RESUMO
BACKGROUND: Despite extensive research on the genetic determinants of glaucoma, the genes identified to date explain only a small proportion of cases in the general population. METHODS: Genome-wide linkage and association analyses of quantitative traits related to glaucoma were performed: intraocular pressure, size and morphology of the optic disc (individual and combined by method of principal components) and thickness of the retinal nerve fibre layer (RNFL), in a large pedigree from a genetically isolated Dutch population. RESULTS: For the size of the optic disc, the study demonstrated a significant linkage signal (logarithm of odds (LOD)=3.6) at the LRP1B region on chromosome 2q21.2-q22.2 and significant association (p=8.95×10(-12)) with the previously reported CDC7/TGFBR3 locus at 1p22. For parameters describing morphology of the optic disc, the study obtained significant linkage signal (LOD=4.6) at regions SIRPA and RNF24/PANK2 at 20p13 (false discovery rate (FDR) based q value <0.05) and genome-wide significant association (p=2.38×10(-9)) with a common variant in the RERE gene at 1p36. Suggestive linkage and association signals indicated loci for morphology of the optic disc at 2q31-q33 (IGFBP2 locus) and for RNFL thickness at 3p22.2 (DCLK3 locus) and 14q22-q23 (SIX1 locus). CONCLUSION: This study identified new linkage regions at 20p13 (SIRPA and RNF24/PANK2 loci) and 2q33-q34 (IGFBP2 locus) for parameters describing morphology of the optic disc. The results of the study also suggested common genetic control of these parameters and RNFL thickness by SIX1 and doublecotin family genes. Finally, association signals for the recently reported RERE and LRP1B loci and the well known CDC7, TGFBR3, and ATOH7 loci were replicated.