Impact of the diagnosis definition on linkage detection

Previous genome scan linkage analyses of the disease Kofendrerd Personality Disorder (KPD) with microsatellites led to detect some regions on chromosomes 1, 3, 5, and 9 that were identical for the three populations AI, KA, and DA but with large differences in significance levels. These differences in results may be explained by the different diagnosis definitions depending on the presence/absence of 12 traits that were used in the 3 populations AI, KA, and DA. Heterogeneity of linkage was thus investigated here according to the absence/presence of each of the 12 traits in the 3 populations. For this purpose, two methods, the triangle test statistic and the predivided sample test were applied to search for genetic heterogeneity. Three regions with a strong heterogeneity of linkage were detected: the region on chromosome 1 according to the presence/absence of the traits a and b, the region on chromosome 3 for the trait b, and the region on chromosome 9 for the traits k and l. These 3 regions were the same as those detected by linkage analyses. No novel region was detected by the heterogeneity tests. Concerning chromosome 1, linkage analyses showed a much stronger evidence of linkage for traits a and b and for a combination of these traits than for KPD. Moreover, there was no indication of linkage to any of the other traits used to define the diagnosis of KPD. A genetic factor located on the chromosome 1 may have been detected here which would be involved specifically in traits a and b or in a combination of these traits

Power comparison of different methods to detect genetic effects and gene-environment interactions

Identifying gene-environment (G × E) interactions has become a crucial issue in the past decades. Different methods have been proposed to test for G × E interactions in the framework of linkage or association testing. However, their respective performances have rarely been compared. Using Genetic Analysis Workshop 15 simulated data, we compared the power of four methods: one based on affected sib pairs that tests for linkage and interaction (the mean interaction test) and three methods that test for association and/or interaction: a case-control test, a case-only test, and a log-linear approach based on case-parent trios. Results show that for the particular model of interaction between tobacco use and Locus B simulated here, the mean interaction test has poor power to detect either the genetic effect or the interaction. The association studies, i.e., the log-linear-modeling approach and the case-control method, are more powerful to detect the genetic effect (power of 78% and 95%, respectively) and taking into account interaction moderately increases the power (increase of 9% and 3%, respectively). The case-only design exhibits a 95% power to detect G × E interaction but the type I error rate is increased

Identification of OCA2 as a novel locus for the co-morbidity of asthma-plus-eczema

Background: Numerous genes have been associated with the three most common allergic diseases (asthma, allergic rhinitis or eczema) but these genes explain only a part of the heritability. In the vast majority of genetic studies, complex phenotypes such as co- morbidity of two of these diseases, have not been considered. This may partly explain missing heritability. Objective: To identify genetic variants specifically associated with the co-morbidity of asthma-plus-eczema. Methods: We first conducted a meta-analysis of four GWAS (Genome-Wide Association Study) of the combined asthma-plus-eczema phenotype (total of 8807 European-ancestry subjects of whom 1208 subjects had both asthma and eczema). To assess whether the association with SNP(s) was specific to the co- morbidity, we also conducted a meta-analysis of homogeneity test of association according to disease status (“asthma-plus-eczema” vs. the presence of only one disease “asthma only or eczema only”). We then used a joint test by combining the two test statistics from the co-morbidity-SNP association and the phenotypic heterogeneity of SNP effect meta-analyses. Results: Seven SNPs were detected for specific association to the asthma-plus-eczema co-morbidity, two with significant and five with suggestive evidence using the joint test after correction for multiple testing. The two significant SNPs are located in the OCA2 gene (Oculocutaneous Albinism II), a new locus never detected for significant evidence of association with any allergic disease. This gene is a promising candidate gene, because of its link to skin and lung diseases, and to epithelial barrier and immune mechanisms. Conclusion: Our study underlines the importance of studying sub-phenotypes as co-morbidities to detect new susceptibility genes

Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood

Background: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. Objective: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood.Methods: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totaling 8,273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analyzed.Results: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P=4.3x10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P<5x10-6) were found at three other loci: 20p12 (rs13037508 within MACROD2; P=4.9x10-7), 14q22 (rs7493885 near NIN; P=2.9x10-6) and 2p22 (rs232542 near CYP1B1; P=4.1x10-6). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings.Conclusion and Clinical Relevance: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms

Replication of Association between ADAM33 Polymorphisms and Psoriasis

Polymorphisms in ADAM33, the first gene identified in asthma by positional cloning, have been recently associated with psoriasis. No replication study of this association has been published so far. Data available in the French EGEA study (Epidemiological study on Genetics and Environment of Asthma, bronchial hyperresponsivensess and Atopy) give the opportunity to attempt to replicate the association between ADAM33 and psoriasis in 2002 individuals. Psoriasis (n = 150) has been assessed by questionnaire administered by an interviewer and a sub-sample of subjects with early-onset psoriasis (n = 74) has been identified based on the age of the subjects at time of interview (<40 years). Nine SNPs in ADAM33 and 11 SNPs in PSORS1 were genotyped. Association analysis was conducted by using two methods, GEE regression-based method and a likelihood-based method (LAMP program). The rs512625 SNP in ADAM33 was found associated with psoriasis at p = 0.01, the usual threshold required for replication (OR [95% CI] for heterozygotes compared to the reference group of homozygotes for the most frequent allele = 0.61 [0.42;0.89]). The rs628977 SNP, which was not in linkage disequilibrium with rs512625, was significantly associated with early-onset psoriasis (p = 0.01, OR [95% CI] for homozygotes for the minor allele compared to the reference group = 2.52 [1.31;4.86]). Adjustment for age, sex, asthma and a PSORS1 SNP associated with psoriasis in the EGEA data did not change the significance of these associations. This suggests independent effects of ADAM33 and PSORS1 on psoriasis. This is the first study that replicates an association between genetic variants in ADAM33 and psoriasis. Interestingly, the 2 ADAM33 SNPs associated with psoriasis in the present analysis were part of the 3-SNPs haplotypes showing the strongest associations in the initial study. The identification of a pleiotropic effect of ADAM33 on asthma and psoriasis may contribute to the understanding of these common immune-mediated diseases

Identification of a new locus at 16q12 associated with time-to-asthma onset

International audienceBackground: Asthma is a heterogeneous disease in which age-of-onset plays an important role.Objective: We sought to identify the genetic variants associated with time-to-asthma onset.Methods: We conducted a large-scale meta-analysis of nine genome-wide association studies of time-to-asthma onset (total of 5,462 asthmatics with a broad range of age-of-asthma onset and 8,424 controls of European ancestry) performed using survival analysis techniques.Results: We detected five regions associated with time-to-asthma onset at genome-wide significant level (P<5x10-8). We evidenced a new locus in 16q12 region (near cylindromatosis turban tumor syndrome gene (CYLD)) and confirmed four asthma risk regions: 2q12 (IL1RL1), 6p21 (HLA-DQA1), 9p24 (IL33) and 17q12-q21 (ZPBP2-GSDMA). Conditional analyses identified two distinct signals at 9p24 (both upstream of IL33) and at 17q12-q21 (near ZPBP2 and within GSDMA). These seven distinct loci explained together 6.0% of the variance in time-to-asthma onset. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P≤0.002) whereas 16q12 SNP was associated with a later asthma onset (P=0.04). A high burden of disease risk alleles at these loci was associated with earlier age-of-asthma onset (4 years versus 9-12 years, P=10-4).Conclusion: The new susceptibility region for time-to-asthma onset at 16q12 harbors variants that correlate with the expression of CYLD and NOD2 (nucleotide-binding oligomerization domain 2), two strong candidates for asthma. This study demonstrates that incorporating the variability of age-of-asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes

Gain of power of the general regression model compared to Cochran-Armitage Trend tests: simulation study and application to bipolar disorder

International audienceAbstractBackgroundMost genome-wide association studies assumed an additive model of inheritance which may result in significant loss of power when there is a strong departure from additivity. The General Regression Model (GRM), which allows performing an assumption-free test for association by testing for both additive effect and deviation from additive effect, may be more appropriate for association tests. Additionally, GRM allows testing the underlying genetic model. We compared the power of GRM association test to additive and other Cochran-Armitage Trend (CAT) tests through simulations and by applying GRM to a large case/control sample, the bipolar Welcome Trust Case Control Cohort data. Simulations were performed on two sets of case/control samples (1000/1000 and 2000/2000), using a large panel of genetic models. Four association tests (GRM and additive, recessive and dominant CAT tests) were applied to all replicates.ResultsWe showed that GRM power to detect association was similar or greater than the additive CAT test, in particular in case of recessive inheritance, with up to 67% gain in power. GRM analysis of genome-wide bipolar disorder Welcome Trust Consortium data (1998 cases/3004 controls) showed significant association in the 16p12 region (rs420259; P = 3.4E-7) which has not been identified using the additive CAT test. As expected, rs42025 fitted a non-additive (recessive) model.ConclusionsGRM provides increased power compared to the additive CAT test for association studies and is easily applicable