A positively selected FBN1 missense variant reduces height in Peruvian individuals.

TitleA positively selected FBN1 missense variant reduces height in Peruvian individuals.
Publication TypeJournal Article
Year of Publication2020
AuthorsAsgari, S, Luo, Y, Akbari, A, Belbin, GM, Li, X, Harris, DN, Selig, M, Bartell, E, Calderon, R, Slowikowski, K, Contreras, C, Yataco, R, Galea, JT, Jimenez, J, Coit, JM, Farroñay, C, Nazarian, RM, O'Connor, TD, Dietz, HC, Hirschhorn, JN, Guio, H, Lecca, L, Kenny, EE, Freeman, EE, Murray, MB, Raychaudhuri, S
Date Published2020 06
KeywordsBody Height, Female, Fibrillin-1, Gene Frequency, Genome-Wide Association Study, Heredity, Humans, Indians, South American, Male, Microfibrils, Mutation, Missense, Peru, Selection, Genetic

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

Alternate JournalNature
PubMed ID32499652
PubMed Central IDPMC7410362
Grant ListR35 HG010692 / HG / NHGRI NIH HHS / United States
U19 AI111224 / AI / NIAID NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
U01 HG009379 / HG / NHGRI NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States