HGG Advances (Jan 2023)
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 Tao,
- Jeroen 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
Affiliations
- Kristin L. Young
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA; Corresponding author
- Virginia Fisher
- Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA
- Xuan Deng
- Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA
- Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
- Misa Graff
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA
- Elise Lim
- Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA
- Bridget M. Lin
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA
- Hanfei Xu
- Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA
- Najaf Amin
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam 3015CN, the Netherlands
- Ping An
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
- Stella Aslibekyan
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Alison E. Fohner
- Department of Epidemiology, University of Washington, Seattle, WA 98101, USA; Institute for Public Health Genetics, University of Washington, Seattle, WA 98101, USA
- Bertha Hidalgo
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Petra Lenzini
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
- Robert Kraaij
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam 3015CN, the Netherlands
- Carolina Medina-Gomez
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam 3015CN, the Netherlands
- Ivana Prokić
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam 3015CN, the Netherlands
- Fernando Rivadeneira
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam 3015CN, the Netherlands
- Colleen Sitlani
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
- Ran Tao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Jeroen van Rooij
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam 3015CN, the Netherlands
- Di Zhang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Jai G. Broome
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98105, USA
- Erin J. Buth
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
- Benjamin D. Heavner
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
- Deepti Jain
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
- Albert V. Smith
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
- Kathleen Barnes
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Tempus Labs, Chicago, IL 60654, USA
- Meher Preethi Boorgula
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Sameer Chavan
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Dawood Darbar
- Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
- Mariza De Andrade
- Health Quantitative Sciences Research, Mayo Clinic, Rochester, MN, USA
- Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
- Jeffrey Haessler
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Marguerite R. Irvin
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Rita R. Kalyani
- Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sharon L.R. Kardia
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
- Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Wonji Kim
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Rasika A. Mathias
- Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Merry-Lynn McDonald
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
- Braxton D. Mitchell
- Department of Medicine, University of Maryland, Baltimore, MD, USA
- Patricia A. Peyser
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
- Elizabeth A. Regan
- Department of Medicine, National Jewish Health, Denver, CO, USA
- Susan Redline
- Department of Medicine, Brigham & Women’s Hospital, Boston, MA, USA
- Alexander P. Reiner
- Department of Epidemiology, University of Washington, Seattle, WA 98101, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Stephen S. Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
- Jennifer A. Smith
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
- Scott Weiss
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Kerri L. Wiggins
- Department of Medicine, University of Washington, Seattle, WA, USA
- Lisa R. Yanek
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Donna Arnett
- College of Public Health, University of Kentucky, Lexington, KY, USA
- Nancy L. Heard-Costa
- Department of Neurology, Boston University, Boston, MA, USA
- Suzanne Leal
- Department of Neurology, Columbia University, New York City, NY, USA
- Danyu Lin
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA
- Barbara McKnight
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
- Michael Province
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
- Cornelia M. van Duijn
- Nuffield Department of Population Health, St. Cross College, Oxford, UK
- Kari E. North
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA
- L. Adrienne Cupples
- Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA
- Ching-Ti Liu
- Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA; Corresponding author
- Journal volume & issue
-
Vol. 4,
no. 1
p. 100163
Abstract
Summary: 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.
