Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height

• Published in: Nature communications Vol. 15; no. 1; pp. 8549 - 11
• Main Authors: Hawkes, Gareth, Beaumont, Robin N., Li, Zilin, Mandla, Ravi, Li, Xihao, Albert, Christine M., Arnett, Donna K., Ashley-Koch, Allison E., Ashrani, Aneel A., Barnes, Kathleen C., Boerwinkle, Eric, Brody, Jennifer A., Carson, April P., Chami, Nathalie, Chen, Yii-Der Ida, Chung, Mina K., Curran, Joanne E., Darbar, Dawood, Ellinor, Patrick T., Fornage, Myrian, Gordeuk, Victor R., Guo, Xiuqing, He, Jiang, Hwu, Chii-Min, Kalyani, Rita R., Kaplan, Robert, Kardia, Sharon L. R., Kooperberg, Charles, Loos, Ruth J. F., Lubitz, Steven A., Minster, Ryan L., Naseri, Take, Viali, Satupa’itea, Mitchell, Braxton D., Murabito, Joanne M., Palmer, Nicholette D., Psaty, Bruce M., Redline, Susan, Shoemaker, M. Benjamin, Silverman, Edwin K., Telen, Marilyn J., Weiss, Scott T., Yanek, Lisa R., Zhou, Hufeng, Liu, Ching-Ti, North, Kari E., Justice, Anne E., Locke, Jonathan M., Owens, Nick, Murray, Anna, Patel, Kashyap, Frayling, Timothy M., Wright, Caroline F., Wood, Andrew R., Lin, Xihong, Manning, Alisa, Weedon, Michael N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 631/208/200; 631/208/205/2138; 631/208/480; Annotations; Association analysis; Body height; Body Height - genetics; Chromosome 17; Conserved sequence; Data analysis; Female; Gene Frequency; Gene sequencing; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomes; Genomic analysis; Humanities and Social Sciences; Humans; Impact analysis; Male; multidisciplinary; Nucleotide sequence; Phenotype; Phenotypes; Phenotypic variations; Polymorphism, Single Nucleotide; Regulatory sequences; Science; Science (multidisciplinary); Whole Genome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52579-w

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 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. Here, the authors perform a rare-variant analysis of whole-genome sequence data that takes advantage of three global biobanks. They identify 29 novel rare variants associated with human height, and demonstrate an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data.