TY - JOUR
T1 - A Positively Selected FBN1 Missense Variant Reduces Height in Peruvian Individuals
AU - Asgari, Samira
AU - Luo, Yang
AU - Akbari, Ali
AU - Belbin, Gillian M.
AU - Li, Xinyi
AU - Harris, Daniel N.
AU - Selig, Martin
AU - Bartell, Eric
AU - Calderon, Roger
AU - Slowikowski, Kamil
AU - Contreras, Carmen
AU - Yataco, Rosa
AU - Galea, Jerome T.
AU - Jimenez, Judith
AU - Coit, Julia M.
AU - Farroñay, Chandel
AU - Nazarian, Rosalynn M.
AU - O’Connor, Timothy D.
AU - Dietz, Harry C.
AU - Hirschhorn, Joel N.
AU - Guio, Heinner
AU - Lecca, Leonid
AU - Kenny, Eimear E.
AU - Freeman, Esther E.
AU - Murray, Megan B.
AU - Raychaudhuri, Soumya
PY - 2020/1/1
Y1 - 2020/1/1
N2 - On average, Peruvian individuals are among the shortest in the world1. 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. In an ethnically diverse group of Peruvian individuals, the population-specific, missense variant in FBN1 (E1297G) is associated with lower height and shows evidence of positive selection within the Peruvian population.
AB - On average, Peruvian individuals are among the shortest in the world1. 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. In an ethnically diverse group of Peruvian individuals, the population-specific, missense variant in FBN1 (E1297G) is associated with lower height and shows evidence of positive selection within the Peruvian population.
KW - Evolutionary biology
KW - Genetic variation
KW - Genome-wide association studies
UR - https://digitalcommons.usf.edu/sok_facpub/191
U2 - 10.1038/s41586-020-2302-0
DO - 10.1038/s41586-020-2302-0
M3 - Article
C2 - 32499652
VL - 582
JO - Nature
JF - Nature
ER -