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Results for “population stratification”

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At least 145 records · Page 8Linked to original sources
PubMed2003

Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta.

OBJECTIVE: Certain forms of primary osteoarthritis (OA), particularly those affecting hand joints, have a genetic component. Recent studies have shown suggestive evidence that hand and knee OA are linked with the interleukin-1 (IL-1) region on human chromosome 2q. This study was undertaken to assess the association of primary OA of the hand (hand OA) with IL-1 region markers. METHODS: Sixty-eight US Caucasoid cases and 51 US Caucasoid controls aged 60 years or older were recruited from the Mid-Atlantic region of the United States. Hand OA was classified by American College of Rheumatology (ACR) Clinical Criteria, and cases were subjected to radiographic examination for subgrouping. Genotyping was done for seven previously described single nucleotide polymorphisms (SNPs) of genes for IL-1alpha (encoded by IL1A), IL-1beta (IL1B), and the IL-1 receptor antagonist (IL1RN), as well as an IL1RN variable number of tandem repeat (VNTR) marker. Six microsatellite markers on other chromosomes (null loci) were also typed. RESULTS: The IL1B 5810 G>A SNP genotypes marker were not in Hardy-Weinberg equilibrium (p<0.05 in both non-erosive and erosive hand OA subgroups). Statistically significant association with the IL1B 5810 AA genotype was found in the erosive hand OA subgroup (relative risk 3.8, p=0.007). This IL1B 5810 AA genotype association was also significant between erosive and non-erosive hand OA subjects (relative risk 4.01, p=0.008). As expected, significant linkage disequilibrium was present between IL1B 5810 SNP and IL1A (-)889 SNP, other IL1B SNPs, and the nearest IL1RN SNP examined. The IL1B 5810A allele occurs most frequently on haplotypes with the SNP alleles IL1B 1423C, IL1B 1903T, IL1B 5887C, and IL1A (-)889C. Genotypes at null loci failed to show evidence suggesting population stratification that might account for spurious association. CONCLUSION: Statistical evidence shows association between erosive hand OA and a genomic region containing the IL1B 5810 SNP in a US Caucasoid population. This supports a potential role for IL-1 in the pathogenesis of a severe phenotype of hand OA.

Aged↗
PubMed2004

[Issues on association studies on complex diseases].

Association study is widely used in elucidating genetic basis of complex diseases such as cardiovascular diseases, type 2 diabetes, essential hypertension and obesity. Some issues were discussed in the review, which include defining and controlling of confounding effects, selection of candidate genes and single nucleotide polymorphisms (SNPs), application of intermediate phenotype and haplotype analyses as well as judgement of the result in association studies. Population stratification is one of the major causes of confounding in association studies. It could be reduced by selecting relatives of affected patients as control, genome control and by using isolated populations which have higher homogeneity in genetic background. A candidate gene could be selected because of its' biological association with some disease or being congenerous to a known gene related to the disease. Appropriate application of intermediate phenotype of diseases and haplotype analyses may increase the opportunity to obtain meaningful findings in association studies. An optimal study design, sufficient sample size and proper controls, in conjunction of modern statistic analyses, association analyses would exert its effect on studies on susceptibility of human common diseases.

Cardiovascular Diseases↗
PubMed1998

Stratification in clinical trials of febrile neutropenia.

Patients with febrile neutropenia are characterized by well described prognostic factors leading to heterogeneity of risk of serious clinical outcomes. These prognostic factors complicate the design and interpretation of clinical trials of antimicrobial therapy in this population. Stratification is a method by which comparability of groups is ensured. This method can be employed prior to randomization or during the analysis. Factors that should be considered for stratification prior to randomization include the underlying neoplasm (leukemia vs solid tumor vs BMT), use of granulocyte growth factors, comorbid conditions and study site (in multicenter trials). In stratified analyses, trend in neutrophil count, site of infection, organism and susceptibility should be considered.

Anti-Bacterial Agents↗
PubMed1997

Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects.

The SLC6A4 locus encodes the serotonin transporter, which in turn mediates the synaptic inactivation of the neurotransmitter serotonin. Two PCR-formatted polymorphisms at this locus have been described, the first of which is a variable number tandem repeat located in exon 2, and the second a repeat sequence polymorphism located in the promoter region. The latter polymorphism alters transcriptional activity of SLC6A4, and has been reported to be associated with anxiety and depression-related traits. We studied allele frequencies, and computed haplotype frequencies and linkage disequilibrium measures, for these two polymorphisms in European-American, African-American, and Japanese populations, and in a set of alcohol-dependent European-American subjects. Allele frequencies for both systems showed variation, with significant differences overall for each system, and significant differences between each pair of populations for both systems. Linkage disequilibrium also varied among the populations. There were no significant differences in allele or haplotype frequencies between the European-American population samples and alcohol-dependent subjects. The population differences demonstrate a potential for population stratification in association studies of either of these SLC6A4 polymorphisms. If genetic variation at this locus really is associated with behavioral variation, these results could reflect either different behavioral adaptations in different populations, or random genetic drift of a behaviorally important but selectively neutral polymorphism.

Alcoholism↗
PubMed2005

Sequence variants of the DRD4 gene in autism: further evidence that rare DRD4 7R haplotypes are ADHD specific.

A high prevalence of rare dopamine receptor D4 (DRD4) alleles in children diagnosed with attention-deficit hyperactivity disorder (ADHD) has been reported [Grady et al., 2003]. In this prior study, extensive resequencing/haplotype data of the DRD4 locus was used to suggest that population stratification was not the explanation for the high prevalence of rare alleles. In the current study, DNA resequencing/haplotyping was conducted on 136 DRD4 alleles obtained from autism probands, collected from the same geographic population as the prior ADHD probands (Orange County, CA). A number of studies have suggested that the susceptibility genes underlying these two disorders might partially overlap. Rare DRD4 variants were not uncovered in this autism sample beyond that expected by chance. These results suggest strongly that the high prevalence of rare DRD4 alleles in ADHD probands is due to ascertainment of the sample by diagnosis of ADHD.

Alleles↗
PubMed2006

Case-control studies in the genomic era: a clinician's guide.

The goal of case-control association studies is to find genetic variants in the human genome that influence common traits. The Human Genome and HapMap projects have added fresh impetus to this goal by cataloguing the raw genetic data behind human DNA variation. Studies that associate these genetic variants with phenotype improve both molecular diagnostics and drug discovery and offer clinicians important opportunities to improve care of patients. In this review I focus on case-control studies, which are the most widely used design and expected to be the most powerful. I also address the problem of case-control non-replication, which is widespread despite enormous effort and use of resources. Important causes of non-replication include inadequate statistical power to detect small and moderate effects, phenotype heterogeneity, population stratification, publication bias, and multiple comparison testing.

Case-Control Studies↗
PubMed2003

Tests for a disease-susceptibility locus allowing for an inbreeding coefficient (F).

We begin by discussing the false positive test results that arise because of cryptic relatedness and population substructure when testing a disease susceptibility locus. We extend and evaluate the Hardy-Weinberg disequilibrium (HWD) method, allowing for an inbreeding coefficient (F) in a similar way that Devlin and Roeder (1999) allowed for inbreeding in a case-control study. Then we compare the HWD measure and the common direct measure of linkage disequilibrium, both when there is no population substructure (F = 0) and when there is population substructure (F not = 0), for a single marker. The HWD test statistic gives rise to false positives caused by population stratification. These false positives can be controlled by adjusting the test statistic for the amount of variance inflation caused by the inbreeding coefficient (F). The power loss for the HWD test that arises when controlling for population structure is much less than that which arises for the common direct measure of linkage disequilibrium. However, in the multiplicative model, the HWD test has virtually no power even when allowing for non-zero F.

Computer Simulation↗
PubMed2006

The effect of assortative mating upon genetic association studies: spurious associations and population substructure in the absence of admixture.

Spurious associations due to confounding factors are an often cited and intensely debated concern for genetic association studies. Great attention has been focused upon the specific threat of confounding due to population stratification. This emphasis has spurred the development of many statistical genetic methods to detect and correct for the potentially confounding effects of admixture. Unfortunately, this emphasis on admixture has led some authors to suggest that if ethnically homogenous populations are used, spurious associations are unlikely to occur. We show that under small and realistic degrees of assortative mating over time, spurious associations arise even in ethnically homogeneous populations. We demonstrate that structured association and genomic control tests can, under certain conditions, correct for these spurious associations. We conclude that investigators should not assume spurious associations will not occur in association studies using ethnically homogenous populations and recommend the use of genomic control methods and/or family-based association tests within genetic association studies.

Chromosome Mapping↗
PubMed2006

Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence.

We examined 13 single nucleotide polymorphisms (SNPs) spanning the coding region of the mu-opioid receptor gene (OPRM1), among 382 European Americans (EAs) affected with substance dependence [alcohol dependence (AD) and/or drug dependence (DD)] and 338 EA healthy controls. These SNPs delineated two haplotype blocks. Genotype distributions for all SNPs were in Hardy-Weinberg equilibrium (HWE) in controls, but in cases, four SNPs in Block I and three SNPs in Block II showed deviation from HWE. Significant differences were found between cases and controls in allele and/or genotype frequencies for six SNPs in Block I and two SNPs in Block II. Association of SNP4 in Block I with DD (allele: P=0.004), SNP5 in Block I with AD and DD (allele: P< or =0.005 for both) and two SNPs in Block II with AD (SNP11 genotype: P=0.002; SNP12 genotype: P=0.001) were significant after correction for multiple testing. Frequency distributions of haplotypes (constructed by five tag SNPs) differed significantly for cases and controls (P<0.001 for both AD and DD). Logistic regression analyses confirmed the association between OPRM1 variants and substance dependence, when sex and age of subjects and alleles, genotypes, haplotypes or diplotypes of five tag SNPs were considered. Population structure analyses excluded population stratification artifact. Additional supporting evidence for association between OPRM1 and AD was obtained in a smaller Russian sample (247 cases and 100 controls). These findings suggest that OPRM1 intronic variants play a role in susceptibility to AD and DD in populations of European ancestry.

Adult↗
PubMed2000

Family-based association studies.

Over the past decade, attention has turned from positional cloning of Mendelian disease genes to the dissection of complex diseases. Both theoretical and empirical studies have shown that traditional linkage studies may be inferior in power compared to studies that directly utilize allele status. Case-control association studies, as an alternative, are subject to bias due to population stratification. As a compromise between linkage studies and case-control studies, family-based association designs have received great attention recently due to their potentially higher power to identify complex disease genes and their robustness in the presence of population substructure. In this review, we first describe the basic family-based association design involving one affected offspring with its two parents, all genotyped for a biallelic genetic marker. Extensions of the original transmission disequilibrium tests to multiallelic markers, families with multiple siblings, families with incomplete parental genotypes, and general pedigree structures are discussed. Further developments of statistical methods to study quantitative traits, to analyse genes on the X chromosome, to incorporate multiple tightly linked markers, to identify imprinting genes, and to detect gene-environment interactions are also reviewed. Finally, we discuss the implications of the completion of the Human Genome Project and the identification of hundreds of thousands of genetic polymorphisms on employing family-based association designs to search for complex disease genes.

Alleles↗
PubMed2002

Variations in immune response genes and their associations with multifactorial immune disorders.

There are three genetic methods often used for detecting genes contributing to susceptibility or resistance to multifactorial diseases: nonparametric linkage analysis, case-control association analysis, and transmission disequilibrium test. In this review, we present the theoretical basis that the case-control association study has the highest power of detecting disease genes if there is no population stratification between patients and controls. Taking advantage of the high power, we have carried out extensive case-control association analyses of candidate genes for the search of susceptibility genes to rheumatic diseases in the Japanese as well as in some other populations. Several new associations have been disclosed, including those of TNFR2, FCGR2B, and CD19 gene polymorphisms with systemic lupus erythematosus, in addition to some unexpected findings such as the common occurrence of NKG2-C null allele in the healthy population. Genome-wide association studies using single nucleotide polymorphisms (SNPs) or microsatellite polymorphisms have become realistic, and development of new high-throughput and cost-effective SNP typing technologies is urgently needed. At the same time, our observations may indicate that the 'classical' candidate gene approach will remain a strong alternative, even in the age of 'post genome-sequence'.

Antigens, CD↗
PubMed2006

How reliable is the sub-population model in DNA testimony?

The performance of the sub-population model first proposed by Balding and Nichols [D.J. Balding, R.A. Nichols, DNA profile match probability calculation: how to allow for population stratification, relatedness, database selection and single bands. Forensic Sci. Int. 64 (1994) 125-140] is examined using a simulation approach. This work extends the investigations of Curran et al. [J.M. Curran, J.S. Buckleton, and C.M. Triggs, What is the magnitude of the sub-population effect? Forensic Sci. Int. 135 (2003) 1-8]. In particular the effect of underestimating the coancestry coefficient, theta, and the effect of departures from the modelling assumptions were investigated. The model tends to give strongly conservative estimates if the estimate for the coancestry coefficient is accurate. If this coefficient is underestimated then a larger fraction of cases give non-conservative estimates. Departures from the modelling assumption that the sub-population is in Hardy-Weinberg and linkage equilibria appear to have very little effect.

Consanguinity↗
PubMed2006

Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis.

BACKGROUND: Tuberculosis, which is caused by Mycobacterium tuberculosis, remains one of the leading causes of mortality worldwide. The C-type lectin DC-SIGN is known to be the major M. tuberculosis receptor on human dendritic cells. We reasoned that if DC-SIGN interacts with M. tuberculosis, as well as with other pathogens, variation in this gene might have a broad range of influence in the pathogenesis of a number of infectious diseases, including tuberculosis. METHODS AND FINDINGS: We tested whether polymorphisms in CD209, the gene encoding DC-SIGN, are associated with susceptibility to tuberculosis through sequencing and genotyping analyses in a South African cohort. After exclusion of significant population stratification in our cohort, we observed an association between two CD209 promoter variants (-871G and -336A) and decreased risk of developing tuberculosis. By looking at the geographical distribution of these variants, we observed that their allelic combination is mainly confined to Eurasian populations. CONCLUSIONS: Our observations suggest that the two -871G and -336A variants confer protection against tuberculosis. In addition, the geographic distribution of these two alleles, together with their phylogenetic status, suggest that they may have increased in frequency in non-African populations as a result of host genetic adaptation to a longer history of exposure to tuberculosis. Further characterization of the biological consequences of DC-SIGN variation in tuberculosis will be crucial to better appreciate the role of this lectin in interactions between the host immune system and the tubercle bacillus as well as other pathogens.

Adult↗
PubMed2002

Gene finding strategies.

Both linkage and association methods have been used to localise and identify genes related to behaviour and other complex traits. The linkage approach (parametric or non-parametric) can be used for whole genome screens to localise genes of unknown function. The parametric linkage approach is very effective for locating single-gene disorders and is usually based on large family pedigrees. The non-parametric method is useful to detect quantitative trait loci (QTLs) for complex traits and was originally developed for sib pair analyses. Genetic association studies are most often used to test the association of alleles at a candidate gene with a disease or with levels of a quantitative trait. Allelic association between a trait and a marker can be studied in a case-control design, but because of possible problems due to population stratification, within-family designs have been proposed as the optimal test for association.

Alleles↗
PubMed2000

Beware the chopsticks gene.

Population stratification is a potential source of error in psychiatric genetics. New study designs and statistical methods can help guard against this problem. Molecular Psychiatry (2000) 5, 11-13.

Ethnicity↗
PubMed2005

Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population.

Wilms' tumor gene (WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys-Drash and Frasier syndromes, which are characterized by glomerular scarring. To test whether genetic variations in WT1 and WIT1 (gene immediately 5' to WT1) associate with focal segmental glomerulosclerosis (FSGS), patients with biopsy-proven idiopathic and HIV-1-associated FSGS were enrolled in a multicenter study. We genotyped SNP rs6508 located in WIT1 exon 1, three SNPs (rs2301250, rs2301252, rs2301254) in the promoter shared by WT1 and WIT1, rs2234590 in exon 6, rs2234591 in intron 6, rs16754 in exon 7, and rs1799937 in intron 9 of WT1. Cases (n = 218) and controls (n = 281) were compared in the African American population. Stratification by HIV-1 infection status showed that SNPs rs6508, rs2301254, and rs1799937 were significantly associated with FSGS [rs6508 odds ratio (OR) 1.82, P = 0.006; rs2301254 OR 1.65, P = 0.049; rs1799937 OR 1.91, P = 0.005] in the non-HIV-1 group and rs2234591 (OR 0.234, P = 0.011) in the HIV-1 group. Haplotype analyses in the population revealed that seven SNPs were associated with FSGS; five SNPs had the highest contingency score [-log10(P value) = 13.57] in the HIV-1 group. This association could not be explained by population substructure. We conclude that SNPs in WT1 and WIT1 genes are significantly associated with FSGS, suggesting that variants in these genes may mediate pathogenesis by altering WT1 function. Furthermore, HIV-1 infection status interacts with genetic variations in both genes to influence this phenotype. We speculate that nephropathy liability alleles in WT1 pathway genes cause podocyte dysfunction and glomerular scarring.

Black or African American↗
PubMed2005

Linkage disequilibrium in European elite maize germplasm investigated with SSRs.

Information about the extent and genomic distribution of linkage disequilibrium (LD) is of fundamental importance for association mapping. The main objectives of this study were to (1) investigate genetic diversity within germplasm groups of elite European maize (Zea mays L.) inbred lines, (2) examine the population structure of elite European maize germplasm, and (3) determine the extent and genomic distribution of LD between pairs of simple sequence repeat (SSR) markers. We examined genetic diversity and LD in a cross section of European and US elite breeding material comprising 147 inbred lines genotyped with 100 SSR markers. For gene diversity within each group, significant (P<0.05) differences existed among the groups. The LD was significant (P<0.05) for 49% of the SSR marker pairs in the 80 flint lines and for 56% of the SSR marker pairs in the 57 dent lines. The ratio of linked to unlinked loci in LD was 1.1 for both germplasm groups. The high incidence of LD suggests that the extent of LD between SSR markers should allow the detection of marker-phenotype associations in a genome scan. However, our results also indicate that a high proportion of the observed LD is generated by forces, such as relatedness, population stratification, and genetic drift, which cause a high risk of detecting false positives in association mapping.

Chromosome Mapping↗
PubMed1998

ADH genotypes and alcohol use and dependence in Europeans.

We have tested for effects of alcohol dehydrogenase (ADH) genotypes on self-reported alcohol consumption and symptoms of alcohol dependence, recorded on three occasions up to 15 years apart, in 377 male and female subjects of European descent. ADH2 genotype had significant effects on both consumption and dependence in the men, but not in the women. The effects of ADH3 genotype were considerably less than those of ADH2, but significant results could be demonstrated when the combined genotypes were considered. The direction of the effects on alcohol consumption and dependence risk were consistent with reports on Asian subjects, and with the in vitro properties of ADH isoenzymes. As with previous studies on the relationship between ADH type and alcohol use, population stratification cannot be excluded as a contributing factor in these results.

Adolescent↗