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Height-reducing variants and selection for short stature in Sardinia

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.

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Figure 1: Regional plots showing association with height for the GHR and KCNQ1 loci.
Figure 2: Worldwide frequencies and LD patterns for the top six SNPs associated with height in the KCNQ1 locus.
Figure 3: Polygenic score analysis for height.

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Acknowledgements

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.

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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.

Corresponding authors

Correspondence to Magdalena Zoledziewska, David Schlessinger or Francesco Cucca.

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The authors declare no competing financial interests.

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

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

Integrated supplementary information

Supplementary Figure 1 GWAS on height for SardiNIA cohort.

(a) Schematic of the sequencing-based GWAS approach. (b) Quantile-quantile plots for the ~12 million variants tested. The black line shows the expected P values under the null distribution. Colored lines represent observed P values for different ranges of frequency. Green circles, MAF = 0.05–0.5; red triangles, MAF = 0.01–0.05; blue squares, MAF = 0.005–0.01; gray dots, MAF = 0.001–0.005. (c) Manhattan plot of the association P values. The y axis shows the association strength (–log10 (P value)) versus the genomic position on the x axis.

Supplementary Figure 2 Height distribution within each genotype class for the top associated variants at GHR and KCNQ1.

(a) The height residual distribution within each genotype class after normalization for age and sex for rs121909358 (chr5:42689036). (b) The height residual distribution within each genotype class for each parent of origin after normalization for age and sex for rs150199504 (chr11:2814960).

Supplementary Figure 3 Haplotype blocks in the region surrounding the Laron variant (rs121909358).

The figure shows the extent of haplotype similarity for the 11 unrelated sequenced carriers. Each of the two chromosomes is plotted separately in the upper panel (if carrying the reference/ancestral allele) and lower panel (if carrying the alternate/derivate allele). Colors represent identical haplotypes; the extension of the haplotype around the core segment bearing the Laron variant varies because of recombination events. The x axis shows the distance from rs12190358 (chr5:42689036).

Supplementary Figure 4 Polygenic score analysis for height.

(a) The analysis of polygenic score using effect sizes published by the GIANT Consortium. (b) The polygenic score analysis using 162 SNPs immune to population stratification22 and in LD (r2 > 0.5) with the height loci published by the GIANT Consortium.

Supplementary Figure 5 Average frequency difference for height-decreasing alleles between European populations.

The figure shows the average frequency difference between the 1000 Genomes Project CEU population (taken as the reference), the SardiNIA cohort (SDI) and other 1000 Genomes Project populations (IBS, TSI, GBR and FIN). The frequency difference is evaluated for the height-decreasing allele of the 691 variants reported in the GIANT Consortium meta-analysis4.

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Zoledziewska, M., Sidore, C., Chiang, C. et al. Height-reducing variants and selection for short stature in Sardinia. Nat Genet 47, 1352–1356 (2015). https://doi.org/10.1038/ng.3403

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