Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants

Kristin L. Young*, Virginia Fisher, Xuan Deng, Jennifer A. Brody, Misa Graff, Elise Lim, Bridget M. Lin, Hanfei Xu, Najaf Amin, Ping An, Stella Aslibekyan, Alison E. Fohner, Bertha Hidalgo, Petra Lenzini, Robert Kraaij, Carolina Medina-Gomez, Ivana Prokić, Fernando Rivadeneira, Colleen Sitlani, Ran TaoJeroen van Rooij, Di Zhang, Jai G. Broome, Erin J. Buth, Benjamin D. Heavner, Deepti Jain, Albert V. Smith, Kathleen Barnes, Meher Preethi Boorgula, Sameer Chavan, Dawood Darbar, Mariza De Andrade, Xiuqing Guo, Jeffrey Haessler, Marguerite R. Irvin, Rita R. Kalyani, Sharon L.R. Kardia, Charles Kooperberg, Wonji Kim, Rasika A. Mathias, Merry Lynn McDonald, Braxton D. Mitchell, Patricia A. Peyser, Elizabeth A. Regan, Susan Redline, Alexander P. Reiner, Stephen S. Rich, Jerome I. Rotter, Jennifer A. Smith, Scott Weiss, Kerri L. Wiggins, Lisa R. Yanek, Donna Arnett, Nancy L. Heard-Costa, Suzanne Leal, Danyu Lin, Barbara McKnight, Michael Province, Cornelia M. van Duijn, Kari E. North, L. Adrienne Cupples, Ching Ti Liu*

*Corresponding author for this work

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Anthropometric traits, measuring body size and shape, are highly heritable and significant clinical risk factors for cardiometabolic disorders. These traits have been extensively studied in genome-wide association studies (GWASs), with hundreds of genome-wide significant loci identified. We performed a whole-exome sequence analysis of the genetics of height, body mass index (BMI) and waist/hip ratio (WHR). We meta-analyzed single-variant and gene-based associations of whole-exome sequence variation with height, BMI, and WHR in up to 22,004 individuals, and we assessed replication of our findings in up to 16,418 individuals from 10 independent cohorts from Trans-Omics for Precision Medicine (TOPMed). We identified four trait associations with single-nucleotide variants (SNVs; two for height and two for BMI) and replicated the LECT2 gene association with height. Our expression quantitative trait locus (eQTL) analysis within previously reported GWAS loci implicated CEP63 and RFT1 as potential functional genes for known height loci. We further assessed enrichment of SNVs, which were monogenic or syndromic variants within loci associated with our three traits. This led to the significant enrichment results for height, whereas we observed no Bonferroni-corrected significance for all SNVs. With a sample size of ∼20,000 whole-exome sequences in our discovery dataset, our findings demonstrate the importance of genomic sequencing in genetic association studies, yet they also illustrate the challenges in identifying effects of rare genetic variants.

Original languageEnglish
Article number100163
JournalHuman Genetics and Genomics Advances
Issue number1
Publication statusPublished - 12 Jan 2023

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