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Gene Variant Associated With Reduced Height Among Peruvians

NEW YORK – Researchers have uncovered a gene variant under positive selection that's linked to shorter height among Peruvians.

Peruvians are among the shortest people in the world, with average heights of 165.3 centimeters (about five feet five inches) for men and 152.9 centimeters (about five feet) for women, and previous studies of Latin and South American populations have suggested that Native American ancestry is correlated with shorter height.

Though height is influenced not only by genetics but also by socioeconomic and environmental factors, a Harvard Medical School-led team of researchers searched for genetic influencers of height among Peruvians. As they reported in Nature today, they homed in on a variant in the FBN1 gene that not only appears linked to shorter height but also has a greater effect size than other known height-associated variants and appears to be under positive selection, especially among coastal Peruvians.

"This study dramatically highlights the advantage of studying different populations and having a diverse, worldwide strategy to understanding the human genome," senior author Soumya Raychaudhuri, professor of medicine and of biomedical informatics at HMS, said in a statement.

The researchers conducted a genome-wide association study using height and genotyping data from 3,134 individuals from 1,947 households in Lima, Peru. They found five SNPs within a locus overlapping the gene FBN1 that were associated with height. One SNP — rs200342067 — was a missense variant, E1297G, while the others were intronic.

They confirmed this association in a separate cohort of Peruvians as well as in two datasets of Hispanic or Latino individuals.

In their initial cohort, rs200342067 was associated with a decrease in height of about 2.2 centimeters and exhibited a similar effect size in the other cohorts of Hispanic or Latino individuals. Harboring two copies of the variant was linked to a 4.4 centimeter decrease in height. 

By contrast, previous studies conducted in largely European populations identified 3,290 variants that influence height, but those variants had smaller effect sizes, influencing less than 0.5 centimeters in height.

"In comparison, this variant that we found has a 2.2 centimeters effect per allele," first author Samira Asgari, a research fellow at Brigham and Women's Hospital, said in a statement. "That's huge for a height variant."

FBN1 encodes fibrillin 1, an extracellular matrix glycoprotein that makes up microfibrils and is involved in tissue development, homeostasis, and repair. The E1297G variant leads to the large, negatively glutamic acid being replaced with the smaller glycine, though the researchers noted that the clinical implications of the swap are unclear.

Other FBN1 variants have been implicated in Marfan or Marfan-like syndromes, which are marked by being of tall stature.

"One critical insight from this study is how genetic variants in the same gene can have very different effects," Asgari added. "Before now, if you asked a geneticist what a variant in this gene would do, they would probably say that they cause a disease. But that's not what we found."

She and her colleagues further found by examining allele frequencies and haplotype scores that the E1297G locus appears to be under positive selection in non-African populations, suggesting that it confers a selective advantage.

They additionally uncovered that within Peruvians the variant is more common among coastal Peruvian populations as compared to populations from the Andes or Amazon, raising the possibility that short stature could be due to adaptations to the environment of the Peruvian coast.

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