Height-reducing variants and selection for short stature in Sardinia

被引：72

作者：

Zoledziewska, Magdalena ^{[1
]}

Sidore, Carlo ^{[1
,2
]}

Chiang, Charleston W. K. ^{[3
]}

Sanna, Serena ^{[1
]}

Mulas, Antonella ^{[1
,4
]}

Steri, Maristella ^{[1
]}

Busonero, Fabio ^{[1
]}

Marcus, Joseph H. ^{[5
]}

Marongiu, Michele ^{[1
]}

Maschio, Andrea ^{[1
,2
,6
]}

Del Vecchyo, Diego Ortega ^{[7
]}

Floris, Matteo ^{[1
,4
,8
]}

Meloni, Antonella ^{[9
]}

Delitala, Alessandro ^{[10
]}

Concas, Maria Pina ^{[1
]}

Murgia, Federico ^{[1
]}

Biino, Ginevra ^{[11
]}

Vaccargiu, Simona ^{[1
]}

Nagaraja, Ramaiah ^{[12
]}

Lohmueller, Kirk E. ^{[3
]}

Timpson, Nicholas J. ^{[13
]}

Soranzo, Nicole ^{[14
,15
]}

Tachmazidou, Ioanna ^{[14
]}

Dedoussis, George ^{[16
]}

Zeggini, Eleftheria ^{[14
]}

Uzzau, Sergio ^{[4
,17
]}

Jones, Chris ^{[8
]}

Lyons, Robert ^{[6
]}

Angius, Andrea ^{[8
]}

Abecasis, Goncalo R. ^{[2
]}

Novembre, John ^{[5
]}

Schlessinger, David ^{[12
]}

Cucca, Francesco ^{[1
,4
]}

机构：

[1] CNR, Ist Ric Genet & Biomed, Cagliari, Italy

[2] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[3] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA

[4] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy

[5] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[6] Univ Michigan, DNA Sequencing Core, Ann Arbor, MI 48109 USA

[7] Univ Calif Los Angeles, Bioinformat Interdept Program, Los Angeles, CA USA

[8] Parco Sci & Tecnol Sardegna, Adv Genom Comp Technol, Ctr Adv Studies Res & Dev Sardinia CRS4, Pula, Italy

[9] Osped Microcitemico, Clin Pediat 2, Cagliari, Italy

[10] Azienda Osped Univ Sassari, Dept Clin & Expt Med, Sassari, Italy

[11] CNR, Ist Genet Mol, I-27100 Pavia, Italy

[12] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA

[13] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol, Avon, England

[14] Wellcome Trust Sanger Inst, Human Genet, Hinxton, England

[15] Univ Cambridge, Dept Haematol, Cambridge, England

[16] Harokopio Univ, Dept Dietet Nutr, Athens, Greece

[17] Porto Conte Ric, Tramariglio, Alghero, Italy

来源：

NATURE GENETICS | 2015年 / 47卷 / 11期

基金：

英国惠康基金; 美国国家卫生研究院; 欧洲研究理事会; 英国经济与社会研究理事会;

关键词：

HORMONE RECEPTOR DEFICIENCY; BECKWITH-WIEDEMANN-SYNDROME; LOCI;

D O I：

10.1038/ng.3403

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1352 / +

页数：7

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