A positively selected FBN1 missense variant reduces height in Peruvian individuals

Abstract

On average, the Peruvian population is among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvians, and identify a novel, population-specific, missense variant in FBN1 (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency=4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). This is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin-1, a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals homozygous for G1297 compared to individuals homozygous for E1297. Moreover, we show that E1297G locus is under positive selection in non-African populations, and the E1297 variant shows subtle evidence of positive selection within the Peruvian population specifically. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, suggesting that short stature might be the result of adaptation to factors associated with the coastal environment in Peru.