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.
Integrated supplementary information
Supplementary Figures 1–5, Supplementary Tables 1–4 and Supplementary Note.