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

Ralf J P van der Valk; Eskil Kreiner-Møller; Marjolein N. Kooijman; Moónica Guxens; Evangelia Stergiakouli; Annika Sääf; Jonathan P. Bradfield; Frank Geller; M. Geoffrey Hayes; Diana L. Cousminer; Antje Körner; Elisabeth Thiering; John A. Curtin; Ronny Myhre; Ville Huikari; Raimo Joro; Marjan Kerkhof; Nicole M. Warrington; Niina Pitkänen; Ioanna Ntalla; Momoko Horikoshi; Riitta Veijola; Rachel M. Freathy; Yik Ying Teo; Sheila J. Barton; David M. Evans; John P. Kemp; Beate St Pourcain; Susan M. Ring; George Davey Smith; Anna Bergström; Inger Kull; Hakon Hakonarson; Frank D. Mentch; Hans Bisgaard; Bo Chawes; Jakob Stokholm; Johannes Waage; Patrick Eriksen; Astrid Sevelsted; Mads Melbye; Cornelia M. van Duijn; Carolina Medina-Gomez; Albert Hofman; Johan C. de Jongste; H. Rob Taal; André G. Uitterlinden; Loren L. Armstrong; Johan Eriksson; William L. Lowe; Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium; Genetic Investigation of ANthropometric Traits (GIANT) Consortium; for the Early Growth Genetics (EGG) Consortium

doi:10.1093/hmg/ddu510

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

Ralf J P van der Valk, Eskil Kreiner-Møller, Marjolein N. Kooijman, Moónica Guxens, Evangelia Stergiakouli, Annika Sääf, Jonathan P. Bradfield, Frank Geller, M. Geoffrey Hayes, Diana L. Cousminer, Antje Körner, Elisabeth Thiering, John A. Curtin, Ronny Myhre, Ville Huikari, Raimo Joro, Marjan Kerkhof, Nicole M. Warrington, Niina Pitkänen, Ioanna NtallaMomoko Horikoshi, Riitta Veijola, Rachel M. Freathy, Yik Ying Teo, Sheila J. Barton, David M. Evans, John P. Kemp, Beate St Pourcain, Susan M. Ring, George Davey Smith, Anna Bergström, Inger Kull, Hakon Hakonarson, Frank D. Mentch, Hans Bisgaard, Bo Chawes, Jakob Stokholm, Johannes Waage, Patrick Eriksen, Astrid Sevelsted, Mads Melbye, Cornelia M. van Duijn, Carolina Medina-Gomez, Albert Hofman, Johan C. de Jongste, H. Rob Taal, André G. Uitterlinden, Loren L. Armstrong, Johan Eriksson, William L. Lowe, Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Genetic Investigation of ANthropometric Traits (GIANT) Consortium, for the Early Growth Genetics (EGG) Consortium

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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.

Original language	English (US)
Pages (from-to)	1155-1168
Number of pages	14
Journal	Human molecular genetics
Volume	24
Issue number	4
DOIs	https://doi.org/10.1093/hmg/ddu510
State	Published - Feb 15 2015

ASJC Scopus subject areas

Genetics(clinical)
Genetics
Molecular Biology

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van der Valk, R. J. P., Kreiner-Møller, E., Kooijman, M. N., Guxens, M., Stergiakouli, E., Sääf, A., Bradfield, J. P., Geller, F., Geoffrey Hayes, M., Cousminer, D. L., Körner, A., Thiering, E., Curtin, J. A., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N. M., Pitkänen, N., ... for the Early Growth Genetics (EGG) Consortium (2015). A novel common variant in DCST2 is associated with length in early life and height in adulthood. Human molecular genetics, 24(4), 1155-1168. https://doi.org/10.1093/hmg/ddu510

@article{5e43a209dcab4287967acfd4de1435e4,

title = "A novel common variant in DCST2 is associated with length in early life and height in adulthood",

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.",

author = "{van der Valk}, {Ralf J P} and Eskil Kreiner-M{\o}ller and Kooijman, {Marjolein N.} and Mo{\'o}nica Guxens and Evangelia Stergiakouli and Annika S{\"a}{\"a}f and Bradfield, {Jonathan P.} and Frank Geller and {Geoffrey Hayes}, M. and Cousminer, {Diana L.} and Antje K{\"o}rner and Elisabeth Thiering and Curtin, {John A.} and Ronny Myhre and Ville Huikari and Raimo Joro and Marjan Kerkhof and Warrington, {Nicole M.} and Niina Pitk{\"a}nen and Ioanna Ntalla and Momoko Horikoshi and Riitta Veijola and Freathy, {Rachel M.} and Teo, {Yik Ying} and Barton, {Sheila J.} and Evans, {David M.} and Kemp, {John P.} and Pourcain, {Beate St} and Ring, {Susan M.} and Smith, {George Davey} and Anna Bergstr{\"o}m and Inger Kull and Hakon Hakonarson and Mentch, {Frank D.} and Hans Bisgaard and Bo Chawes and Jakob Stokholm and Johannes Waage and Patrick Eriksen and Astrid Sevelsted and Mads Melbye and {van Duijn}, {Cornelia M.} and Carolina Medina-Gomez and Albert Hofman and {de Jongste}, {Johan C.} and {Rob Taal}, H. and Uitterlinden, {Andr{\'e} G.} and Armstrong, {Loren L.} and Johan Eriksson and Lowe, {William L.} and {Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium} and {Genetic Investigation of ANthropometric Traits (GIANT) Consortium} and {for the Early Growth Genetics (EGG) Consortium}",

year = "2015",

month = feb,

day = "15",

doi = "10.1093/hmg/ddu510",

language = "English (US)",

volume = "24",

pages = "1155--1168",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "4",

}

van der Valk, RJP, Kreiner-Møller, E, Kooijman, MN, Guxens, M, Stergiakouli, E, Sääf, A, Bradfield, JP, Geller, F, Geoffrey Hayes, M, Cousminer, DL, Körner, A, Thiering, E, Curtin, JA, Myhre, R, Huikari, V, Joro, R, Kerkhof, M, Warrington, NM, Pitkänen, N, Ntalla, I, Horikoshi, M, Veijola, R, Freathy, RM, Teo, YY, Barton, SJ, Evans, DM, Kemp, JP, Pourcain, BS, Ring, SM, Smith, GD, Bergström, 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, Rob Taal, H, Uitterlinden, AG, Armstrong, LL, Eriksson, J, Lowe, WL, Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Genetic Investigation of ANthropometric Traits (GIANT) Consortium & for the Early Growth Genetics (EGG) Consortium 2015, 'A novel common variant in DCST2 is associated with length in early life and height in adulthood', Human molecular genetics, vol. 24, no. 4, pp. 1155-1168. https://doi.org/10.1093/hmg/ddu510

TY - JOUR

T1 - A novel common variant in DCST2 is associated with length in early life and height in adulthood

AU - van der Valk, Ralf J P

AU - Kreiner-Møller, Eskil

AU - Kooijman, Marjolein N.

AU - Guxens, Moónica

AU - Stergiakouli, Evangelia

AU - Sääf, Annika

AU - Bradfield, Jonathan P.

AU - Geller, Frank

AU - Geoffrey Hayes, M.

AU - Cousminer, Diana L.

AU - Körner, Antje

AU - Thiering, Elisabeth

AU - Curtin, John A.

AU - Myhre, Ronny

AU - Huikari, Ville

AU - Joro, Raimo

AU - Kerkhof, Marjan

AU - Warrington, Nicole M.

AU - Pitkänen, Niina

AU - Ntalla, Ioanna

AU - Horikoshi, Momoko

AU - Veijola, Riitta

AU - Freathy, Rachel M.

AU - Teo, Yik Ying

AU - Barton, Sheila J.

AU - Evans, David M.

AU - Kemp, John P.

AU - Pourcain, Beate St

AU - Ring, Susan M.

AU - Smith, George Davey

AU - Bergström, Anna

AU - Kull, Inger

AU - Hakonarson, Hakon

AU - Mentch, Frank D.

AU - Bisgaard, Hans

AU - Chawes, Bo

AU - Stokholm, Jakob

AU - Waage, Johannes

AU - Eriksen, Patrick

AU - Sevelsted, Astrid

AU - Melbye, Mads

AU - van Duijn, Cornelia M.

AU - Medina-Gomez, Carolina

AU - Hofman, Albert

AU - de Jongste, Johan C.

AU - Rob Taal, H.

AU - Uitterlinden, André G.

AU - Armstrong, Loren L.

AU - Eriksson, Johan

AU - Lowe, William L.

AU - Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium

AU - Genetic Investigation of ANthropometric Traits (GIANT) Consortium

AU - for the Early Growth Genetics (EGG) Consortium

PY - 2015/2/15

Y1 - 2015/2/15

N2 - 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.

AB - 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.

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U2 - 10.1093/hmg/ddu510

DO - 10.1093/hmg/ddu510

M3 - Article

C2 - 25281659

AN - SCOPUS:84985023154

SN - 0964-6906

VL - 24

SP - 1155

EP - 1168

JO - Human molecular genetics

JF - Human molecular genetics

IS - 4

ER -

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

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