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

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 tested rare (<0.1% minor-allele-frequency) single variants and aggregates 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 -7 cm 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. These results demonstrate an approach for identifying non-coding rare variants in regulatory regions from WGS data associated with complex traits.

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. Kalyan, 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, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, 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