Rare and low-frequency coding variants alter human adult height

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Title: Rare and low-frequency coding variants alter human adult height
Authors: Marouli, E
Graff, M
Medina-Gomez, C
Lo, KS
Wood, AR
Kjaer, TR
Fine, RS
Lu, Y
Elliott, P
Chambers, JC
Evangelou, E
Kooner, JS
Oxvig, C
Kutalik, Z
Rivadeneira, F
Loos, RJF
Frayling, TM
Hirschorn, JS
Deloukas, P
Lettre, G
Item Type: Journal Article
Abstract: Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ 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 .
Issue Date: 1-Feb-2017
Date of Acceptance: 16-Dec-2016
URI: http://hdl.handle.net/10044/1/43708
DOI: https://dx.doi..org/10.1038/nature21039
ISSN: 0028-0836
Publisher: MacMillan Publishers
Start Page: 186
End Page: 190
Journal / Book Title: Nature
Volume: 542
Copyright Statement: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Sponsor/Funder: British Heart Foundation
Medical Research Council (MRC)
Wellcome Trust
Medical Research Council (MRC)
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Action on Hearing Loss
Home Office
National Institutes of Health
National Institute for Health Research
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Public Health England
Funder's Grant Number: SP/04/02
G0700931
084723/Z/08/Z
G0601966
NF-SI-0611-10136
RDC01 79560
G51_Chambers
7370192
1 U01 DK085545-01
RDC01 79560
MR/K002414/1
MR/L01632X/1
MR/L01341X/1
RTJ6219303-1
6509268
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
GENOME-WIDE ASSOCIATION
MISSING HERITABILITY
GENETIC ARCHITECTURE
INTERLEUKIN-11
MUTATIONS
MICE
General Science & Technology
MD Multidisciplinary
Publication Status: Published
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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