A positively selected FBN1 missense variant reduces height in Peruvian individuals

Samira Asgari, Yang Luo, Ali Akbari, Gillian M. Belbin, Xinyi Li, Daniel N. Harris, Martin Selig, Eric Bartell, Roger Calderon, Kamil Slowikowski, Carmen Contreras, Rosa Yataco, Jerome T. Galea, Judith Jimenez, Julia M. Coit, Chandel Farroñay, Rosalynn M. Nazarian, Timothy D. O’Connor, Harry C. Dietz, Joel N. Hirschhorn, Heinner Guio, Leonid Lecca, Eimear E. Kenny, Esther E. Freeman, Megan B. Murray and Soumya Raychaudhuri ()
Additional contact information
Samira Asgari: Harvard Medical School
Yang Luo: Harvard Medical School
Ali Akbari: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Gillian M. Belbin: Icahn School of Medicine at Mount Sinai
Xinyi Li: Harvard Medical School
Daniel N. Harris: University of Maryland School of Medicine
Martin Selig: Harvard Medical School
Eric Bartell: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Roger Calderon: Socios En Salud
Kamil Slowikowski: Harvard Medical School
Carmen Contreras: Socios En Salud
Rosa Yataco: Socios En Salud
Jerome T. Galea: University of South Florida
Judith Jimenez: Socios En Salud
Julia M. Coit: Harvard Medical School
Chandel Farroñay: Socios En Salud
Rosalynn M. Nazarian: Harvard Medical School
Timothy D. O’Connor: University of Maryland School of Medicine
Harry C. Dietz: Johns Hopkins University School of Medicine
Joel N. Hirschhorn: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Heinner Guio: Instituto Nacional de Salud
Leonid Lecca: Socios En Salud
Eimear E. Kenny: Icahn School of Medicine at Mount Sinai
Esther E. Freeman: Harvard Medical School
Megan B. Murray: Harvard Medical School
Soumya Raychaudhuri: Harvard Medical School

Nature, 2020, vol. 582, issue 7811, 234-239

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2302-0

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