Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1.

Background Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder that arises due to pathogenic variants in tumor suppressorNF1. NF1 has variable expressivity that may be due, at least in part, from heritable elements such as modifier genes; however, few genetic modifiers have been identified to date. Methods In this study, we performed a genome-wide association analysis of the number of cafe-au-lait macules (CALM) that are considered a tumor-like trait as a clinical phenotype modifying NF1. Results A borderline genome-wide significant association was identified in the discovery cohort (CALM1,N = 112) between CALM number and rs12190451 (and rs3799603,r(2) = 1.0;p = 7.4 x 10(-8)) in the intronic region ofRPS6KA2. Although, this association was not replicated in the second cohort (CALM2,N = 59) and a meta-analysis did not show significantly associated variants in this region, a significant corroboration score (0.72) was obtained for theRPS6KA2signal in the discovery cohort (CALM1) using Complementary Pairs Stability Selection for Genome-Wide Association Studies (ComPaSS-GWAS) analysis, suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error. Conclusion rs12190451 is located in a melanocyte-specific enhancer and may influenceRPS6KA2expression in melanocytes-warranting further functional studies.