A common variant of HMGA2 is associated with adult and childhood height in the general population

Weedon, M. N., Wellcome Trust Case Control Consortium, Brown, Matthew A., Bradbury, Linda A. and et al. (2007) A common variant of HMGA2 is associated with adult and childhood height in the general population. Nature Genetics, 39 10: 1245-1250. doi:10.1038/ng2121


Author Weedon, M. N.
Wellcome Trust Case Control Consortium
Brown, Matthew A.
Bradbury, Linda A.
et al.
Title A common variant of HMGA2 is associated with adult and childhood height in the general population
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1061-4036
1546-1718
Publication date 2007-10-01
Sub-type Article (original research)
DOI 10.1038/ng2121
Open Access Status DOI
Volume 39
Issue 10
Start page 1245
End page 1250
Total pages 6
Editor Myles Axton
Place of publication New York, U.S.A.
Publisher Nature Publishing Group
Language eng
Subject 1114 Paediatrics and Reproductive Medicine
1103 Clinical Sciences
Abstract Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
Formatted abstract
Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10 -8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10-11, overall P = 4 × 10-16, including the genome-wide association data). We also observed the association in children (P = 1 × 10-6, N = 6,827) and a tall/short case-control study (P = 4 × 10-6, N = 3,207). We estimate that rs1042725 explains ∼0.3% of population variation in height (∼0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.

Keyword Body height
Case-control studies
Child
Genotype
HMGA2 protein
Linkage Disequilibrium
Polymorphism
Single Nucleotide
Variation (Genetics)
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 HD034242
U01 HG004438
U01 HG004446
MC_UU_12013/3
MR/K014536/1
R01 HD034243
MR/K002449/1
U01 HG004424
U01 NS047537
R01 DK075787
G0601361
U01 HG004415
102215
N01ES75558
HHSN268200782096C
MC_PC_15018
R01 HD056465
MC_UP_A620_1017
MC_UU_12013/1
MC_UU_12013/4
R01 CA141688
U01 HG004423
MC_UU_12011/4
098381
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
ERA 2012 Admin Only
UQ Diamantina Institute Publications
 
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Created: Thu, 01 Apr 2010, 18:35:26 EST by June Temby on behalf of UQ Diamantina Institute