ESPEYB20 3. Bone, Growth Plate and Mineral Metabolism Advances in Growth, Bone Biology, and Mineral Metabolism (6 abstracts)
3.16. A saturated map of common genetic variants associated with human height
Yengo L , Vedantam S , Marouli E , Sidorenko J , Bartell E , Sakaue S , Graff M , Eliasen AU , Jiang Y , Raghavan S , Miao J , Arias JD , Graham SE , Mukamel RE , Spracklen CN , Yin X , Chen SH , Ferreira T , Highland HH , Ji Y , Karaderi T , Lin K , Lüll K , Malden DE , Medina-Gomez C & Machado M …(See abstract for full author list)
Nature. 2022 Oct;610(7933):704–712. doi: 10.1038/s41586-022-05275-y. PMID: 36224396. https://www.nature.com/articles/s41586-022-05275-y
In Brief: This comprehensive genome-wide association study (GWAS) identified over 20 000 loci associated with adult height. This groundbreaking research revealed that up to 21% of the human genome can be linked to variation in human height, providing a deeper understanding of the complex regulation of human height.
Commentary: This one of the largest GWAS to date involving 5.4 million individuals. It discovered 12 111 independent SNPs associated with adult height, which collectively account for nearly all of the estimated common SNP-based heritability for this trait. These SNPs clustered within 7209 non-overlapping genomic segments with a mean size of around 90 kb, covering roughly 21% of the genome. The density of independent associations was uneven across the genome, with regions of increased density being enriched for growth plate genes1. Intriguingly, the findings also showed disparities in the amount of phenotypic variance explained by these SNPs across different ancestral populations – about 40–45% in populations of European ancestry, but only 10–20% in populations of non-European ancestries.
Effect sizes, associated regions, and gene prioritization were consistent across ancestries. Therefore, the diminished prediction accuracy for adult height observed in non-European ancestries is due to differences in linkage disequilibrium and allele frequency rather than differences in the underlying genetic architecture. Importantly, relevant biological pathways associated with height could be identified with smaller sample sizes than those needed to implicate causal genes and variants, highlighting the importance of pathway-level analyses. However, while the study provides a comprehensive map of specific genomic regions containing the majority of common height-associated variants, it also emphasizes that the map is saturated for populations of European ancestry and more work is required to achieve equivalent saturation for other ancestries. This conclusion underscores the importance of diversity in genetic studies and the need for further research to comprehensively understand the genetic architecture of human height across all ancestries.
Reference: 1. Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height. Lui JC, Nilsson O, Chan Y, Palmer CD, Andrade AC, Hirschhorn JN, Baron J. Hum Mol Genet. 2012 Dec 1;21(23):5193–5201. PMID: 22914739
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ESPE Yearbook of Paediatric Endocrinology
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