A major non-HLA locus in celiac disease maps to chromosome 19

BACKGROUND AND AIMS: The pathogenesis of celiac disease is still unknown despite its well-known association with human leukocyte antigen (HLA)-DQ2 and DQ8. It is clear that non-HLA genes contribute to celiac disease development as well, but none of the previous genome-wide screens in celiac disease have resulted in identification of these genes. METHODS: We, therefore, performed a 2-stage, genome-wide screen in 101 affected sibpairs from 82 Dutch families who met strict diagnostic criteria. The small intestinal biopsy samples, on which the original celiac disease diagnoses had been based, showed a Marsh III lesion in all patients on reevaluation by 1 pathologist. For association analysis of markers in regions linked to celiac disease, 216 independent MIII patients and 216 age- and sex-matched controls were available. RESULTS: As expected, highly significant linkage to the HLA-region was detected (multipoint maximum lod score [MMLS] = 8.14). More importantly, significant linkage was also present at 19p13.1 (MMLS = 4.31), with the peak at marker D19S899. Moreover, this marker was also significantly associated with celiac disease in the case-control study (corrected P = 0.016). Furthermore, we identified suggestive linkage to 6q21-22, which is approximately 70 cM downstream from the HLA region (MMLS = 3.10). CONCLUSIONS: Significant linkage of celiac disease to chromosome region 19p13.1 was detected in our genome-wide screen. These results were confirmed by the association of D19S899 to celiac disease in an independent case-control cohort. Furthermore, we identified a possible second celiac disease locus on chromosome region 6q21-22.     

内镜下多点活检鉴别诊断克罗恩病和溃疡性结肠炎的临床价值

目的 探讨在克罗恩病（CD）和溃疡性结肠炎（UC）的鉴别诊断中内镜下多点活检的临床意义。方法 回顾性分析2019年3月—2022年3月在徐州医科大学附属淮安医院就诊的47例CD患者（CD组）及53例UC患者（UC组）的临床资料,并收集其内镜下活检病理切片。比较两组临床资料、实验室指标、临床表现、内镜下表现及内镜下活检病理学诊断结果。结果 CD组与UC组的性别构成、发病年龄、病程、血小板计数、红细胞沉降率比较,差异无统计学意义（P >0.05）。UC组腹泻率、血便率高于CD组,发热率、贫血率及肠外表现率低于CD组（P <0.05）。两组内镜下表现中,UC组乙状结肠病变、直肠病变、病变连续分布、环行溃疡构成比高于CD组（P <0.05）,回盲部病变、升结肠病变、病变节段分布、纵行溃疡、结节样增生、阿弗他溃疡、鹅卵石征构成比低于CD组（P <0.05）。两组内镜下活检病理学诊断结果中,UC组黏膜结构表面不规则、绒毛样表面、腺体萎缩、腺体分枝、腺体扭曲或不规则,黏膜表面上皮糜烂或变扁、黏液细胞数量减少,急性隐窝炎、隐窝脓肿、固有层中性粒细胞数量增多构成比高于CD组（P <0.05）,黏膜上皮裂隙样溃疡、假幽门腺化生,黏膜局灶间断性炎性细胞浸润、肉芽肿样小结构成比低于CD组（P <0.05）。结论 在CD与UC的鉴别诊断中需将内镜下表现与多点活检病理学诊断结果进行综合分析,并结合临床表现,以提高诊断的准确性。     

The sumLINK statistic for genetic linkage analysis in the presence of heterogeneity

We present the “sumLINK” statistic—the sum of multipoint LOD scores for the subset of pedigrees with nominally significant linkage evidence at a given locus—as an alternative to common methods to identify susceptibility loci in the presence of heterogeneity. We also suggest the “sumLOD” statistic (the sum of positive multipoint LOD scores) as a companion to the sumLINK. sumLINK analysis identifies genetic regions of extreme consistency across pedigrees without regard to negative evidence from unlinked or uninformative pedigrees. Significance is determined by an innovative permutation procedure based on genome shuffling that randomizes linkage information across pedigrees. This procedure for generating the empirical null distribution may be useful for other linkage‐based statistics as well. Using 500 genome‐wide analyses of simulated null data, we show that the genome shuffling procedure results in the correct type 1 error rates for both the sumLINK and sumLOD. The power of the statistics was tested using 100 sets of simulated genome‐wide data from the alternative hypothesis from GAW13. Finally, we illustrate the statistics in an analysis of 190 aggressive prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics, where we identified a new susceptibility locus. We propose that the sumLINK and sumLOD are ideal for collaborative projects and meta‐analyses, as they do not require any sharing of identifiable data between contributing institutions. Further, loci identified with the sumLINK have good potential for gene localization via statistical recombinant mapping, as, by definition, several linked pedigrees contribute to each peak. Genet. Epidemiol. 33:628–636, 2009. © 2009 Wiley‐Liss, Inc.     

Use of Variable Marker Density,Principal Components,and Neural Networks in the Dissection of Disease Etiology

Several approaches were taken to identify the loci contributing to the quantitative and qualitative phenotypes in the Genetic Analysis Workshop 12 simulated data set. To identify possible quantitative trait loci (QTL), the quantitative traits were analyzed using SOLAR. The four replicates identified as the “best replicates” by the simulators, 42, 25, 33, and 38, were analyzed separately. Each of the five quantitative phenotypes was analyzed individually in the four replicates. To increase the power to detect QTL with pleiotropic effects, principal component analysis was performed and one new multivariate phenotype was estimated. In each instance, after performing a 10‐cM genome screen, fine mapping was completed in the initially identified linked regions to further evaluate the evidence for linkage. This approach of initially performing a coarse marker screen followed by analyses using much higher marker density successfully identified all the QTL playing a role in the quantitative phenotypes. The principal component phenotype did not substantially improve the power of QTL detection or localization. A neural network approach was utilized to identify loci contributing to disease status. The neural network technique identified the strongest gene influencing disease status as well as a locus contributing to quantitative traits 3 and 4; however, the inputs that contributed the greatest information were markers not in QTL regions. © 2001 Wiley‐Liss, Inc.     

Quantitation of lipid in biological tissue by chemical shift magnetic resonance imaging

A method combining several previously used approaches is described for the rapid, accurate quantitation of the fat content of biological tissue based on chemical shift images (CSI) corrected for magnetic field inhomogeneity, and compensated for T₁, and T₂, effects. The gravimetrically determined lipid content of fatty tissues (pork fat, rabbit and human liver) that had been differentially depleted of lipid by chloroform extraction correlated well (r = 0.99) with the lipid image intensities of the respective tissues. This multi-point CSI method was used to quantitate lipid in fresh fatty human liver tissue (wet and dry) containing varying amounts of lipid. Plots of integrated lipid intensity versus tissue lipid content gave straight parallel lines for hydrated (r = 0.94) and dehydrated (r = 0.98) tissues, permitting determination of a proportionality constant for measuring absolute amounts of lipid present in a specific biological tissue. These results suggest the feasibility of using the method in vivo for absolute quantitation of lipid in tissues of agricultural (e.g. pork, beef) and medical (e.g. human liver) interest.     

Multipoint linkage mapping of the Xq25-q26 region in a family affected by the X-linked lymphoproliferative syndrome

We have performed, in a large Swiss family, a study of linkage between various DNA markers in the Xq24-27 region and the locus for the X-linked lymphoproliferative syndrome (XLP). Our results indicated that the marker DXS37 in Xq25-q26 is genetically linked to the XLP syndrome. The multipoint linkage analysis showed that the disease locus is distal to DXS11, but proximal to the hypoxanthine phosphoribosyl-transferase gene (HPRT).     

Comparison of association methods for dense marker data

While data sets based on dense genome scans are becoming increasingly common, there are many theoretical questions that remain unanswered. How can a large number of markers in high linkage disequilibrium (LD) and rare disease variants be simulated efficiently? How should markers in high LD be analyzed: individually or jointly? Are there fast and simple methods to adjust for correlation of tests? What is the power penalty for conservative Bonferroni adjustments? Assuming that association scans are adequately powered, we attempt to answer these questions. Performance of single‐point and multipoint tests, and their hybrids, is investigated using two simulation designs. The first simulation design uses theoretically derived LD patterns. The second design uses LD patterns based on real data. For the theoretical simulations we used polychoric correlation as a measure of LD to facilitate simulation of markers in LD and rare disease variants. Based on the simulation results of the two studies, we conclude that statistical tests assuming only additive genotype effects (i.e. Armitage and especially multipoint T²) should be used cautiously due to their suboptimal power in certain settings. A false discovery rate (FDR)‐adjusted combination of tests for additive, dominant and recessive effects had close to optimal power. However, the common genotypic χ² test performed adequately and could be used in lieu of the FDR combination. While some hybrid methods yield (sometimes spectacularly) higher power they are computationally intensive. We also propose an “exact” method to adjust for multiple testing, which yields nominally higher power than the Bonferroni correction. Genet. Epidemiol. 2008. © 2008 Wiley‐Liss, Inc.     

Distribution of model-based multipoint heterogeneity lod scores

The distribution of two‐point heterogeneity lod scores (HLOD) has been intensively investigated because the conventional χ² approximation to the likelihood ratio test is not directly applicable. However, there was no study investigating th e distribution of the multipoint HLOD despite its wide application. Here we want to point out that, compared with the two‐point HLOD, the multipoint HLOD essentially tests for homogeneity given linkage and follows a relatively simple limiting distribution , which can be obtained by established statistical theory. We further examine the theoretical result by simulation studies. Genet. Epidemiol. 34: 912‐916, 2010.© 2010 Wiley‐Liss, Inc.     

Distribution and magnitude of type I error of model-based multipoint lod scores: implications for multipoint mod scores

The multipoint lod score and mod score methods have been advocated for their superior power in detecting linkage. However, little has been done to determine the distribution of multipoint lod scores or to examine the properties of mod scores. In this paper we study the distribution of multipoint lod scores both analytically and by simulation. We also study by simulation the distribution of maximum multipoint lod scores when maximized over different penetrance models. The multipoint lod score is approximately normally distributed with mean and variance that depend on marker informativity, marker density, specified genetic model, number of pedigrees, pedigree structure, and pattern of affection status. When the multipoint lod scores are maximized over a set of assumed penetrances models, an excess of false positive indications of linkage appear under dominant analysis models with low penetrances and under recessive analysis models with high penetrances. Therefore, caution should be taken in interpreting results when employing multipoint lod score and mod score approaches, in particular when inferring the level of linkage significance and the mode of inheritance of a trait.