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Nat Genet. 2015 Nov;47(11):1352-1356. doi: 10.1038/ng.3403. Epub 2015 Sep 14.

Height-reducing variants and selection for short stature in Sardinia.

Author information

1
Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
2
Center for Statistical Genetics, Ann Arbor, University of Michigan, MI, USA.
3
Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, USA.
4
Università degli Studi di Sassari, Sassari, Italy.
5
Department of Human Genetics, University of Chicago, IL, USA.
6
University of Michigan, DNA Sequencing Core, Ann Arbor, MI, USA.
7
Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
8
Center for Advanced Studies, Research, and Development in Sardinia (CRS4), AGCT Program, Parco Scientifico e Tecnologico della Sardegna, Pula, Italy.
9
II Clinica Pediatrica, Ospedale Microcitemico, Cagliari, Italy.
10
Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy.
11
Istituto di Genetica Molecolare, CNR, Pavia, Italy.
12
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
13
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
14
Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1HH.
15
Department of Haematology, University of Cambridge, Hills Rd, Cambridge CB2 0AH.
16
Department of Dietetics-Nutrition, Harokopio University, 17671 Athens, Greece.
17
Porto Conte Ricerche srl, Tramariglio, Alghero, Italy.
#
Contributed equally

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.

PMID:
26366551
PMCID:
PMC4627578
DOI:
10.1038/ng.3403
[Indexed for MEDLINE]
Free PMC Article

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