ECTS Abstracts (2015) 1 P242

Resequencing of WNT16 in Extreme BMD Groups from the BARCOS Cohort: Detection and Association Analysis of Common and Rare Variants

Nuria Martinez-Gil1, Marina Gerousi1, Roser Urreizti1, Monica Cozar1, Natalia Garcia-Girlat2, Maria Rodriguez-Sanz2, Leonardo Mellibosky2, Xavier Nogues2, Adolfo Diez-Perez2, Daniel Grinberg1 & Susana Balcells1

1Department of Genetics, University of Barcelona, Barcelona, Catalonia, Spain; 2Hospital del Mar - IMIM, Barcelona, Catalonia, Spain.

Osteoporosis is a complex disease determined by both genetic and environmental factors. Genetic influence is polygenic, and this defect is caused by the additive effect of many susceptibility genes, as shown by several GWAs including the last metaanalysis by Estrada et al. (2012). In this study, 56 loci were found associated with BMD, 14 of which were also associated with osteoporotic fracture. Several of these genes belong to the Wnt signaling pathway, including WNT16 (rs380187). To better understand the role of WNT16 in BMD determination and fracture susceptibility, we aimed to explore the allelic architecture of WNT16 by resequencing all coding exons in two extreme BMD groups from the BARCOS cohort: 55 women with the highest BMD (HBM) and 53 with the lowest BMD (LBM). Once these variants were determined, the most promising were genotyped in the complete BARCOS cohort. Association was tested by ANCOVA, adjusting by years since menopause. We found 17 SNVs, all previously described. Five of them were observed in only one or two samples. Although none of them presented significant differences between the extreme groups, a trend was observed for 4 of them. These 4 SNPs and the 5 rare variants were genotyped in n=1625 women form BARCOS. Nominal significant results were obtained for SNVs rs2707466, rs142005327 and rs2908004. SNP rs2707466 and rs2908004 are missense variants (p.T253I/p.T263I and p.G72R/p.G82R, respectively) and in our cohort they are in strong linkage disequilibrium with rs380187 (the “GWAs hit”). rs142005327 is an intronic 2-bp insertion, previously found associated to BMD by Hendrickx et al. (2014). One of the rare variants was found in only one HBM woman of the BARCOS cohort. It is an intronic change located in a putative transcriptional regulation site.

This study adds evidences on the role of WNT16 in bone biology.

Disclosure: The authors declared no competing interests. This work was supported by the Spanish Ministry of Science (SAF2011-25431) and the Catalan Government (2009SGR-971 and 2014SGC-932).