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A novel common variant in DCST2 is associated with length in early life and height in adulthood

Title: A novel common variant in DCST2 is associated with length in early life and height in adulthood
Authors: Van der Valk, RJP
Kreiner-Moller, E
Kooijman, MN
Guxens, M
Stergiakouli, E
Saaf, A
Bradfield, JP
Geller, F
Hayes, MG
Cousminer, DL
Koerner, A
Sergeyev, E
Grallert, H
Custovic, A
Jacobsson, B
Jarvelin, M-R
Atalay, M
Koppelman, GH
Pennell, CE
Niinikoski, H
Dedoussis, GV
Thiering, E
Mccarthy, MI
Frayling, TM
Sunyer, J
Timpson, NJ
Rivadeneira, F
Bonnelykke, K
Jaddoe, VWV
Curtin, JA
Myhre, R
Huikari, V
Joro, R
Kerkhof, M
Warrington, NM
Pitkanen, N
Ntalla, I
Horikoshi, M
Veijola, R
Freathy, RM
Teo, Y-Y
Barton, SJ
Evans, DM
Kemp, JP
St Pourcain, B
Ring, SM
Smith, GD
Bergstrom, A
Kull, I
Hakonarson, H
Mentch, FD
Bisgaard, H
Chawes, B
Stokholm, J
Waage, J
Eriksen, P
Sevelsted, A
Melbye, M
Van Duijn, CM
Medina-Gomez, C
Hofman, A
De Jongste, JC
Taal, HR
Uitterlinden, AG
Armstrong, LL
Eriksson, J
Palotie, A
Bustamante, M
Estivill, X
Gonzalez, JR
Llop, S
Kiess, W
Mahajan, A
Flexeder, C
Tiesler, CMT
Murray, CS
Simpson, A
Magnus, P
Sengpiel, V
Hartikainen, A-L
Keinanen-Kiukaanniemi, S
Lewin, A
Alves, ADSC
Blakemore, AI
Buxton, JL
Kaakinen, M
Rodriguez, A
Sebert, S
Vaarasmaki, M
Lakka, T
Lindi, V
Gehring, U
Postma, DS
Ang, W
Newnham, JP
Lyytikainen, L-P
Pahkala, K
Raitakari, OT
Panoutsopoulou, K
Zeggini, E
Boomsma, DI
Groen-Blokhuis, M
Ilonen, J
Franke, L
Hirschhorn, JN
Pers, TH
Liang, L
Huang, J
Hocher, B
Knip, M
Saw, S-M
Holloway, JW
Melen, E
Grant, SFA
Feenstra, B
Lowe, WL
Widen, E
Item Type: Journal Article
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.
Issue Date: 3-Oct-2014
Date of Acceptance: 29-Sep-2014
URI: http://hdl.handle.net/10044/1/40893
DOI: http://dx.doi.org/10.1093/hmg/ddu510
ISSN: 1460-2083
Publisher: Oxford University Press
Start Page: 1155
End Page: 1168
Journal / Book Title: Human Molecular Genetics
Volume: 24
Issue: 4
Copyright Statement: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0/).
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/K014536/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Genetics & Heredity
GENOME-WIDE ASSOCIATION
LOW-BIRTH-WEIGHT
DC-STAMP
GLUCOCEREBROSIDASE MUTATIONS
GROWTH-RETARDATION
IMPUTED DATA
DISEASE
LOCI
GENE
TOOL
Adaptor Proteins, Signal Transducing
Adult
Age Factors
Alleles
Body Height
Computational Biology
Databases, Genetic
Genetic Association Studies
Genetic Variation
Genotype
Humans
Infant, Newborn
Membrane Proteins
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Quantitative Trait, Heritable
Reproducibility of Results
Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium
Genetic Investigation of ANthropometric Traits (GIANT) Consortium
Early Growth Genetics (EGG) Consortium
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)