Biomedical subjects

Bobby P C Koeleman

Publications and source records attributed to Bobby P C Koeleman.

At least 19 recordsLinked to original sources

PubMed2007

Explorative two-locus linkage analysis suggests a multiplicative interaction between the 7q32 and 16p13 myoclonic seizures-related photosensitivity loci.

In traits suspected to be governed by at least two loci, linkage analysis incorporating the joint action of both loci may improve the power to detect linkage, increase the precision of estimating locus positions and provide insight into the underlying etiological mechanism. Recently, we mapped two susceptibility loci for epilepsy-related photosensitivity (or photoparoxysmal response, PPR) at regions 7q32 (PPR1) and 16p13 (PPR2) in PPR families with prominent myoclonic seizures background (MS-related PPR). To follow-up these results and evaluate interaction effects between these regions, we conducted two-locus (2L) linkage analyses using parametric and non-parametric methods. The 2L linkage was calculated under a multiplicative (MULT) epistasis model, encompassing models where each locus is necessary but not sufficient for MS-related PPR and a heterogeneity (HET) model, encompassing models in which each locus is by itself sufficient but not necessary for MS-related PPR expression. We found maximal 2L linkage under the (MULT) model, which was significantly better than the 2L linkage under the (HET) model (P = 0.001). The 2L analyses gave no increase in power to detect linkage over the single-locus analyses nor did they improve location estimates at PPR1 and PPR2, as expected under a best-fit 2L (MULT) model in an affecteds-only analysis. Our findings suggest that the genes underlying the PPR1 and PPR2 susceptibility loci may have similar functions or act in the same biochemical pathway.

Chromosome Mapping↗

PubMed2006

MICA is associated with type 1 diabetes in the Belgian population, independent of HLA-DQ.

To ascertain association of MICA with type 1 diabetes (T1D) in the Belgian population, well-characterized antibody-positive patients were analyzed for MICA transmembrane gene polymorphism in both an association study and a nuclear family study. The frequency of MICA5 was significantly increased in the T1D patient group (18%) compared with the control population (12%, OR=1.6, pc<10(-3)), whereas MICA9 was decreased (11% versus 16%, OR=0.7, pc<0.01). A p value<10(-3) for the association of MICA conditional on HLA class II and p=0.01 for the conditional extended transmission disequilibrium test were obtained, indicating that MICA is associated with type 1 diabetes, independent of HLA-DQ. Analysis of estimated extended HLA-DQ-MICA haplotypes revealed individual effects of MICA alleles. The most significant effect was seen for MICA5 on the HLA-DQA1*03-DQB1*0302-MICA haplotype (OR=2.5, p<10(-3)). A significant protective effect was seen for the combination of DQA1*01-DQB1*0602/3 and MICA5.1 (OR=0.3, p<10(-3)). However, patients stratified according to the presence or absence of the different MICA alleles did not differ in terms of age at onset, sex, or other diabetes-related clinical and epidemiological data. In conclusion, MICA is associated with type 1 diabetes in the Belgian population and the observed association does not result from the HLA-DQ associated risk.

Adolescent↗

PubMed2006

Analysis of a functional BTNL2 polymorphism in type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus.

The aim of this study was to test whether the functional variant rs2076530 of the BTNL2 gene confers susceptibility to the autoimmune diseases type 1 diabetes (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Our study populations consisted of 326 patients with T1D and 351 healthy subjects, 808 patients with RA and 1137 healthy controls, and 372 patients with SLE and 280 healthy controls. Genotyping of the BTNL2 gene rs2076530 polymorphism was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. We observed statistically significant differences in the distribution of BTNL2rs2076530 alleles between patients with T1D, RA, and SLE and healthy controls (p=0.0035, 0.000003, and 0.00002, respectively), but in two divergent ways: the G allele was associated with T1D and RA, and the A allele was associated with SLE. However, the polymorphism exhibited strong linkage disequilibrium with HLA DQB1-DRB1 haplotypes previously identified as predisposing to the diseases. When the BTNL2 polymorphism was tested conditional on HLA DQB1-DRB1haplotypes, the BTNL2 effect was no longer significant in all three study populations. The BTNL2 rs2076530 polymorphism is associated with T1D, RA, and SLE because of its strong linkage disequalibrium with predisposing HLA DQB1-DRB1 haplotypes in Caucasian populations.

Arthritis, Rheumatoid↗

PubMed2006

Polymorphisms in human connexin40 gene promoter are associated with increased risk of hypertension in men.

OBJECTIVE: Gap junctions, formed by connexins (Cx), are important in the regulation of vascular tone. Previously, we reported two closely linked polymorphisms (-44G --> A and +71A --> G) within regulatory regions of the gene for Cx40, a major connexin in the vascular wall and the kidney. In the present study, we examined the hypothesis that these polymorphic variants are associated with hypertension and that they interact with blood pressure in healthy individuals. METHODS: Cx40 genotypes were determined in 191 subjects with essential hypertension, 198 normotensive individuals, and a healthy control population (178 twin pairs, 108 monozygotic, 70 dizygotic). RESULTS: We found a significant contribution of the minor Cx40 allele or genotype (-44AA/+71GG) to the risk of hypertension in men (P = 0.013 or P = 0.035; odds ratio, 1.87 or 2.10, respectively), but not in women. Moreover, in the healthy control population a significant effect of Cx40 genotype and sex on systolic blood pressure was found (P < 0.05 and P < 0.0001, respectively). Women carrying the minor Cx40 genotype had significantly higher systolic blood pressure compared with non-carriers (P < 0.05). In men, systolic blood pressure in carriers of the minor Cx40 genotype was not significantly different from the other two genotypes, possibly because of the small number of men in this group. However, men carrying the -44GA/+71AG genotype had higher standing systolic blood pressure compared with the more common Cx40 genotype (-44GG; P = 0.033). CONCLUSION: These findings suggest that the Cx40 polymorphisms may form a genetic susceptibility factor for essential hypertension in men.

Aged↗

PubMed2006

A novel splicing mutation in KCNQ2 in a multigenerational family with BFNC followed for 25 years.

PURPOSE: A large multigenerational family with benign familial neonatal convulsions (BFNC) was revisited to identify the disease-causing mutation and to assess long-term outcome. METHODS: We supplemented the original data with recent clinical and neurophysiologic data on patients and first-degree relatives, including information on seizure recurrence. We conducted linkage analysis at the EBN1 and EBN2 loci, followed by mutation analysis of KCNQ2. We evaluated the qualitative effect of the KCNQ2 mutation at the messenger RNA (mRNA) level by using reverse-transcribed total RNA isolated from leukocytes. RESULTS: Thirteen relatives had a history of neonatal convulsions, 11 of whom showed remission within 2 months. One patient showed an atypical course of neonatal convulsions, developing photosensitive myoclonic epilepsy at age 13 years. We found suggestive linkage of the BFNC phenotype to the 20q13-EBN1 locus (lod score, 2.03) and an intronic mutation IVS14-6 C>A in KCNQ2 segregating with the trait in all affected members, but absent in 100 unrelated control subjects. This mutation creates a new, preferentially used, splice site. Alternative splicing adds 4 nt containing a premature stop codon to the transcript, resulting in a truncated protein after position R588. CONCLUSIONS: We detected and characterized a novel splicing mutation in the brain-specific KCNQ2 gene by using easily accessible blood leukocytes. Aberrant splicing cosegregates with BFNC but not with photosensitivity.

Adolescent↗

PubMed2006

Heterogeneity at the JME 6p11-12 locus: absence of mutations in the EFHC1 gene in linked Dutch families.

PURPOSE: The EFHC1 gene, encoding a protein with a Ca(2+)-sensing EF-hand motif, is localized at 6p12 and was recently reported as mutated in six Mexican juvenile myoclonic epilepsy (JME) families linked to this region. We had previously confirmed linkage between JME and 6p11-12 in 18 Dutch families, and shown exclusionary lod scores at 6p21.3. We therefore evaluated the relevance of EFHC1 in our set of 6p11-12-linked families. METHODS: We screened all coding and regulatory regions of EFHC1 by direct sequencing, and the detected variants were tested in a case-control association study. RESULTS: We found none of the five mutations previously reported in the Mexican families, but identified nine variants, three of which are novel: 5' upstream region (c.-146_147delGC), nonsynonymous (R159W, R182H, M448T, I619L), intronic (IVS3 + 10A>G, IVS8 + 175_176delTT, IVS10 + 59C>T), and 3' UTR (c.+121C>A). These variants did not cosegregate with JME and did not account for the observed linkage at the 6p11-12 locus. Furthermore, no significant association was detected between JME and these variants in 112 unrelated patients and 180 controls. Finally, none of the mutations reported in Mexican families was found in 100 unrelated patients. CONCLUSIONS: We found no evidence that EFHC1 is a major genetic risk factor for JME susceptibility in Dutch patients. The EFHC1 variants reported in Mexican families may be mendelian variants specific for those families, suggesting that for Dutch patients and possibly many other populations, the main disease variant at the 6p11-12 is yet to be identified.

Calcium-Binding Proteins↗

PubMed2006

Detecting multiple associations in genome-wide studies.

Recent developments in the statistical analysis of genome-wide studies are reviewed. Genome-wide analyses are becoming increasingly common in areas such as scans for disease-associated markers and gene expression profiling. The data generated by these studies present new problems for statistical analysis, owing to the large number of hypothesis tests, comparatively small sample size and modest number of true gene effects. In this review, strategies are described for optimising the genotyping cost by discarding promising genes at an earlier stage, saving resources for the genes that show a trend of association. In addition, there is a review of new methods of analysis that combine evidence across genes to increase sensitivity to multiple true associations in the presence of many non-associated genes. Some methods achieve this by including only the most significant results, whereas others model the overall distribution of results as a mixture of distributions from true and null effects. Because genes are correlated even when having no effect, permutation testing is often necessary to estimate the overall significance, but this can be very time consuming. Efficiency can be improved by fitting a parametric distribution to permutation replicates, which can be re-used in subsequent analyses. Methods are also available to generate random draws from the permutation distribution. The review also includes discussion of new error measures that give a more reasonable interpretation of genome-wide studies, together with improved sensitivity. The false discovery rate allows a controlled proportion of positive results to be false, while detecting more true positives; and the local false discovery rate and false-positive report probability give clarity on whether or not a statistically significant test represents a real discovery.

Genetic Techniques↗

PubMed2006

Identification of TUB as a novel candidate gene influencing body weight in humans.

Previously, we identified a locus on 11p influencing obesity in families with type 2 diabetes. Based on mouse studies, we selected TUB as a functional candidate gene and performed association studies to determine whether this controls obesity. We analyzed the genotypes of 13 single nucleotide polymorphisms (SNPs) around TUB in 492 unrelated type 2 diabetic patients with known BMI values. One SNP (rs1528133) was found to have a significant effect on BMI (1.54 kg/m(2), P = 0.006). This association was confirmed in a population enriched for type 2 diabetes, using 750 individuals who were not selected for type 2 diabetes. Two SNPs in linkage disequilibrium with rs1528133 and mapping to the 3' end of TUB, rs2272382, and rs2272383 also affected BMI by 1.3 kg/m2 (P = 0.016 and P = 0.010, respectively). Combined analysis confirmed this association (P = 0.005 and P = 0.002, respectively). Moreover, comparing 349 obese subjects (BMI >30 kg/m(2)) from the combined cohort with 289 normal subjects (BMI <25 kg/m(2)) revealed that the protective alleles have a lower frequency in obese subjects (odds ratio 1.32 [95% CI 1.04-1.67], P = 0.022). Altogether, data from the tubby mouse as well as these data suggest that TUB could be an important factor in controlling the central regulation of body weight in humans.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Oligogenic inheritance in photosensitive juvenile myoclonic epilepsy?

The interplay of multiple genetic factors, as opposed to monogenic inheritance, is suspected to play a role in many idiopathic generalized epilepsies. This leads to a digenic or oligogenic inheritance model, which although rather simplified, may explain at least some of the clinical observations. Here we describe a family in which the clinical phenotype in the offspring can be explained by a combination of photosensitivity and epilepsy traits that segregated independently of each other. This case history demonstrates the need to evaluate family histories in more detail in order to uncover potential clinical markers for genetic factors in complex epilepsies.

Adult↗

PubMed2005

Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect.

Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.

Amino Acid Sequence↗

PubMed2005

CTLA4 is differentially associated with autoimmune diseases in the Dutch population.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is an important negative regulator of T-cell response and its genetic association with type 1 diabetes (T1D) has recently been demonstrated. The frequent co-association of autoimmune diseases (AID) and the implication from multiple genome scans that the CTLA4 gene region is a general autoimmune region, led us to study the role of CTLA4 in independent cohorts of T1D, coeliac disease (CD) and rheumatoid arthritis (RA) patients. We present independent data that confirm the association of CTLA4 in Dutch patients with juvenile onset T1D and show differential association of CTLA4 with CD and RA. The CTLA4 gene polymorphisms were tested for association in 350 T1D, 310 CD, 520 RA patients and 900 controls. In addition, 218 families were tested by the transmission disequilibrium test (TDT). T1D patients showed the highest association with the MH30*G: -1147*C: +49*G: CT60*G: JO37_3*G (haplotype 2) in both a case/control cohort (P=0.002, OR=1.42) and by TDT (P=0.02, OR=1.43). In contrast, this haplotype showed no association in the RA and CD cohorts. However, we observed an increased frequency of the MH30*G: -1147*T: +49*A: CT60*G: JO37_3*A (haplotype 3) in the CD patients diagnosed at a young age (OR=1.6, P=0.026, P (c)=0.052). Furthermore, when T1D and CD patients were stratified based on the HLA risk, the T1D susceptible CTLA4 haplotype 2 was over-represented in the high HLA-risk T1D and CD groups. In conclusion, we confirmed association between CTLA4 haplotype 2 and T1D in the Dutch population. Association with another CTLA4 haplotype (haplotype 3) was confirmed for CD, but only in those patients who had an early age of expression. No effect was found between RA and CTLA4. The association of the CTLA4 haplotype 2 with the high-risk HLA genotype in T1D and CD, which share DQ2 as the one of high-risk alleles, might provide a clue to understanding the common genetic background of AID.

Adolescent↗

PubMed2005

Detection of single nucleotide polymorphisms in the ABCG2 gene in a Dutch population.

BACKGROUND: ABCG2 is a drug transporter involved in the protection of tissues by actively transporting toxic substances and xenobiotics out of cells. Cancer cells overexpressing the ABCG2 gene show multidrug resistance to mitoxantrone-, methotrexate-, doxorubicin-, and camptothecin-based anticancer drugs, such as topotecan and SN-38. Large interindividual differences have been shown in oral availability and clearance of drugs that are substrates for ABCG2. Variation in the ABCG2 gene, such as single nucleotide polymorphisms (SNPs), can possibly explain the variability in pharmacokinetics of ABCG2 substrates. AIM: This study was performed to screen for SNPs in the ABCG2 gene to determine the frequencies of currently known and previously unknown SNPs in a Dutch population. METHODS: Blood samples were obtained from 100 healthy volunteers to isolate genomic DNA. PCR amplification was performed, followed by DNA sequencing. The population, of which the ethnicity was 93% Caucasian, consisted of 79 female individuals and 21 males. RESULTS: In total, 19 SNPs were found in the ABCG2 gene, of which 7 were previously unknown. The SNPs G8883A in exon 5 and C44168T in exon 14 cause an amino acid change of R160Q and R575X, respectively. Most of the previously unknown SNPs were found in introns. CONCLUSIONS: The results will be used in future studies to explore the influence of the different SNPs on ABCG2 protein expression, activity, and substrate specificity. In addition, the results can be used to study the effects of genetic polymorphisms in the ABCG2 gene on the pharmacokinetic profile of anticancer drugs.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2004

HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert-Eaton myasthenic syndrome.

Patients with small cell lung cancer (SCLC) survive longer if they have the antibody-mediated Lambert-Eaton myasthenic syndrome (LEMS), making this autoimmune disorder a prototype disease for studying cancer immunosurveillance. Patients with nontumor LEMS (NT-LEMS) never develop SCLC but are otherwise indistinguishable clinically. Therefore, we have compared immunogenetic factors in SCLC-LEMS and NT-LEMS and studied their role in the pathogenesis of LEMS and survival from SCLC. In 48 British and 29 Dutch Caucasian LEMS patients, we studied clinical symptoms, antibody titers, HLA types and alleles at six nearby located microsatellite loci. Highly significant associations were found in NT-LEMS, which appeared strongest with HLA-B8, but also involved HLA-DQ2, -DR3 and six flanking microsatellite alleles. SCLC-LEMS patients were not different from controls. Smoking was a strong predictor of SCLC. In contrast, HLA-B8 positivity correlated with a decreased risk of SCLC even among the smokers. Moreover, in SCLC-LEMS patients, HLA-B8 positivity correlated with prolonged survival after LEMS onset. We propose that two distinct immunopathogenetic routes can lead to one clinically and serologically indistinguishable autoimmune myasthenic syndrome. HLA-DR3-B8 is strongly associated with LEMS in nontumor patients only. In other LEMS patients, SCLC apparently provides a powerful autoimmunogenic stimulus that overrides HLA restrictions in breaking tolerance to calcium channels. Moreover, negativity for HLA-B8 combined with smoking behavior points more strongly to an underlying SCLC and predicts a worse prognosis in SCLC-LEMS patients.

Adolescent↗

PubMed2004

Genome-wide linkage scan of epilepsy-related photoparoxysmal electroencephalographic response: evidence for linkage on chromosomes 7q32 and 16p13.

Photoparoxysmal response (PPR) is an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. It is an epilepsy-related electroencephalographic trait with high prevalence in idiopathic epilepsies, especially in common idiopathic generalized epilepsies (IGEs), such as childhood absence epilepsy and juvenile myoclonic epilepsy. This degree of co-morbidity suggests that PPR may be involved in the predisposition to IGE. The identification of genes for PPR would, therefore, aid the dissection of the genetic basis of IGE. Sixteen PPR-multiplex families were collected to conduct a genome-wide linkage scan using broad (all PPR types) and narrow (exclusion of PPR types I and II and the occipital epilepsy cases) models of affectedness for PPR. We found an empirical genome-wide significance for parametric (HLOD) and non-parametric (NPL) linkage (Pgw(HLOD)=0.004 and Pgw(NPL)=0.01) for two respective chromosomal regions, 7q32 at D7S1804 (HLOD=3.47 with alpha=1, P(NPL)=3.39x10(-5)) and 16p13 at D16S3395 (HLOD=2.44 with alpha=1, P(NPL)=7.91x10(-5)). These two genomic regions contain genes that are important for the neuromodulation of cortical dynamics and may represent good targets for candidate-gene studies. Our study identified two susceptibility loci for PPR, which may be related to the underlying myoclonic epilepsy phenotype present in the families studied.

Chromosome Mapping↗

PubMed2004

Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation.

Alterations in distribution, density, and properties of cardiac gap junctions, which mediate electrical coupling of cardiomyocytes, are considered potentially arrhythmogenic. We recently reported 2 linked polymorphisms within regulatory regions of the gene for the atrial gap junction protein connexin40 (Cx40) at nucleotides -44 (G-->A) and +71 (A-->G), which were associated with familial atrial standstill. The present study examined whether these Cx40 polymorphisms were associated with increased atrial vulnerability in vivo and arrhythmia susceptibility. In 30 subjects without structural heart disease, of whom 14 had documented sporadic paroxysmal atrial fibrillation (AF) and 16 had no AF history, inducibility of AF was assessed using an increasingly aggressive atrial stimulation protocol. Coefficient of spatial dispersion of refractoriness (CD) was calculated. CD was defined as the SD of 12 local mean fibrillatory intervals recorded at right atrial sites, expressed as a percentage of the overall mean fibrillatory interval. Cx40 genotypes were determined by direct DNA sequencing. Subjects were stratified according to normal or increased CD with a cutoff value of 3.0, because CD >3.0 was previously shown to be strongly associated with enhanced atrial vulnerability. The prevalence of the minor Cx40 allele (-44A) and -44AA genotype was significantly higher in subjects with increased dispersion (n=13) compared with those with CD < or =3.0 (n=17; P=0.00046 and P=0.025; odds ratios of 6.7 and 7.4) and a control population (n=253; P=0.00002 and P=3.90x10(-7)). Carriers of -44AA genotype had a significantly higher CD compared with those with -44GG genotype (6.37+/-1.21 versus 2.38+/-0.39, P=0.018), whereas heterozygotes had intermediate values (3.95+/-1.38, NS). All subjects with increased CD had a history of idiopathic AF compared with only 1 subject with normal CD. The -44A allele and -44AA genotype were significantly more frequent in subjects with prior AF than in those without (P=0.0019 and P=0.031; odds ratios 5.3 and 6.2). This study provides strong evidence linking Cx40 polymorphisms to enhanced atrial vulnerability and increased risk of AF. The full text of this article is available online at http://circres.ahajournals.org.

Action Potentials↗

PubMed2004

Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies.

Large exploratory studies, including candidate-gene-association testing, genomewide linkage-disequilibrium scans, and array-expression experiments, are becoming increasingly common. A serious problem for such studies is that statistical power is compromised by the need to control the false-positive rate for a large family of tests. Because multiple true associations are anticipated, methods have been proposed that combine evidence from the most significant tests, as a more powerful alternative to individually adjusted tests. The practical application of these methods is currently limited by a reliance on permutation testing to account for the correlated nature of single-nucleotide polymorphism (SNP)-association data. On a genomewide scale, this is both very time-consuming and impractical for repeated explorations with standard marker panels. Here, we alleviate these problems by fitting analytic distributions to the empirical distribution of combined evidence. We fit extreme-value distributions for fixed lengths of combined evidence and a beta distribution for the most significant length. An initial phase of permutation sampling is required to fit these distributions, but it can be completed more quickly than a simple permutation test and need be done only once for each panel of tests, after which the fitted parameters give a reusable calibration of the panel. Our approach is also a more efficient alternative to a standard permutation test. We demonstrate the accuracy of our approach and compare its efficiency with that of permutation tests on genomewide SNP data released by the International HapMap Consortium. The estimation of analytic distributions for combined evidence will allow these powerful methods to be applied more widely in large exploratory studies.

Association↗

PubMed2004

Evidence for linkage between juvenile myoclonic epilepsy-related idiopathic generalized epilepsy and 6p11-12 in Dutch families.

PURPOSE: Previous linkage studies provided evidence for juvenile myoclonic epilepsy (JME) susceptibility loci at 6p11-12, HLA-6p21.3 region, 15q14, and 5q34. These results indicate locus heterogeneity or interpopulation differences, thus underlining the importance of replication studies. METHODS: We describe a replication linkage study of the 6p-q13 region in 18 families ascertained from JME probands of Dutch descent. In the presence of heterogeneity, the definition of the disease status may be crucial, and we therefore used two disease phenotypes: narrow [JME/idiopathic generalized epilepsy (IGE)-"only"] and broad (JME/IGE-plus-fast EEG background activity). RESULTS: We found evidence of linkage at 6p11-12 in multipoint analyses (p < 0.01 in a replication study) for both these disease definitions. Analysis of this region, assuming heterogeneity and autosomal dominant inheritance with a conservative 60% of penetrance, gave a maximum multipoint parametric lod score of 2.07 at D6S1573 for the narrow phenotype and peaked at 2.53 between D6S1623 and D6S1573 for the broad phenotype. The p value for nonparametric linkage reached 0.0013 for the narrow phenotype and 0.0010 for the broad. Significant exclusion (lod score <or=2) was found for the HLA region and for 10 to 30 cM telomeric to HLA. Our results provide evidence for a susceptibility locus for JME/IGE-plus-fast EEG background activity at 6p11-12. CONCLUSIONS: Additionally, by using a narrow definition, we were able to confirm previous evidence for a JME-IGE locus at this location.

Adolescent↗

PubMed2003

Rank truncated product of P-values, with application to genomewide association scans.

Large exploratory studies are often characterized by a preponderance of true null hypotheses, with a small though multiple number of false hypotheses. Traditional multiple-test adjustments consider either each hypothesis separately, or all hypotheses simultaneously, but it may be more desirable to consider the combined evidence for subsets of hypotheses, in order to reduce the number of hypotheses to a manageable size. Previously, Zaykin et al. ([2002] Genet. Epidemiol. 22:170-185) proposed forming the product of all P-values at less than a preset threshold, in order to combine evidence from all significant tests. Here we consider a complementary strategy: form the product of the K most significant P-values. This has certain advantages for genomewide association scans: K can be chosen on the basis of a hypothesised disease model, and is independent of sample size. Furthermore, the alternative hypothesis corresponds more closely to the experimental situation where all loci have fixed effects. We give the distribution of the rank truncated product and suggest some methods to account for correlated tests in genomewide scans. We show that, under realistic scenarios, it provides increased power to detect genomewide association, while identifying a candidate set of good quality and fixed size for follow-up studies.

Algorithms↗