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Nature Research, Nature Genetics, 11(47), p. 1352-1356, 2015

DOI: 10.1038/ng.3403

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Height-reducing variants and selection for short stature in Sardinia

Journal article published in 2015 by Magdalena Zoledziewska, Carlo Sidore, Serena Sanna ORCID, Maristella Steri ORCID, Charleston W. K. Chiang ORCID, Antonella Mulas, Group Understanding Society Scientific, Simona Vaccargiu, Fabio Busonero, Ramaiah Nagaraja, Joseph H. Marcus, Michele Marongiu, Nicholas J. Timpson ORCID, Andrea Maschio ORCID, Nicole Soranzo ORCID and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.