Defining the role of common variation in the genomic and biological architecture of adult human height.

Nat Genet
Authors
Keywords
Abstract

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Year of Publication
2014
Journal
Nat Genet
Volume
46
Issue
11
Pages
1173-86
Date Published
2014 Nov
ISSN
1546-1718
URL
DOI
10.1038/ng.3097
PubMed ID
25282103
PubMed Central ID
PMC4250049
Links
Grant list
R01 DK093757 / DK / NIDDK NIH HHS / United States
SP/08/002/24118 / British Heart Foundation / United Kingdom
CZB/4/710 / Chief Scientist Office / United Kingdom
CZB/4/672 / Chief Scientist Office / United Kingdom
RP-PG-0310-1002 / Department of Health / United Kingdom
G0601463 / Medical Research Council / United Kingdom
U01 HG007419 / HG / NHGRI NIH HHS / United States
RG/08/008/25291 / British Heart Foundation / United Kingdom
G0500070 / Medical Research Council / United Kingdom
R01 HL109946 / HL / NHLBI NIH HHS / United States
FS/11/35/28871 / British Heart Foundation / United Kingdom
MC_UP_A100_1003 / Medical Research Council / United Kingdom
T32 GM080178 / GM / NIGMS NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
P01 GM099568 / GM / NIGMS NIH HHS / United States
085301 / Wellcome Trust / United Kingdom
RG/08/014/24067 / British Heart Foundation / United Kingdom
R01 DK072193 / DK / NIDDK NIH HHS / United States
FS/12/33/29561 / British Heart Foundation / United Kingdom
MC_UU_12019/1 / Medical Research Council / United Kingdom
R01 DK075787 / DK / NIDDK NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/L003120/1 / Medical Research Council / United Kingdom
MC_UU_12015/1 / Medical Research Council / United Kingdom
PG/07/085/23349 / British Heart Foundation / United Kingdom
MC_U106179471 / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
FS/14/12/30540 / British Heart Foundation / United Kingdom
MC_UU_12015/2 / Medical Research Council / United Kingdom
FS/12/8/29377 / British Heart Foundation / United Kingdom
P30 DK072488 / DK / NIDDK NIH HHS / United States
MC_U106179472 / Medical Research Council / United Kingdom
G1002084 / Medical Research Council / United Kingdom
090532 / Wellcome Trust / United Kingdom
MC_PC_U127561128 / Medical Research Council / United Kingdom
RG/09/012/28096 / British Heart Foundation / United Kingdom
098395 / Wellcome Trust / United Kingdom
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01 GM075091 / GM / NIGMS NIH HHS / United States
P30 GM103341 / GM / NIGMS NIH HHS / United States
MR/K006584/1 / Medical Research Council / United Kingdom
MR/K013351/1 / Medical Research Council / United Kingdom
MC_UU_12015/5 / Medical Research Council / United Kingdom
323195 / European Research Council / International
R01 HL117626 / HL / NHLBI NIH HHS / United States
098381 / Wellcome Trust / United Kingdom
T32 HL007055 / HL / NHLBI NIH HHS / United States
P30 CA071789 / CA / NCI NIH HHS / United States
MR/L01629X/1 / Medical Research Council / United Kingdom
RG/10/12/28456 / British Heart Foundation / United Kingdom