Height-reducing variants and selection for short stature in Sardinia

Magdalena Zoledziewska, Carlo Sidore, Charleston W K Chiang, Serena Sanna, Antonella Mulas, Maristella Steri, Fabio Busonero, Joseph H Marcus, Michele Marongiu, Andrea Maschio, Diego Ortega Del Vecchyo, Matteo Floris, Antonella Meloni, Alessandro Delitala, Maria Pina Concas, Federico Murgia, Ginevra Biino, Simona Vaccargiu, Ramaiah Nagaraja, Kirk E LohmuellerNicholas J Timpson, Nicole Soranzo, Ioanna Tachmazidou, George Dedoussis, Eleftheria Zeggini, Sergio Uzzau, Chris Jones, Robert Lyons, Andrea Angius, Gonçalo R Abecasis, John Novembre, David Schlessinger, Francesco Cucca, UK10K Consortium

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalNature Genetics
Publication statusPublished - 14 Sep 2015


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