Rare and low-frequency coding variants alter human adult height
File(s)
Accepted version
Author(s)
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
.
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
.
Date Issued
2017-02-01
Date Acceptance
2016-12-16
Citation
Nature, 2017, 542, pp.186-190
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
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
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
Subjects
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