determining the genetic component of the age-related macular degeneration (AMD) complex trait has been the primary goal of ophthalmic genetics research for almost a decade. During this time, genes of several Mendelian traits affecting the macula have been identified. In this review, we will discuss the consequences of molecular defects in the VMD2, EFEMP1, TIMP3, ELOVL4 and ABCA4 genes, and their association with macular disease. We will also analyze our current knowledge on the implications of genetic variations in these genes for AMD by summarizing data from all studies which have investigated the possible role of these candidate genes in the etiology of AMD. Finally, we will elaborate on methods for genetic dissection of complex traits and discuss the appropriate applications of these methods for identifying genetic determinants of AMD.

Humans↗

PubMed2023

Pervasive correlations between causal disease effects of proximal SNPs vary with functional annotations and implicate stabilizing selection.

Journal Article↗

PubMed2004

Adult-onset Alopecia areata is a complex polygenic trait in the C3H/HeJ mouse model.

Alopecia areata (AA) is an autoimmune disease that targets actively growing (anagen) hair follicles in humans and other mammals. C3H/HeJ, but not C57BL/6J, mice spontaneously develop an adult-onset form of AA. A segregating population of C3HB6F2 female mice (n=1096), generated from crossing these two strains, was used for genome-wide linkage analysis to identify AA genetic susceptibility. Previous analysis identified susceptibility intervals on chromosomes 17 (Alaa1) and 9 (Alaa2). Using additional markers in these intervals and saturation mapping purported intervals on chromosomes 8 and 15, two additional regions were identified (Alaa3 and Alaa4, respectively). Human gene association studies identified specific human leukocyte antigen intervals comparable with those (major histocompatibility complex) found in Alaa1 in the mouse. Other human studies identified genes not found in this linkage study, but these human transcription factors are directly regulated by genes within Alaa1. These results indicate the necessity of integrating both gene association and genome-wide linkage studies in both mice and humans to understand the complex nature of these and other polygenic diseases.

Age of Onset↗

PubMed1999

The genetic epidemiology of multiple sclerosis.

Epidemiological studies have implicated an interplay between genetic and environmental factors in the aetiology of multiple sclerosis (MS). There is a familial recurrence rate of approximately 15%. Meta-analysis of the recurrence risk shows that the rate is highest overall for siblings, then parents and children, with lower rates in second- and third-degree relatives. Recurrence is highest for monozygotic twins. Conversely, the frequency in adoptees is similar to the population lifetime risk. The age-adjusted risk for half siblings is also less than for full siblings. Recurrence is higher in the children of conjugal pairs with MS than the offspring of single affected. These classical genetic observations suggest that MS is a complex trait in which susceptibility is determined by several genes acting independently or epistatically. Comparisons between co-affected sibling pairs provide no evidence for correlation with age or year at onset and mode of presentation or disability. Thus far, the identification of susceptibility genes has proved elusive but genetic strategies are now in place which should illuminate the problem. The main dividend will be an improved understanding of the pathogenesis. To date, population studies have demonstrated an association between the class II major histocompatibility complex (MHC) alleles DR15 and DQ6 and their corresponding genotypes. An association with DR4, with or without the primary DR15 link, is seen in some Mediterranean populations. Candidate gene approaches have otherwise proved unrewarding. Four groups of investigators have undertaken a systematic search of the genome. In common with most other complex traits, no major susceptibility gene has been identified but regions of interest have been provisionally identified. These genetic analyses are predicated on the assumption that MS is one disease. Genotypic and phenotypic analyses are beginning to question this assumption. A major part of future studies in the genetics of MS will be to resolve the question of disease heterogeneity.

Europe↗

PubMed2000

Transmission/disequilibrium tests using multiple tightly linked markers.

Transmission/disequilibrium tests have attracted much attention in genetic studies of complex traits because (a) their power to detect genes having small to moderate effects may be greater than that of other linkage methods and (b) they are robust against population stratification. Highly polymorphic markers have become available throughout the human genome, and many such markers can be studied within short physical distances. Studies using multiple tightly linked markers are more informative than those using single markers. However, such information has not been fully utilized by existing statistical methods, resulting in possibly substantial loss of information in the identification of genes underlying complex traits. In this article, we propose novel statistical methods to analyze multiple tightly linked markers. Simulation studies comparing our methods versus existing methods suggest that our methods are more powerful. Finally, we apply the proposed methods to study genetic linkage between the dopamine D2 receptor locus and alcoholism.

Alcoholism↗

PubMed1995

Genetics of multiple sclerosis.

The cause of MS is unknown. There is considerable circumstantial evidence that MS is a complex trait, probably autoimmune in nature, and is determined by both genetic and environmental factors. At present, it must be acknowledged, however, that our understanding of the pathogenesis of MS is minimal. Very little is known about the genes determining disease susceptibility and perhaps even less is understood about environmental factors that influence penetrance or the geographic distribution. This lack of knowledge results neither from lack of effort nor from a shortage of fertile imaginations. Almost every imaginable hypothesis has, in the past, found some support. The intractability of the problem could well result from its complexity, because answers to testable hypotheses are commonly negative or ambiguous. Today, the opportunity exists for researchers to provide such answers because of recent major developments. The first development is the recognition that MS research requires a relatively large pool of well-ascertained, carefully diagnosed, and longitudinally well-characterized MS patients. The last two developments are the identification and successful application of statistical and molecular genetic techniques carrying sufficient power to allow the exploration of complex traits such as MS.

Animals↗

PubMed2005

The non-major histocompatibility complex quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation, and joint damage.

OBJECTIVE: To construct rats congenic for the chromosome 2 arthritis-regulatory quantitative trait locus Cia10, originally identified in a (DA x ACI)F(2) intercross rat strain that had been assessed for collagen-induced arthritis (CIA), and to determine the effect of this congenic interval on arthritis severity, joint histologic structure, and cytokine transcription in rats with pristane-induced arthritis (PIA). METHODS: A 52.6-MB interval derived from the ACI (CIA- and PIA-resistant) strain and containing the Cia10 interval was introgressed into the DA (arthritis-susceptible) background through genotype-guided congenic breeding. Homozygous male and female DA.ACI(Cia10) congenic rats were studied for their susceptibility to and severity of PIA, and were compared with same-sex DA rats. Histologic analyses were done on hind paws collected on day 32 following the pristane injection. Levels of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) messenger RNA (mRNA) were measured with real-time polymerase chain reaction on synovial tissues from day-32 ankles. RESULTS: Both male and female DA.ACI(Cia10) congenic rats developed a significantly milder form of arthritis, with a 95% and 92% reduction in the arthritis severity index compared with DA male and female controls, respectively (males P < or = 0.001 and females P = 0.003). DA.ACI(Cia10) congenic rat synovial tissue was more likely to preserve its normal histologic architecture, including minimal to no cartilage and bone erosions, synovial hyperplasia, and pannus formation, and reduced numbers of vessels (angiogenesis), when compared with DA synovial tissue. There was a 2.7- and 2.4-fold reduction in the amount of IL-1beta and TNFalpha mRNA, respectively, in the synovial tissue of DA.ACI(Cia10) congenic rats compared with DA rats. Sequencing analyses of complementary DNA for the Cia10-predicted candidate gene Ptpn8, the rat homolog of the rheumatoid arthritis (RA)-susceptibility gene PTPN22, revealed no polymorphisms between the DA and ACI strains. CONCLUSION: This study determined that Cia10 harbors a major autoimmune arthritis-regulatory gene. This gene regulates clinical disease severity, histologic damage, and the levels of at least two central proinflammatory cytokines. We are in the process of narrowing down the critical region for positional cloning of the Cia10 gene. The identification of this gene will provide novel targets or pathways for focused candidate-gene studies in RA.

Animals↗