| Title: | Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height |
| Journal: | Nature Communications |
| Published: | 3 Oct 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39362880/ |
| DOI: | https://doi.org/10.1038/s41467-024-52579-w |
Publication 13282
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Abstract
The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < 6×10−10$$6\times {10}^{-10}$$ after conditioning on previously reported variants, with effect sizes ranging from −7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.</p>
11 Keywords
- Body Height
- Female
- Gene Frequency
- Genetic Variation
- Genome, Human
- Genome-Wide Association Study
- Humans
- Male
- Phenotype
- Polymorphism, Single Nucleotide
- Whole Genome Sequencing
57 Authors
- Gareth Hawkes
- Robin N. Beaumont
- Zilin Li
- Ravi Mandla
- Xihao Li
- Christine M. Albert
- Donna K. Arnett
- Allison E. Ashley-Koch
- Aneel A. Ashrani
- Kathleen C. Barnes
- Eric Boerwinkle
- Jennifer A. Brody
- April P. Carson
- Nathalie Chami
- Yii-Der Ida Chen
- Mina K. Chung
- Joanne E. Curran
- Dawood Darbar
- Patrick T. Ellinor
- Myrian Fornage
- Victor R. Gordeuk
- Xiuqing Guo
- Jiang He
- Chii-Min Hwu
- Rita R. Kalyani
- Robert Kaplan
- Sharon L. R. Kardia
- Charles Kooperberg
- Ruth J. F. Loos
- Steven A. Lubitz
- Ryan L. Minster
- Take Naseri
- Satupa'itea Viali
- Braxton D. Mitchell
- Joanne M. Murabito
- Nicholette D. Palmer
- Bruce M. Psaty
- Susan Redline
- M. Benjamin Shoemaker
- Edwin K. Silverman
- Marilyn J. Telen
- Scott T. Weiss
- Lisa R. Yanek
- Hufeng Zhou
- Ching-Ti Liu
- Kari E. North
- Anne E. Justice
- Jonathan M. Locke
- Nick Owens
- Anna Murray
- Kashyap Patel
- Timothy M. Frayling
- Caroline F. Wright
- Andrew R. Wood
- Xihong Lin
- Alisa Manning
- Michael N. Weedon
1 Application
| Application ID | Title |
|---|---|
| 9072 | The Genetics of anthropometric traits ? Height, weight, BMI and waist circumference |
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