The largest density of conditionally independent associations was observed on chromosome 15 near ACAN, a gene mutated in short stature and skeletal dysplasia syndromes, where 25 GWS SNPs co-localize within 100 kb of one another (Fig. 2 and Supplementary Fig. 17). We show in Supplementary Note 3 and Extended Data Fig. 5a–d, using haplotype- and simulation-based analyses, that a multiplicity of independent causal variants is the most likely explanation of this observation. We also found that signal density is partially explained by the presence of a recently identified21,22 height-associated variable-number tandem repeat (VNTR) polymorphism at this locus (Supplementary Note 3). In fact, the 25 independent GWS SNPs clustered within 100 kb of rs4932198 explain more than 40% of the VNTR length variation in multiple ancestries (Extended Data Fig. 5e), and an additional approximately 0.24% (P = 8.7 × 10−55) of phenotypic variance in EUR above what is explained by the VNTR alone (Extended Data Fig. 5f). Altogether, our conclusion is consistent with previous evidence of multiple types of common variation influencing height through ACAN gene function, involving multiple enhancers23, missense variants24 and tandem repeat polymorphisms21,22.
