Accounting for parent-of-origin effects detects association between 4q35 genetic variants and combined asthma-plus-rhinitis phenotype. C. Sarnowski1,2,3, G. Malerba4, Q. Vincent5, C. Laprise6, K. Rohde7, M. Moffatt8, P. Margaritte-Jeannin1,2,3, M.-H. Dizier1,2,3, P. F. Pignatti4, W. O. C. Cookson8, M. Lathrop3, F. Demenais1,2,3, E. Bouzigon1,2,3, and EGEA collaborative group 1) U946, INSERM, PARIS,75010, France; 2) Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire dHématologie, France; 3) Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), France; 4) Section of Biology and Genetics, Department of Mother and Child and Biology-Genetics, University of Verona, Italy; 5) U550, INSERM, PARIS, France; 6) Université du Québec à Chicoutimi, Canada; 7) Max-Delbrück-Center for Molecular Medicine (MDC), Germany; 8) National Heart Lung Institute, Imperial College, UK.

   A strong linkage signal was previously detected in the 4q35 region with the combined asthma-plus-rhinitis phenotype in 640 families from European ancestry (French (EGEA), British (MRCA) and Italian) when accounting for imprinting (LOD=3.14, P=2.5x10-5). We further investigated this region in 161 families (206 offspring) from the French EGEA study (Epidemiological study on the Genetics and Environment of Asthma) using a panel of 1300 SNPs (spanning 6Mb). Two different methods aiming to detect parent-of-origin and/or maternal genotype effects were used to test for association between these SNPs and asthma-plus-rhinitis phenotype: 1) the Monte-Carlo Pedigree Parent-Asymmetry-Test (MCPPAT) and 2) the Parent-of-origin-Likelihood ratio Test (PO-LRT). We identified 26 markers associated with asthma-plus-rhinitis (P0.005) among which one reached the multiple testing-corrected threshold of P6.5x10-5. Analyses conducted with imputed data (Hapmap2) strengthened the evidence for association with three genes. In order to replicate our findings, we conducted association analysis in 152 French Canadian families (Saguenay-Lac-Saint-Jean) under the same epigenetic model detected in the discovery set. The combination of EGEA and SLSJ results using a fixed-effect model evidenced association with two SNPs tagging two different genes (Pcomb=9x10-5 and Pcomb=9x10-4) under parent-of-origin effect model. Further linkage analyses performed in EGEA sibships stratified according to the genotypes at each of the two most significant SNPs showed that one SNP accounted for most of the linkage signal detected in the 4q35 region. Moreover, association analyses performed separately with each allergy-related phenotypes (asthma, rhinitis, atopy) suggested that the other SNP is more likely associated to atopy (P=5x10-5) than the combined asthma-plus-rhinitis phenotype. Further investigation is needed to confirm our findings and to better understand the role of these loci in asthma-plus-rhinitis and their relationships with respect to allergy. The combination of these results with expression and methylation data will help pinpointing towards the functional SNPs influencing asthma-plus-rhinitis and allergy phenotypes. This study highlights that taking into account complex mechanisms facilitates the identification of new genes. Funded: French Min Education & Research, AFSSET, ANR-CEBS, ANR-CEST, GABRIEL & Région Ile de France.

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