Biomedical subjects

H Bickeböller

Publications and source records attributed to H Bickeböller.

17 recordsLinked to original sources

PubMed2006

Case-control association tests correcting for population stratification.

In case-control association studies unobserved population stratification may act as a confounder, leading to an increased number of false positive results. Methods accounting for population structure by using additional genetic markers broadly follow one of two concepts: Genomic Control (GC) and Structured Association (SA). While extending existing methods of Structured Association we show that it is necessary to incorporate phenotypic information when inferring population structure, otherwise a systematic bias is introduced. Moreover, for moderate population stratification a Wald test statistic should be preferred as a Structured Association test statistic in comparison to a likelihood ratio test. The introduced extensions are compared to existing methods of Structured Association, as well as to Genomic Control, in a simulation study which is based on realistic situations of large case-control studies with moderate population stratification. A disadvantage of Genomic Control turns out to be the large variation in estimating the variance inflation factor, as well as the power loss if population structure increases. We come to the overall conclusion that Structured Association, if applied correctly, is superior to Genomic Control, at least in the case of simple population structure as simulated here.

Case-Control Studies↗

PubMed2006

Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study.

BACKGROUND: A single nucleotide polymorphism (SNP) in the coding region of the prion protein gene (PRNP) at codon 129 has been repeatedly shown to be an associated factor to sporadic Creutzfeldt-Jakob disease (sCJD), but additional major predisposing DNA variants for sCJD are still unknown. Several previous studies focused on the characterisation of polymorphisms in PRNP and the prion-like doppel gene (PRND), generating contradictory results on relatively small sample sets. Thus, extensive studies are required for validation of the polymorphisms in PRNP and PRND. METHODS: We evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593 German sCJD patients and 748 German healthy controls. Genotyping was performed using MALDI-TOF mass spectrometry. RESULTS: In addition to PRNP 129, we detected a significant association between sCJD and allele frequencies of six further PRNP SNPs. No significant association of PRND T174M with sCJD was shown. We observed strong linkage disequilibrium within eight adjacent PRNP SNPs, including PRNP 129. However, the association of sCJD with PRNP 1368 and PRNP 34296 appeared to be independent on the genotype of PRNP 129. We additionally identified the most common haplotypes of PRNP to be over-represented or under-represented in our cohort of patients with sCJD. CONCLUSION: Our study evaluated previous findings of the association of SNPs in the PRNP and PRND genes in the largest cohorts for association study in sCJD to date, and extends previous findings by defining for the first time the haplotypes associated with sCJD in a large population of the German CJD surveillance study.

5' Untranslated Regions↗

PubMed2003

Modeling and dissection of longitudinal blood pressure and hypertension phenotypes in genetic epidemiological studies.

We discuss analyses of the Genetic Analysis Workshop 13 data from the Framingham Heart Study and simulations based on this study. We summarize analyses that investigated measures of systolic blood pressure or hypertension as the main phenotype, with the main focus being the modeling of this complex longitudinal phenotype. The approaches include familial aggregation methods and one-stage and two-stage linkage methods. For one-stage linkage methods, phenotype modeling is carried out jointly with the linkage analysis or incorporated in the analysis design. For two-stage linkage methods, phenotypes are first modeled in order to develop summary measures that are then analyzed in a subsequent linkage analysis. Results depend on phenotype selection and on how analyses account for longitudinality, treatment effects, and heterodasticity.

Blood Pressure↗

PubMed2001

Weighting schemes in pooled linkage analysis.

To identify susceptibility gene regions for complex diseases a combined linkage analysis of several genome scans might give additional insights to individual studies. In this article we consider different weighting schemes to combine the score statistics of individual studies to an overall statistic within multipoint nonparametric linkage analysis by GENEHUNTER/ALLEGRO. With the Genetic Analysis Workshop (GAW) 12 asthma data sets the weights are dominated by the large differences in the relevant sample sizes.

Adult↗

PubMed2001

Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes.

Several genome-wide screens for asthma and related phenotypes have been published to date but data on fine-mapping are scarce. For higher resolution we performed a fine-mapping study with 2 cM average spacing in often discussed asthma candidate regions (2p, 5q, 6p, 7p, 9q, 11p, and 12q) to narrow down the regions of interest. All participants of a Caucasian family study (97 families with at least two affected sib pairs) were genotyped for 49 supplementary polymorphic dinucleotide markers. Our results indicate increased evidence for linkage on chromosome 6p, 9q, and 12q. These candidate regions were further analyzed with SNP polymorphisms in the endothelin 1 (EDN1), lymphotoxin alpha (LTA), and neuronal nitric oxide synthase (NOS1) genes. In addition, IL4 -590C>T and IL10 -592C>A, localized on chromosomes 5q and 1q, respectively, have been analyzed for SNP association. Of the six SNPs tested, four revealed weak association with the examined phenotypes. These are the IL10 -592C>A SNP in the interleukin 10 gene (p=0.036 for eosinophil cell counts), the 4124T>C SNP in EDN1 (p=0.044 for asthma), the 3391C>T SNP in NOS1 with eosinophil cell counts (p=0.0086), and the 5266C>T polymorphism, also in the NOS1 gene, for high IgE levels (p=0.022). In summary, fine mapping data enable us to confine asthma candidate regions, while variants of EDN1 and NOS1, or nearby genes, may play an important role in this context.

Asthma↗

PubMed2000

Association of beta(2)-adrenoreceptor variants with bronchial hyperresponsiveness.

Because of its involvement in the regulation of airway tone, the beta(2)-adrenoreceptor is considered a candidate for bronchial hyperresponsiveness (BHR) associated with asthma. This notion is supported by several reports that have implicated the chromosomal region 5q31-q33 harboring the gene for the beta(2)-adrenoreceptor in the genetics of asthma and related phenotypes. We performed a population-based association study focusing on BHR as a qualitative trait and omitting other asthma-related phenotypes. From a German population sample of 1,150 individuals we extracted all 152 bronchohyperreactive probands, who were compared with 295 bronchonormoreactive control subjects. All individuals were genotyped for three single nucleotide polymorphisms of the beta(2)-adrenoreceptor gene resulting in variants at the amino acid positions 16, 27, and 164. The genotyping protocol used allowed the determination of haplotypes of these polymorphisms. Whereas no individual polymorphism was associated with BHR, the Gly16/Gln27/Th164 haplotype was significantly underrepresented in the case group indicating a protective effect of this haplotype with regard to BHR. Upon reanalysis by sex a significant association persisted only for female probands.

Airway Resistance↗

PubMed1999

Systematic search for susceptibility genes in different populations.

We analyzed the first replicate of each of the four simulated population samples from three distinct populations by linkage and association genome scans and could identify three regions with susceptibility loci for the disease: on chromosome 1, marker D1G024, with strong evidence for gene x environment interaction; or chromosome 3, around marker D3G045; and on chromosome 5, markers D5G035-D5G042. Our results were obtained without knowing the true disease model and are compared with this model in the discussion.

Alleles↗

PubMed1999

Incorporating larger families in identity-by-descent based linkage analysis.

Genome scans for alcoholism susceptibility genes were carried out using identity-by-descent-based statistics for qualitative traits. We compared the results when 1) multipoint information was used for all families, where some had to be truncated, 2) multipoint information was used only for small families while large (untruncated) pedigrees were analyzed with a single-point approach, and 3) single-point analysis was used for all pedigrees. Differences between the methods were observed, but neither method could identify regions related to the susceptibility for alcoholism.

Alcoholism↗

PubMed1999

Analysis of principal component based quantitative phenotypes for alcoholism.

Principal component analysis was used to construct quantitative phenotypes for alcoholism. These were analyzed for linkage to genomic regions with a variance components approach. The four phenotypes considered were a factor describing medical symptoms of alcohol dependency, a factor describing a psychological profile correlated with susceptibility to alcoholism, monoamine oxidase B (MAOB) activity and an average measurement of the P3 component of event-related potentials (ERP) at the Fp electrode placements. One region (around marker GATA123C09 on chromosome 3) with suggestive evidence for linkage was detected for the P3 (Fp) measurement. For three of the four distinct phenotypes, modest evidence for linkage to a similar region (around marker ADH3 on chromosome 4) was found.

Alcoholism↗

PubMed1997

Investigation of the candidate genes ACTHR and golf for bipolar illness by the transmission/disequilibrium test.

Several versions of the transmission/disequilibrium test (TDT) were applied to the two candidate genes ACTHR and Golf for bipolar illness. Analyses were carried out separately for paternal and maternal transmission. Evidence for linkage and association was found for ACTHR for paternal transmission in support of a parent-of-origin effect. Possible evidence for segregation distortion was found for one of the two markers for Golf for maternal transmission.

Bipolar Disorder↗

PubMed1997

Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex.

The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE epsilon3 allele, an increased risk associated with the APOE epsilon4 allele (odds ratio [OR] [epsilon4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE epsilon2 allele (OR[epsilon2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the epsilon4 allele dosage on susceptibility was confirmed (OR[epsilon4/epsilon4] vs. the epsilon3/epsilon3 genotype = 11.2 [95% CI = 4.0-31.6]; OR[epsilon3/epsilon4] vs. the epsilon3/epsilon3 genotype = 2.2 [95% CI = 1.5-3.5]). The frequency of the epsilon4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the epsilon4 allele versus the epsilon3 allele, OR(epsilon4), were not equal in all age classes: OR(epsilon4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In epsilon3/epsilon4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women.

Age of Onset↗

PubMed1996

Distribution of genome shared IBD by half-sibs: approximation by the Poisson clumping heuristic.

The distribution of the proportion of genome shared identical by descent (IBD) by c half-sibs is calculated for a general c. With data availability the consideration of the chromosome as a whole rather than discrete loci becomes of increasing practical importance. Assuming the genomic continuum model, which allows for recombination, the crossover process in a chromosome pedigree is viewed as a continuous-time Markov random walk on the vertices of a hypercube with time parameter map distance along the chromosome. The desired distribution corresponds to the distribution of sojourn times of the process in a small set of vertices. The sojourn times are well approximated via the Poisson clumping heuristic. It is shown explicitly that there is no "equivalent" number of independently segregating loci that will yield the same results as with the genomic continuum model. Results are given for the human genome.

Crossing Over, Genetic↗

PubMed1996

The probability distribution of the amount of an individual's genome surviving to the following generation.

The probability that at least p% of an individual's genome is passed on collectively to his children is calculated. With data availability the consideration of the chromosome as a whole rather than discrete loci becomes of increasing practical importance. Assuming the genomic continuum model, which allows for recombination, the crossover process in a chromosome pedigree is viewed as a continuous-time Markov random walk on the vertices of a hypercube with time parameter map distance along the chromosome. The desired probability corresponds to the probability of sojourn times of the process in a small set of vertices, which are well approximated via the Poisson clumping heuristic. Results are given for the human genome. It is very likely that an individual with at least four children passes on at least 90% of his genome. There exists no "equivalent" number of independently segregating loci for this distribution.

Genetics, Population↗

PubMed1995

Systematic search of susceptibility loci with methods using gametic disequilibrium.

Susceptibility genes are identified for a simulated complex trait by a systematic genome search for linkage between disease and a genetic marker in the presence of gametic disequilibrium. The transmission/disequilibrium tests TDTa or TDTg for multiallelic markers compare transmitted and nontransmitted alleles or the genotypes formed by the two transmitted alleles and the genotypes formed by the two nontransmitted alleles, respectively. With these two tests we were able to identify the two markers D1G31 and D5G23. Under the simulating model these are in fact two susceptibility genes involved in the disease.

Alleles↗

PubMed1995

Comparing the power of linkage detection by the transmission disequilibrium test and the identity-by-descent test.

The aim of this study is to compare the power of the transmission disequilibrium test (TDT) to that of the identity-by-descent (IBD) distribution test. The relative powers of these tests depend both on the underlying genetic model and on the available family data. Families with two affected sibs are always more informative than those with one affected child and one unaffected child. The IBD test is always more powerful in the first situation and, contrary to the TDT, is independent of the presence of gametic disequilibrium. When there is strong linkage disequilibrium, the TDT can be more powerful than the IBD test. In that case, linkage can be detected by the TDT even in families with only one affected child.

Chromosome Mapping↗

PubMed1995

Statistical properties of the allelic and genotypic transmission/disequilibrium test for multiallelic markers.

The transmission/disequilibrium test (TDT) is extended in two ways for a multiallelic marker: (1) to compare transmitted and nontransmitted alleles from a single heterozygous parent and (2) to compare genotypes formed by the two transmitted alleles and genotypes formed by the two nontransmitted alleles using the information on both parents, heterozygous or not, simultaneously.

Alleles↗

PubMedDate not supplied

Genetic control of lipoprotein(a) concentrations is different in Africans and Caucasians.

Lipoprotein(a) (Lp(a)) represents a quantitative trait in human plasma associated with atherothrombotic disease. Large variation in the distribution of Lp(a) concentrations exists across populations which is at present unexplained. Sib-pair linkage analysis has suggested that the apo(a) gene on chromosome 6q27 is the major determinant of Lp(a) levels in Caucasians. We have here dissected the genetic architecture of the Lp(a) trait in Africans (Khoi San, South African Blacks) and Caucasians (Austrians) by family/sib-pair analysis. Heritability estimates ranged from h2 = 51% in Blacks, h2 = 61% in Khoi San, to h2 = 71% in Caucasians. Analysis by a variance components model also demonstrated that the proportion of the total phenotypic variance explained by genetic factors is smaller in Africans (65%) than in Caucasians (74%). Importantly the sib-pair analysis clearly identified the apo(a) gene as the major locus in Caucasians which explained the total genetic variance. In the African samples the apo(a) gene accounted for only half the genetic variance. Together with previous results from population studies our data indicate that genetic control of Lp(a) levels seems to be distinctly different between Africans and Caucasians. In the former genetic factors distinct from the apo(a) locus and also non-genetic factors may play a major role.

Black People↗