Genome-wide association analysis identifies 20 loci that influence adult height

Weedon, Michael N.; Lango, Hana; Lindgren, Cecilia M.; Wallace, Chris; Evans, David M.; Mangino, Massimo; Freathy, Rachel M.; Perry, John; Stevens, Suzanne; Hall, Alistair S.; Samani, Nilesh J.; Shields, Beverly; Prokopenko, Inga; Farrall, Martin; Dominiczak, Anna F.; Johnson, Toby; Bergmann, Sven; Beckmann, Jacques S.; Vollenweider, Péter; Waterworth, Dawn; Mooser, Vincent; Palmer, Colin N. A.; Morris, Andrew D.; Ouwehand, Willem H.; Caulfield, Mark J.; Munroe, Patricia B.; Hattersley, Andrew T.; McCarthy, Mark; Frayling, Timothy M.

doi:10.1038/ng.121

Cited by 733 publications

(596 citation statements)

References 27 publications

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“…The genetic risk simply tallies the number of trait-increasing alleles across all selected SNPs. 7,8 More sophisticated methods have been developed to weigh SNPs by the corresponding allelic effects, which are estimated from an independent training cohort. 9,10 These methods are computationally efficient and perform well in populations where large cohorts are available.…”

Section: Introductionmentioning

confidence: 99%

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

Coram

Fang

Candille

et al. 2017

The American Journal of Human Genetics

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An essential component of precision medicine is the ability to predict an individual's risk of disease based on genetic and non-genetic factors. For complex traits and diseases, assessing the risk due to genetic factors is challenging because it requires knowledge of both the identity of variants that influence the trait and their corresponding allelic effects. Although the set of risk variants and their allelic effects may vary between populations, a large proportion of these variants were identified based on studies in populations of European descent. Heterogeneity in genetic architecture underlying complex traits and diseases, while broadly acknowledged, remains poorly characterized. Ignoring such heterogeneity likely reduces predictive accuracy for minority individuals. In this study, we propose an approach, called XP-BLUP, which ameliorates this ethnic disparity by combining trans-ethnic and ethnic-specific information. We build a polygenic model for complex traits that distinguishes candidate trait-relevant variants from the rest of the genome. The set of candidate variants are selected based on studies in any human population, yet the allelic effects are evaluated in a population-specific fashion. Simulation studies and real data analyses demonstrate that XP-BLUP adaptively utilizes trans-ethnic information and can substantially improve predictive accuracy in minority populations. At the same time, our study highlights the importance of the continued expansion of minority cohorts.

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Section: Introductionmentioning

confidence: 99%

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

Coram

Fang

Candille

et al. 2017

The American Journal of Human Genetics

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“…43 A possible limitation of this study is the limited sample size. Recent studies indicate that several thousand subjects need to be recruited in order to obtain sufficient power to detect the effect sizes typically expected for complex phenotypes (with each contributing variant explaining as little as 0.1-1.3% of the variation), 44,45 although successful GWAS have been conducted using only 96 cases and 50 controls. 46 Obviously, large sample sizes can never be recruited in small isolated populations such as the Saami.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study for age-related hearing impairment in the Saami

et al. 2010

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This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genomewide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55Â10 À7 ), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventhranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene.

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“…Height loss is largely explained by the change in spine length (ChinappenHorsley et al 2008). Therefore, unsurprisingly, recent genome-wide association studies (GWAS) for adult height identified, among other bone-related genes, GDF5, a cartilage-derived morphogenetic protein (Soranzo et al 2009;Sanna et al 2008;Weedon et al 2008). Earlier, it was suggested that ESR1 polymorphisms influence the age-related decrease in stature (Ioannidis et al 2004).…”

Section: Biomarkers Of Agingmentioning

confidence: 99%

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

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Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.

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Genome-wide association analysis identifies 20 loci that influence adult height

Cited by 733 publications

References 27 publications

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

A genome-wide association study for age-related hearing impairment in the Saami

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

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