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A major problem in gene-gene interaction studies in large marker panels is how to correct for multiple testing while accounting for the dependence between marker pairs due to the presence of linkage disequilibrium. The "gold standard" approach is to perform permutations of case/control labels. However, this is often not feasible in practice, due to computational demands. Here, we propose a correction based on the effective number of independent tests of interaction between marker pairs. This number depends on the effective number of independent single-marker tests. We tested its validity using simulated samples, as well as that of another correction of marker pair tests. We showed that our approach was valid while the other correction strongly underestimated the effective number of independent tests. Our method provides estimates of the effective number of independent tests close to those reported in the literature for a Genome-Wide Interaction Study on a 550K chip. Our correction method is quick and simple, and can be applied whatever the marker panel and the underlying linkage disequilibrium pattern., (© 2015 John Wiley & Sons Ltd/University College London.)

The first genome wide screening performed on Italian affected sib-pair families (Greco et al. 1998) gave evidence for linkage with coeliac disease in the 5q region. This finding was replicated in a second independent dataset (Greco et al. 2001). Overall, pooling both samples, the highest MLS value (2.92) was found for the most centromeric marker tested, D5S640. In the present study, the 5q31-q33 region was saturated with 12 new markers around D5S640, in order to verify whether there would be a shift of the MLS position. This study allowed us to support our previous finding of linkage for the region 5q31-q33, with the most significant MLS value at D5S2014, very close to the marker D5S640. No evidence for interaction between this risk factor and the one in the HLA region was found. Furthermore, many different groups have independently obtained analogous results for this region, confirming the presence of a susceptibility locus in the region 5q31-q33. This region contains several interesting candidate genes for coeliac disease.

Coeliac disease (CD) is a malabsorptive disorder of the small intestine resulting from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the whole genetic susceptibility. Several regions of potential linkage on chromosomes 3q, 5q, 10q, 11q, 15q and 19q have already been reported in the literature. These six regions were analyzed with the Maximum Lod Score method on a dense set of markers. A new sample of 89 Italian sibpairs was available for study. There was no evidence for linkage for any of the regions tested, except for chromosome 5q. For this region, our data, as well as a sample of 93 sibpairs from our first genome screen (Greco et al. 1998), are compatible with the presence of a risk factor for CD with a moderate effect.

Linkage analysis was performed between Gm and Pi in 843 French families. The overall recombination fraction is equal to 0.25 with a sex difference ratio of 1.4 (recombination fraction of 0.20 in males and 0.29 in females), confirming previous results in the literature. Our study does not confirm the existence of a heterogeneity in recombination rate of Pi S versus non-S alleles, but it confirms the previous finding that the presence of the Pi Z allele tends to decrease the recombination rate between the two loci. This decrease appears to be similar in both sexes, and not uniquely in males as previously noted. This result suggests a possible linkage disequilibrium between the Pi Z allele and a presumably large inversion between the two loci Gm and Pi.

We propose a new method to analyse data on HLA associated diseases. The method uses the simultaneous information on the marker associations and segregation with the disease. It may also take into account the differential risk of being affected for specific relatives of a patient as well as the differential HLA haplotype sharing according to the marker genotype of the patient. It is based on the principle of minimization of a sum of independent chi-squares. It allows us to test the goodness-of-fit of various models in an easy and economical way. The method is applied to a sample of 269 French IDDM patients and their relatives leading to the rejection of models with one locus closely linked to HLA with two and three alleles.