Combined linkage peak fine-mapping strategy identifies locus for muscle strength on chromosome 12. A. Windelinckx¹, G. De Mars¹, W. Huygens¹, M. Peeters¹, J. Aerssens², R. Vlietinck³, G. Beunen¹, M. Thomis¹ 1) Dept of Biomedical Kinesiology, K.U.Leuven, Belgium; 2) Dept of Translational Medical Research, Tibotec, Belgium; 3) Dept of Human Genetics, K.U.Leuven, Belgium.

   Given the increasing use of genomewide linkage scans for complex traits, fine-mapping of the resulting linkage peaks becomes an important challenge. Fine-mapping techniques mostly focus on refining linkage peaks by genotyping additional markers. However, often no selection regarding e.g. location or functionality is done on the markers, resulting in a less than ideal approach for follow-up association analyses using the same marker data. In an alternative strategy, (association) analyses are restricted to polymorphisms within positional candidate genes. The latter approach does not allow for additional linkage analyses and is only appropriate when focus is on a limited number of candidate genes. To overcome the disadvantages of both strategies, we propose a combined strategy by covering the whole linkage region with additional markers, selected based on their location in or near positional candidate genes. Selection of candidate genes is based on a gene prioritisation procedure based on similarity to genes known to influence the trait of interest using a bioinformatics approach (ENDEAVOUR). TagSNPs and coding SNPs within the candidate genes are determined using CEPH genotypes within Haploview and SNP selection is based on functionality, initial priority ranking of the gene, minor allele frequency and budgetary and genotyping platform technological criteria. Analyses are performed using linkage and association analyses and combined family-based association analysis. Application of this strategy on a previously determined linkage peak (90cM) for isometric and dynamic knee muscle strength on chromosome 12 resulted in the identification of a new locus for muscle strength. Linkage analyses on selected strength measurements resulted in maximal LOD-scores ranging from 0.30 to 2.05 and follow-up family-based association analyses identified a marker locus with p-values for association between 0.000044 and 0.43. This SNP is located in a gene that presumably has a role in the myostatin signaling pathway.