Rare and low-frequency coding variants alter human adult height

Rare and low-frequency coding variants alter human adult height · SciRah

^aWilliam Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
^bDepartment of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27514, USA
^cDepartment of Epidemiology, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands
^dDepartment of Internal Medicine, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands
^eMontreal Heart Institute, Montreal, Quebec H1T 1C8, Canada
^fGenetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK
^gDepartment of Molecular Biology and Genetics, Aarhus University, Aarhus, 8000, Denmark
^hBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
ⁱDepartment of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
^jDivision of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA
^kDivision of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA
^lThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
^mThe Genetics of Obesity and Related Metabolic Traits Program, Ichan School of Medicine at Mount Sinai, New York, New York 10069, USA
ⁿHuman Genetics Center, The University of Texas School of Public Health, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
^oInstitute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, 1010, Switzerland
^pSwiss Institute of Bioinformatics, Lausanne, 1015, Switzerland
^qdeCODE Genetics/Amgen inc., Reykjavik, 101, Iceland
^rDepartment of Computational Biology, University of Lausanne, Lausanne, 1011, Switzerland
^sDepartment of Haematology, University of Cambridge, Cambridge CB2 0PT, UK
^tDepartment of Genetic Epidemiology, University of Regensburg, Regensburg, D-93051, Germany
^uEstonian Genome Center, University of Tartu, Tartu, 51010, Estonia
^vWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
^wDepartment of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA
^xMcDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri 63108, USA
^yDepartment of Cardiovascular Sciences, Univeristy of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK
^zNIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK
^aaCenter for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA
^abCenter for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA
^acNuffield Department of Clinical Medicine, Oxford OX3 7BN, UK
^adInstitute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California 90502, USA
^aeNetherlands Comprehensive Cancer Organisation, Utrecht, 3501 DB, The Netherlands
^afRadboud University Medical Center, Nijmegen, 6500 HB, The Netherlands

Abstract

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1–4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1–2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways. Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth. As a highly heritable polygenic trait, human height has provided a model for the genetic analysis of complex traits. So far about 700 common genetic variants have been linked to height through genome-wide association studies, but the role of low-frequency and rare variants has not been systematically explored. Guillaume Lettre, Joel Hirschhorn and colleagues in the GIANT Consortium now report their analysis of coding regions in the genomes of 711,418 individuals. They identify 120 loci newly associated with height, including 32 rare and 51 low-frequency coding variants. They highlight 83 candidate genes with low-frequency height-associated variants and implicate biological pathways with known roles in growth disorders as well as new candidates. Their analyses provide insights into the genomic architecture of human height.

TL;DRThe results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways. (Semantic Scholar)

Rare and low-frequency coding variants alter human adult height

Abstract

Plain-language summary

Discussion