期刊
NATURE GENETICS
卷 47, 期 11, 页码 1352-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3403
关键词
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资金
- US National Institutes of Health (National Institute on Aging, National Heart, Lung, and Blood Institute)
- US National Institutes of Health (National Human Genome Research Institute)
- National Human Genome Research Institute [HG005581, HG005552, HG006513, HG007089, HG007022]
- National Heart, Lung, and Blood Institute [HL117626]
- Intramural Research Program of the US National Institutes of Health, National Institute on Aging [N01-AG-1-2109, HHSN271201100005C]
- Sardinian Autonomous Region [cRP3-154, L.R.7/2009]
- grant FaReBio 'Farmaci e Reti Biotecnologiche di Qualita'
- InterOmics MIUR Flagship Project [PB05]
- US National Institutes of Health National Research Service Award (NRSA) [F32GM106656]
- UC MEXUS-CONACYT [213627]
- Italian Ministry of Education, University and Research (MIUR) grant [5571/DSPAR/2002]
- Wellcome Trust [098051, WT091310]
- European Research Council [ERC-2011-StG 280559-SEPI]
- European Union (European Social Fund (ESF))
- 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
- Economic and Social Research Council
- UK10K
- MRC [MC_UU_12013/3] Funding Source: UKRI
- Medical Research Council [MC_UU_12013/3] Funding Source: researchfish
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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