Identification of ten loci associated with height highlights new biological pathways in human growth

Lettre, Guillaume; Jackson, Anne; Gieger, Christian; Schumacher, Fredrick; Berndt, Sonja I.; Sanna, Serena; Eyheramendy, S.; Voight, Benjamin F.; Butler, Johannah L.; Guiducci, Candace; Illig, Thomas; Hackett, Rachel; Heid, Iris M.; Jacobs, Kevin B.; Lyssenko, Valeriya; Uda, Manuela; Boehnke, Michael; Chanock, Stephen J.; Groop, Leif; Hu, Frank B.; Isomaa, Bo; Kraft, Peter; Peltonen, Leena; Salomaa, Veikko; Schlessinger, David; Hunter, David J.; Hayes, Richard B.; Abecasis, Gonçalo R.; Wichmann, H‐Erich; Mohlke, Karen L.; Hirschhorn, Joel N.

doi:10.1038/ng.125

Cited by 538 publications

(412 citation statements)

References 40 publications

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“…Selection of 54 SNPs used in the study Of the 54 loci influencing human height shown in Supplementary Table 1, 16 were published by Weedon et al, 5 11 by Lettre et al 6 and 27 by Gudbjartsson et al 7 Of the 59 markers reported to be strongly associated with height in these three studies, five were mapped within the same chromosome region. For these loci, we picked up markers with the lowest P-value.…”

Section: Genotyping and Imputationsmentioning

confidence: 99%

Predicting human height by Victorian and genomic methods

et al. 2009

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In the Victorian era, Sir Francis Galton showed that 'when dealing with the transmission of stature from parents to children, the average height of the two parents, y is all we need care to know about them' (1886). One hundred and twenty-two years after Galton's work was published, 54 loci showing strong statistical evidence for association to human height were described, providing us with potential genomic means of human height prediction. In a population-based study of 5748 people, we find that a 54-loci genomic profile explained 4-6% of the sex-and age-adjusted height variance, and had limited ability to discriminate tall/short people, as characterized by the area under the receiver-operating characteristic curve (AUC). In a family-based study of 550 people, with both parents having height measurements, we find that the Galtonian mid-parental prediction method explained 40% of the sex-and age-adjusted height variance, and showed high discriminative accuracy. We have also explored how much variance a genomic profile should explain to reach certain AUC values. For highly heritable traits such as height, we conclude that in applications in which parental phenotypic information is available (eg, medicine), the Victorian Galton's method will long stay unsurpassed, in terms of both discriminative accuracy and costs. For less heritable traits, and in situations in which parental information is not available (eg, forensics), genomic methods may provide an alternative, given that the variants determining an essential proportion of the trait's variation can be identified.

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Section: Genotyping and Imputationsmentioning

confidence: 99%

Predicting human height by Victorian and genomic methods

et al. 2009

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“…BMD is a highly heritable (Pocock et al 1987), complex trait and, similar to human height Lettre et al 2008;Weedon et al 2008), tens or possibly hundreds of loci are believed to influence the variation of BMD, indicating that many loci remain to be identified.…”

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confidence: 99%

Population genomics in a disease targeted primary cell model

Grundberg

Kwan²,

Ge³

et al. 2009

Genome Res.

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The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < ;10 À3 ) were tested for cisassociation of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 3 10 À10 À 7 3 10 À16 ) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P combined = 5.6 3 10 À5 ). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r 2 = 0.5, P = 2.6 3 10 À15 ). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

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“…Adult height has been most amenable to GWAS for a number of reasons: it is invariably measured or at least self-reported with reasonable accuracy; it is a relatively stable trait; and it shows the highest heritability of all body measures -80% of the population variation in adult height is estimated to be genetic in origin. While the initial adult height GWAS papers were notable for the absence of genes implicated in hormone pathways [1,2], it is very reassuring to see that many of the major genes involved in the GH-IGF1 axis, and other hormonal pathways, were represented among the 180 adult height loci, including PITX1, GH1, GHSR, IGF1R, INSR1, ESR1, CYP19A1 (the aromatase gene), IGF2BP2, and IGF2BP3. These findings confirm the increasing recognition that hormonal modulation of such pathways, even in healthy children, may significantly impact on adult height.…”

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confidence: 99%

Population Genetics and Pharmacogenetics

Ong¹

2011

Yearbook of Pediatric Endocrinology 2011

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Identification of ten loci associated with height highlights new biological pathways in human growth

Cited by 538 publications

References 40 publications

Predicting human height by Victorian and genomic methods

Predicting human height by Victorian and genomic methods

Population genomics in a disease targeted primary cell model

Population Genetics and Pharmacogenetics

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