Whole genome association testing in 333,100 individuals across three biobanks identifies rare non-coding single variant and genomic aggregate associations with height
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, intergenic and deep-intronic annotation. We observed 29 independent variants associated with height atP< 6 × 10−10after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7cm. We also identified and replicated non-coding aggregate-based associations proximal toHMGA1containing variants associated with a 5cm taller height and of highly-conserved variants inMIR497HGon chromosome 17. We have developed a novel approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 23. Nov. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.11.19.566520 |
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| PPN (Katalog-ID): |
XBI041601769 |
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| 100 | 1 | |a Hawkes, Gareth |e verfasserin |0 (orcid)0000-0002-3367-789X |4 aut | |
| 245 | 1 | 0 | |a Whole genome association testing in 333,100 individuals across three biobanks identifies rare non-coding single variant and genomic aggregate associations with height |
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| 520 | |a 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, intergenic and deep-intronic annotation. We observed 29 independent variants associated with height atP< 6 × 10−10after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7cm. We also identified and replicated non-coding aggregate-based associations proximal toHMGA1containing variants associated with a 5cm taller height and of highly-conserved variants inMIR497HGon chromosome 17. We have developed a novel approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits. | ||
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| 700 | 1 | |a Li, Zilin |4 aut | |
| 700 | 1 | |a Mandla, Ravi |4 aut | |
| 700 | 1 | |a Li, Xihao |4 aut | |
| 700 | 1 | |a Albert, Christine M. |4 aut | |
| 700 | 1 | |a Arnett, Donna K. |4 aut | |
| 700 | 1 | |a Ashley-Koch, Allison E. |4 aut | |
| 700 | 1 | |a Ashrani, Aneel A. |4 aut | |
| 700 | 1 | |a Barnes, Kathleen C. |4 aut | |
| 700 | 1 | |a Boerwinkle, Eric |4 aut | |
| 700 | 1 | |a Brody, Jennifer A. |4 aut | |
| 700 | 1 | |a Carson, April P. |4 aut | |
| 700 | 1 | |a Chami, Nathalie |4 aut | |
| 700 | 1 | |a Chen, Yii-Der Ida |4 aut | |
| 700 | 1 | |a Chung, Mina K. |4 aut | |
| 700 | 1 | |a Curran, Joanne E. |4 aut | |
| 700 | 1 | |a Darbar, Dawood |4 aut | |
| 700 | 1 | |a Ellinor, Patrick T. |4 aut | |
| 700 | 1 | |a Fornage, Myrian |4 aut | |
| 700 | 1 | |a Gordeuk, Victor R. |4 aut | |
| 700 | 1 | |a Guo, Xiuqing |4 aut | |
| 700 | 1 | |a He, Jiang |4 aut | |
| 700 | 1 | |a Hwu, Chii-Min |4 aut | |
| 700 | 1 | |a Kalyani, Rita R. |4 aut | |
| 700 | 1 | |a Kaplan, Robert |4 aut | |
| 700 | 1 | |a Kardia, Sharon L.R. |4 aut | |
| 700 | 1 | |a Kooperberg, Charles |4 aut | |
| 700 | 1 | |a Loos, Ruth J.F. |4 aut | |
| 700 | 1 | |a Lubitz, Steven A. |4 aut | |
| 700 | 1 | |a Minster, Ryan L. |4 aut | |
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| 700 | 1 | |a Murabito, Joanne M. |4 aut | |
| 700 | 1 | |a Palmer, Nicholette D. |4 aut | |
| 700 | 1 | |a Psaty, Bruce M. |4 aut | |
| 700 | 1 | |a Redline, Susan |4 aut | |
| 700 | 1 | |a Benjamin Shoemaker, M. |4 aut | |
| 700 | 1 | |a Silverman, Edwin K. |4 aut | |
| 700 | 1 | |a Telen, Marilyn J. |4 aut | |
| 700 | 1 | |a Weiss, Scott T. |4 aut | |
| 700 | 1 | |a Yanek, Lisa R. |4 aut | |
| 700 | 1 | |a Zhou, Hufeng |4 aut | |
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