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.

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We thank all the volunteers who generously participated in this study and made this research possible. All participants provided informed consent, and the studies were approved by local research ethic committees: Comitato Etico di Azienda Sanitaria Locale 8, Lanusei (2009/0016600) and Comitato Etico di Azienda Sanitaria Locale 1, Sassari (2171/CE). This study was funded in part by the US National Institutes of Health (National Institute on Aging, National Heart, Lung, and Blood Institute, and National Human Genome Research Institute). This research was supported by National Human Genome Research Institute grants HG005581, HG005552, HG006513, HG007089, HG007022 and HG007089; by National Heart, Lung, and Blood Institute grant HL117626; by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging, contracts N01-AG-1-2109 and HHSN271201100005C; by Sardinian Autonomous Region (L.R. 7/2009) grant cRP3-154; by grant FaReBio2011 'Farmaci e Reti Biotecnologiche di Qualità'; by the PB05 InterOmics MIUR Flagship Project; by a US National Institutes of Health National Research Service Award (NRSA) postdoctoral fellowship (F32GM106656) to C.W.K.C.; by UC MEXUS-CONACYT doctoral fellowship 213627 to D.O.D.V.; and by Italian Ministry of Education, University and Research (MIUR) grant 5571/DSPAR/2002. The HELIC study was funded by the Wellcome Trust (098051) and the European Research Council (ERC-2011-StG 280559-SEPI). The TEENAGE study has been supported by the Wellcome Trust (098051), European Union (European Social Fund (ESF)) and Greek national funds through the Operational Programme 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF) research funding programme Heracleitus II, Investing in Knowledge Society Through the European Social Fund. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. Information on how to access the data can be found on the Understanding Society website (https://www.understandingsociety.ac.uk/). This study makes use of data generated by the UK10K Consortium, derived from samples from UK10K_COHORTS_TWINSUK (the TwinsUK cohort) and UK10K_COHORT_ALSPAC (the Avon Longitudinal Study of Parents and Children cohort). A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org/. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We thank J. Berg for scripts and suggestions on the polygenic score analysis.

Author information

Author notes

    • Magdalena Zoledziewska
    • , Carlo Sidore
    • , Charleston W K Chiang
    •  & Serena Sanna

    These authors contributed equally to this work.

    • Gonçalo R Abecasis
    • , John Novembre
    • , David Schlessinger
    •  & Francesco Cucca

    These authors jointly supervised this work.


  1. Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.

    • Magdalena Zoledziewska
    • , Carlo Sidore
    • , Serena Sanna
    • , Antonella Mulas
    • , Maristella Steri
    • , Fabio Busonero
    • , Michele Marongiu
    • , Andrea Maschio
    • , Matteo Floris
    • , Maria Pina Concas
    • , Federico Murgia
    • , Simona Vaccargiu
    • , Andrea Angius
    •  & Francesco Cucca
  2. Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Carlo Sidore
    • , Andrea Maschio
    •  & Gonçalo R Abecasis
  3. Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, USA.

    • Charleston W K Chiang
    •  & Kirk E Lohmueller
  4. Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.

    • Antonella Mulas
    • , Matteo Floris
    • , Sergio Uzzau
    •  & Francesco Cucca
  5. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.

    • Joseph H Marcus
    •  & John Novembre
  6. DNA Sequencing Core, University of Michigan, Ann Arbor, Michigan, USA.

    • Andrea Maschio
    •  & Robert Lyons
  7. Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, California, USA.

    • Diego Ortega Del Vecchyo
  8. Center for Advanced Studies, Research and Development in Sardinia (CRS4), Advanced Genomics Computing Technology (AGCT) Program, Parco Scientifico e Tecnologico della Sardegna, Pula, Italy.

    • Matteo Floris
    • , Chris Jones
    •  & Andrea Angius
  9. II Clinica Pediatrica, Ospedale Microcitemico, Cagliari, Italy.

    • Antonella Meloni
  10. Department of Clinical and Experimental Medicine, Azienda Ospedaliero Universitaria di Sassari, Sassari, Italy.

    • Alessandro Delitala
  11. Istituto di Genetica Molecolare, CNR, Pavia, Italy.

    • Ginevra Biino
  12. Laboratory of Genetics, National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.

    • Ramaiah Nagaraja
    •  & David Schlessinger
  13. Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • Nicholas J Timpson
  14. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Nicole Soranzo
    • , Ioanna Tachmazidou
    •  & Eleftheria Zeggini
  15. Department of Haematology, University of Cambridge, Cambridge, UK.

    • Nicole Soranzo
  16. Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.

    • George Dedoussis
  17. Porto Conte Ricerche, Tramariglio, Alghero, Italy.

    • Sergio Uzzau


  1. UK10K Consortium

    A full list of members and affiliations appears in the Supplementary Note.

  2. The Understanding Society Scientific Group

    A full list of members and affiliations appears in the Supplementary Note.


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M.Z., G.R.A., J.N., D.S. and F.C. conceived and supervised the study. M.Z., C.S., C.W.K.C., J.N., D.S. and F.C. drafted the manuscript. S.S., K.E.L. and G.R.A. revised the manuscript and wrote specific sections of it. A.A., C.J. and R.L. supervised sequencing experiments. F.B. and A. Maschio performed sequencing experiments. C.S., M.S., M.M. and S.S. carried out genetic association analyses. C.S. analyzed DNA sequence data. M.Z., A. Mulas, F.B., S.U. and R.N. carried out SNP array genotyping. M.Z. and A. Mulas verified genotypes by TaqMan genotyping. J.H.M., C.W.K.C., M.S., M.F., D.O.D.V., K.E.L. and J.N. performed polygenic score and related population genetic analyses. A. Meloni and A.D. performed clinical characterization of Laron carriers. S.V. provided DNA for the Sardinian replication sample set. F.M., M.P.C., G.B., M.S. and S.S. performed replication analysis. N.S., N.J.T., G.D., I.T., E.Z. and the UK10K group provided KCNQ1 fine-mapping data. All authors reviewed and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Magdalena Zoledziewska or David Schlessinger or Francesco Cucca.

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