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Michael Knapp

Publications and source records attributed to Michael Knapp.

34 records · Page 2Linked to original sources
PubMed2004

Association of the interleukin-1 receptor antagonist gene with asthma.

The interleukin-1 cluster on human chromosome 2q12-2q14 harbors various promising candidate genes for asthma and other inflammatory diseases. We conducted a systematic association study with single-nucleotide polymorphisms (SNPs) located in candidate genes situated in this cluster. Single-marker, two-locus and three-locus haplotype analysis of SNPs yielded several significant results (p < 0.05-0.0021) for the human IL1RN gene encoding the IL-1 receptor antagonist protein, an antiinflammatory cytokine that plays an important role in maintaining the balance between inflammatory and antiinflammatory cytokines. These findings were replicated and confirmed in an independent Italian family sample in which significant, although weaker, association with asthma was detected. A sequencing approach to the coding region of the human IL1RN gene revealed additional DNA variants, from which a selection was also associated with the disease in German and Italian samples. Calculation of the linkage disequilibrium for the human IL1RN gene showed strong linkage disequilibrium for nearly all analyzed SNPs. Further haplotype analysis indicated that six SNPs are sufficient for tagging all haplotypes with a prevalence of more than 1%. The most frequent haplotype constructed from these SNPs was 1.4-fold overtransmitted in the German family sample.

Asthma↗
PubMed2004

Affected-sib-pair test for linkage based on constraints for identical-by-descent distributions corresponding to disease models with imprinting.

Holmans' possible triangle test for affected sib pairs has proven to be a powerful tool for linkage analysis. This test is a likelihood-ratio test for which maximization is restricted to the set of possible sharing probabilities. Here, we extend the possible triangle test to take into account genomic imprinting, which is also known as parent-of-origin effect. While the classical test without imprinting looks at whether affected sib pairs share 0, 1, or 2 alleles identical-by-descent, the likelihood-ratio test allowing for imprinting further distinguishes whether the sharing of exactly one allele is through the father or mother. Thus, if the disease gene is indeed subject to imprinting, the extended test presented here can take into account that affecteds will have inherited the mutant allele preferentially from one particular parent. We calculate the sharing probabilities at a marker locus linked to a disease susceptibility locus. Using our formulation, the constraints on these probabilities given by Dudoit and Speed ([1999] Statistics in Genetics; New York: Springer) can easily be verified. Next, we derive the asymptotic distribution of the restricted likelihood-ratio test statistic under the null hypothesis of no linkage, and give LOD-score criteria for various test sizes. We show, for various disease models, that the test allowing for imprinting has significantly higher power to detect linkage if imprinting is indeed present, at the cost of only a small reduction in power in case of no imprinting. Altogether, unlike many methods currently available, our novel model-free sib-pair test adequately models the epigenetic parent-of-origin effect, and will hopefully prove to be a useful tool for the genetic mapping of complex traits.

Alleles↗
PubMed2004

Maximum-likelihood estimation of haplotype frequencies in nuclear families.

The importance of haplotype analysis in the context of association fine mapping of disease genes has grown steadily over the last years. Since experimental methods to determine haplotypes on a large scale are not available, phase has to be inferred statistically. For individual genotype data, several reconstruction techniques and many implementations of the expectation-maximization (EM) algorithm for haplotype frequency estimation exist. Recent research work has shown that incorporating available genotype information of related individuals largely increases the precision of haplotype frequency estimates. We, therefore, implemented a highly flexible program written in C, called FAMHAP, which calculates maximum likelihood estimates (MLEs) of haplotype frequencies from general nuclear families with an arbitrary number of children via the EM-algorithm for up to 20 SNPs. For more loci, we have implemented a locus-iterative mode of the EM-algorithm, which gives reliable approximations of the MLEs for up to 63 SNP loci, or less when multi-allelic markers are incorporated into the analysis. Missing genotypes can be handled as well. The program is able to distinguish cases (haplotypes transmitted to the first affected child of a family) from pseudo-controls (non-transmitted haplotypes with respect to the child). We tested the performance of FAMHAP and the accuracy of the obtained haplotype frequencies on a variety of simulated data sets. The implementation proved to work well when many markers were considered and no significant differences between the estimates obtained with the usual EM-algorithm and those obtained in its locus-iterative mode were observed. We conclude from the simulations that the accuracy of haplotype frequency estimation and reconstruction in nuclear families is very reliable in general and robust against missing genotypes.

Algorithms↗
PubMed2003

Association of tumor necrosis factor alpha gene -G308A polymorphism with schizophrenia.

BACKGROUND: Tumor necrosis factor alpha (TNFalpha), a cytokine involved in inflammatory processes, has been implicated in the pathophysiology of schizophrenia. The chromosomal location in the major histocompatibility complex (MHC) region on 6p21.1-21.3, a region with evidence for linkage, suggests a role in susceptibility to schizophrenia. Association of the minor (A) allele of the -G308A TNFalpha gene polymorphism with schizophrenia has been reported [Mol. Psychiatry 6 (2001) 79]. METHODS: Association of the -G308A TNFalpha gene and the lymphotoxin alpha (LTalpha)+A252G gene polymorphisms with schizophrenia was studied in 79 sib pair families with linkage in the MHC region and in 128 trio families using the transmission disequilibrium test (TDT). RESULTS: Weak association of the common G allele was detected for TNFalpha -G308A in both samples independently with borderline significance in the sib pair families (0.064) and with a nominally significant value of P=0.022 in the trio families. Combining both samples produced P=0.003, while LTalpha+A252G, located approximately 2-3 kb distally, revealed P=0.03 and the two locus haplotype yielded a P value of 0.001. CONCLUSION: Our data suggests association of the common G allele of the -G308A TNFalpha gene polymorphism with schizophrenia in a sample of 207 families. However, linkage disequilibrium with a different allele of the TNFalpha gene or another gene in the MHC region cannot be excluded.

Alleles↗
PubMed2003

Genome association studies of complex diseases by case-control designs.

One way to perform linkage-disequilibrium (LD) mapping of genetic traits is to use single markers. Since dense marker maps-such as single-nucleotide polymorphism and high-resolution microsatellite maps-are available, it is natural and practical to generalize single-marker LD mapping to high-resolution haplotype or multiple-marker LD mapping. This article investigates high-resolution LD-mapping methods, for complex diseases, based on haplotype maps or microsatellite marker maps. The objective is to explore test statistics that combine information from haplotype blocks or multiple markers. Based on two coding methods, genotype coding and haplotype coding, Hotelling's T2 statistics TG and TH are proposed to test the association between a disease locus and two haplotype blocks or two markers. The validity of the two T2 statistics is proved by theoretical calculations. A statistic TC, an extension of the traditional chi2 method of comparing haplotype frequencies, is introduced by simply adding the chi2 test statistics of the two haplotype blocks together. The merit of the three methods is explored by calculation and comparison of power and of type I errors. In the presence of LD between the two blocks, the type I error of TC is higher than that of TH and TG, since TC ignores the correlation between the two blocks. For each of the three statistics, the power of using two haplotype blocks is higher than that of using only one haplotype block. By power comparison, we notice that TC has higher power than that of TH, and TH has higher power than that of TG. In the absence of LD between the two blocks, the power of TC is similar to that of TH and higher than that of TG. Hence, we advocate use of TH in the data analysis. In the presence of LD between the two blocks, TH takes into account the correlation between the two haplotype blocks and has a lower type I error and higher power than TG. Besides, the feasibility of the methods is shown by sample-size calculation.

Case-Control Studies↗
PubMed2003

High-resolution SNP scan of chromosome 6p21 in pooled samples from patients with complex diseases.

We apply a high-throughput protocol of chip-based mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight; MALDI-TOF) as a method of screening for differences in single-nucleotide polymorphism (SNP) allele frequencies. Using pooled DNA from individuals with asthma, Crohn's disease (CD), schizophrenia, type 1 diabetes (T1D), and controls, we selected 534 SNPs from an initial set of 1435 SNPs spanning a 25-Mb region on chromosome 6p21. The standard deviations of measurements of time of flight at different dots, from different PCRs, and from different pools indicate reliable results on each analysis step. In 90% of the disease-control comparisons we found allelic differences of <10%. Of the T1D samples, which served as a positive control, 10 SNPs with significant differences were observed after taking into account multiple testing. Of these 10 SNPs, 5 are located between DQB1 and DRB1, confirming the known association with the DR3 and DR4 haplotypes whereas two additional SNPs also reproduced known associations of T1D with DOB and LTA. In the CD pool also, two earlier described associations were found with SNPs close to DRB1 and MICA. Additional associations were found in the schizophrenia and asthma pools. They should be confirmed in individual samples or can be used to develop further quality criteria for accepting true differences between pools. The determination of SNP allele frequencies in pooled DNA appears to be of value in assigning further genotyping priorities also in large linkage regions.

Asthma↗
PubMed2003

Introducing a new recruitment approach to sample collection for genetic association studies in opioid dependence.

OBJECTIVE: In a modified case-control association study we tested the assumption that two polymorphisms (A(118)G in exon 1 and IVS2+31 in intron 2) of the human mu-opioid receptor gene (OPRM1) confer susceptibility to opioid dependence. METHODS: In contrast to classical case-control studies both groups, opioid dependent cases and non-opioid dependent controls were recruited from individuals who have had access to drugs including opioids and who had been sentenced for violation of the "Dangerous Drugs Act" in Germany. RESULTS: For the two allelic variants of OPRM1 under study we did not find evidence for association with opioid dependence. CONCLUSIONS ;Despite absence of association we think that this recruitment approach introduced here, is useful since it putatively offers a more adequate matching for case-control association studies of opioid dependent individuals.

Adult↗
PubMed2003

[No Association of the - 141C Ins/Del Polymorphism of the Dopamine D2 Receptor with Schizophrenia]

Recently, a putative functional polymorphism (- 141C Ins/Del) in the 5'-flanking region of the dopamine D (2) receptor was found. An association of the Ins allele with schizophrenia has been described in a Japanese sample. In the present study this association was examined in a German schizophrenia patient population. In a family based approach 190 German family trios were analyzed for the - 141C Ins/Del genotype. Using the transmission disequilibrium test (TDT) we found no evidence for an association of the Ins allele with schizophrenia (TDT = 0.152, P = 0.696). In parallel, we performed an independent case control study with 268 schizophrenic patients and 244 controls. Again, we did not detect an overrepresentation of the Ins allele in patients (P = 0.124). Thus, our data do not support the hypothesis that the - 141C Ins variant plays a major role in predisposition to schizophrenia. To confirm our conclusion further preferentially family based studies are needed.

Journal Article↗
PubMed2003

Family-based association analysis with tightly linked markers.

Refining genomic regions which have been identified by linkage analysis to contain a disease susceptibility locus has proven to be a challenging task. Detecting association between the disease and a genetic marker can significantly narrow down the candidate region. Since an adequate sample of families is already available from the genome scan, family-based association tests may be used to search for association. The use of haplotypes consisting of tightly linked markers can be more powerful for detecting association than the use of individual markers. An extension of the transmission/disequilibrium test to allow the simultaneous analysis of more than one marker locus is complicated by ambiguity of phase in some families of the sample. The present paper shows that a recently proposed method for the analysis of nuclear families with a single affected child can be viewed as a special application of a more general principle. This observation justifies several modifications, potentially increasing the power, as well as an extension of the method to allow the analysis of general nuclear families. Finally, the problem of missing parental genotypes is discussed.

Chromosome Mapping↗
PubMed2003

[No association of 141C-ins/del polymorphism in the D2 dopamine receptor gene in schizophrenia].

Recently, a putative functional polymorphism (-141C Ins/Del) in the 5'-flanking region of the dopamine D2 receptor was found. An association of the Ins allele with schizophrenia has been described in a Japanese sample. In the present study this association was examined in a German schizophrenia patient population. In a family based approach 190 German family trios were analyzed for the -141C Ins/Del genotype. Using the transmission disequilibrium test (TDT) we found no evidence for an association of the Ins allele with schizophrenia (TDT = 0.152, P = 0.696). In parallel, we performed an independent case control study with 268 schizophrenic patients and 244 controls. Again, we did not detect an overrepresentation of the Ins allele in patients (P = 0.124). Thus, our data do not support the hypothesis that the -141C Ins variant plays a major role in predisposition to schizophrenia. To confirm our conclusion further preferentially family based studies are needed.

Adult↗
PubMed2002

Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families.

Genetic variants in a gene on 6p22.3, dysbindin, have been shown recently to be associated with schizophrenia (Straub et al. 2002a). There is no doubt that replication in other independent samples would enhance the significance of this finding considerably. Since the gene is located in the center of the linkage peak on chromosome 6p that we reported earlier, we decided to test six of the most positive DNA polymorphisms in a sib-pair sample and in an independently ascertained sample of triads comprising 203 families, including the families for which we detected linkage on chromosome 6p. Evidence for association was observed in the two samples separately as well as in the combined sample (P=.00068 for SNP rs760761). Multilocus haplotype analysis increased the significance further to .00002 for a two-locus haplotype and to .00001 for a three-locus haplotype. Estimation of frequencies for six-locus haplotypes revealed one common haplotype with a frequency of 73.4% in transmitted, and only 57.6% in nontransmitted, parental haplotypes. All other six-locus haplotypes occurring at a frequency of >1% were less often transmitted than nontransmitted. Our results represent a first successful replication of linkage disequilibrium in psychiatric genetics detected in a region with previous evidence of linkage and will encourage the search for causes of schizophrenia by the genetic approach.

Carrier Proteins↗
PubMed2002

Transmission/disequilibrium tests of androgen receptor and glutathione S-transferase pi variants in prostate cancer families.

Population-based case-control studies have found relationships between risk of prostate cancer and genetic polymorphisms in the CAG repeat and GGC repeat of the X-linked androgen receptor gene (AR) as well as the autosomal gene coding for glutathione S-transferase pi (GSTP1). This family-based study utilized the transmission disequilibrium test to examine whether there was evidence that these polymorphisms could account for familial aggregation of prostate cancer. Seventy-nine North American pedigrees were studied. Most of these families had 3 or more affected first-degree relatives. Genotype information was obtained on 578 individuals. The reconstruction combined transmission disequilibrium test (RC-TDT) was used to test for linkage. There was no evidence of linkage to the CAG and GGC repeat sequences in the AR gene or the pentanucleotide (ATAAA) repeat in the GSTP1 gene when each allele was analyzed separately or when alleles were grouped by repeat length. Our findings do not support the hypothesis that familial clustering of prostate cancer in high-risk families is attributable to these genetic variants.

Adult↗
PubMed2002

Arylamine N-acetyltransferase type 2 and glutathione S-transferases M1 and T1 polymorphisms in familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) exhibits a variable phenotype even in carriers of the same adenomatous polyposis coli germline mutation. Xenobiotic-metabolizing enzymes such as N-acetyltransferases (NATs) and glutathione S-transferases (GSTs) were reported to modify the individual risk for colorectal cancer. We examined whether the polymorphisms of the NAT2, GSTM1, and GSTT1 enzymes affect age at diagnosis of first colorectal adenomas or extracolonic manifestations in 411 FAP patients. Neither age at diagnosis of colorectal adenomas nor occurrence of extra-intestinal tumors differed significantly between genotypes at the NAT2 and GSTM1 loci, whereas GSTT1 polymorphism showed an uncertain association with extra-intestinal manifestations. Combinations of supposed at risk genotypes of the three enzymes showed no significant differences either. Thus, NAT2, GSTM1, or GSTT1 are unlikely to modify the disease phenotype in FAP patients.

Adenomatous Polyposis Coli↗
PubMed2002

Efficiency of haplotype frequency estimation when nuclear family information is included.

In genetic studies the haplotype structure of the regarded population is expected to carry important information. Experimental methods to derive haplotypes, however, are expensive and none of them has yet become standard methodology. On the other hand, maximum likelihood haplotype estimation from unphased individual genotypes may incur inaccuracies. We therefore investigated the relative efficiency of haplotype frequency estimation when nuclear family information is included compared to estimation from experimentally derived haplotypes. Efficiency was measured in terms of variance ratios of the estimates. The variances were derived from the binomial distribution for experimentally derived haplotypes, and from the Fisher information matrix corresponding to the general likelihood function of the haplotype frequency parameters, including family information. We subsequently compared these variance ratios to the variance ratios for the case of estimation from individual genotypes. We found that the information gained from a single child compensates missing phase information to a high degree, resulting in estimates almost as reliable as those derived from observed haplotypes. Thus, if children have already been genotyped for other reasons, it is highly recommendable to include them into the estimation. If child information is not already present, it depends on the number of loci and the haplotype diversity if it is useful to genotype a single child just to reduce phase ambiguity. In general, if the number of loci is less than or equal to three or if the number of haplotypes with a frequency >5% is less than or equal to four, haplotype estimation from individuals is quite good already and the improvement gained from a single child can not compensate the genotyping effort for it. On the other hand, under scenarios with many loci and high haplotype diversity, haplotype frequency estimation from trios can be more efficient than haplotype frequency estimation from individuals also on a per genotype base.

Data Interpretation, Statistical↗