Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk

Variants in GDF5 are associated with human arthritis and height reduction, but the causal mutations are still unknown. We surveyed GDF5 for regulatory regions in transgenic mice, and fine-mapped separate enhancers controlling expression in joints versus growing ends of long bones. A large downstream regulatory region harbors a novel growth enhancer (GROW1), which is required for normal GDF5 expression at ends of developing bones, and for normal bone lengths in vivo. Human GROW1 contains a common base pair change that reduces enhancer activity and colocalizes with peaks of positive selection in humans. The derived allele is rare in Africa, but common in Eurasia and found in Neandertals and Denisovans. Our studies suggest that an ancient regulatory variant in GROW1 has been repeatedly selected in northern environments, and that past selection on growth phenotypes explains the high frequency of a GDF5 haplotype that also increases arthritis susceptibility in many human populations.