Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

Janine F. Felix; Jonathan P. Bradfield; Claire Monnereau; Ralf J P Van Der Valk; Evie Stergiakouli; Alessandra Chesi; Romy Gaillard; Bjarke Feenstra; Elisabeth Thiering; Eskil Kreiner-Møller; Anubha Mahajan; Pitkänen Niina Pitkänen; Raimo Joro; Alana Cavadino; Ville Huikari; Steve Franks; Maria M. Groen-Blokhuis; Diana L. Cousminer; Julie A. Marsh; Terho Lehtimäki; John A. Curtin; Jesus Vioque; Tarunveer S. Ahluwalia; Ronny Myhre; Thomas S. Price; Vilor-Tejedor Natalia Vilor-Tejedor; Loïc Yengo; Niels Grarup; Ioanna Ntalla; Wei Ang; Mustafa Atalay; Hans Bisgaard; Alexandra I. Blakemore; Amelie Bonnefond; Lisbeth Carstensen; Johan Eriksson; Claudia Flexeder; Lude Franke; Frank Geller; Mandy Geserick; Anna Liisa Hartikainen; Claire M A Haworth; Joel N. Hirschhorn; Albert Hofman; Jens Christian Holm; Momoko Horikoshi; Jouke Jan Hottenga; Jinyan Huang; Haja N. Kadarmideen; Mika Kähönen; Wieland Kiess; Hanna Maaria Lakka; Timo A. Lakka; Alexandra M. Lewin; Liming Liang; Leo Pekka Lyytikäinen; Baoshan Ma; Per Magnus; Shana E. McCormack; George McMahon; Frank D. Mentch; Christel M. Middeldorp; Clare S. Murray; Katja Pahkala; Tune H. Pers; Roland Pfäffle; Dirkje S. Postma; Christine Power; Angela Simpson; Verena Sengpiel; Carla M T Tiesler; Maties Torrent; André G. Uitterlinden; Joyce B. Van Meurs; Rebecca Vinding; Johannes Waage; Jane Wardle; Eleftheria Zeggini; Babette S. Zemel; George V. Dedoussis; Oluf Pedersen; Philippe Froguel; Jordi Sunyer; Robert Plomin; Bo Jacobsson; Torben Hansen; Juan R. Gonzalez; Adnan Custovic; Olli T. Raitakari; Craig E. Pennell; Widén Elisabeth Widén; Dorret I. Boomsma; Gerard H. Koppelman; Sylvain Sebert; Marjo Riitta Järvelin; Elina Hyppönen; Mark I. McCarthy; Virpi Lindi; Niinikoski Harri; Antje Körner; Klaus Bønnelykke; Joachim Heinrich; Mads Melbye; Fernando Rivadeneira; Hakon Hakonarson; Susan M. Ring; George Davey Smith; Thorkild I A Sørensen; Nicholas J. Timpson; Struan F A Grant; Vincent W V Jaddoe; Heidi J. Kalkwarf; Joan M. Lappe; Vicente Gilsanz; Sharon E. Oberfield; John A. Shepherd; Andrea Kelly

doi:10.1093/hmg/ddv472

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

Janine F. Felix, Jonathan P. Bradfield, Claire Monnereau, Ralf J P Van Der Valk, Evie Stergiakouli, Alessandra Chesi, Romy Gaillard, Bjarke Feenstra, Elisabeth Thiering, Eskil Kreiner-Møller, Anubha Mahajan, Pitkänen Niina Pitkänen, Raimo Joro, Alana Cavadino, Ville Huikari, Steve Franks, Maria M. Groen-Blokhuis, Diana L. Cousminer, Julie A. Marsh, Terho LehtimäkiJohn A. Curtin, Jesus Vioque, Tarunveer S. Ahluwalia, Ronny Myhre, Thomas S. Price, Vilor-Tejedor Natalia Vilor-Tejedor, Loïc Yengo, Niels Grarup, Ioanna Ntalla, Wei Ang, Mustafa Atalay, Hans Bisgaard, Alexandra I. Blakemore, Amelie Bonnefond, Lisbeth Carstensen, Johan Eriksson, Claudia Flexeder, Lude Franke, Frank Geller, Mandy Geserick, Anna Liisa Hartikainen, Claire M A Haworth, Joel N. Hirschhorn, Albert Hofman, Jens Christian Holm, Momoko Horikoshi, Jouke Jan Hottenga, Jinyan Huang, Haja N. Kadarmideen, Mika Kähönen, Wieland Kiess, Hanna Maaria Lakka, Timo A. Lakka, Alexandra M. Lewin, Liming Liang, Leo Pekka Lyytikäinen, Baoshan Ma, Per Magnus, Shana E. McCormack, George McMahon, Frank D. Mentch, Christel M. Middeldorp, Clare S. Murray, Katja Pahkala, Tune H. Pers, Roland Pfäffle, Dirkje S. Postma, Christine Power, Angela Simpson, Verena Sengpiel, Carla M T Tiesler, Maties Torrent, André G. Uitterlinden, Joyce B. Van Meurs, Rebecca Vinding, Johannes Waage, Jane Wardle, Eleftheria Zeggini, Babette S. Zemel, George V. Dedoussis, Oluf Pedersen, Philippe Froguel, Jordi Sunyer, Robert Plomin, Bo Jacobsson, Torben Hansen, Juan R. Gonzalez, Adnan Custovic, Olli T. Raitakari, Craig E. Pennell, Widén Elisabeth Widén, Dorret I. Boomsma, Gerard H. Koppelman, Sylvain Sebert, Marjo Riitta Järvelin, Elina Hyppönen, Mark I. McCarthy, Virpi Lindi, Niinikoski Harri, Antje Körner, Klaus Bønnelykke, Joachim Heinrich, Mads Melbye, Fernando Rivadeneira, Hakon Hakonarson, Susan M. Ring, George Davey Smith, Thorkild I A Sørensen, Nicholas J. Timpson, Struan F A Grant, Vincent W V Jaddoe, Heidi J. Kalkwarf, Joan M. Lappe, Vicente Gilsanz, Sharon E. Oberfield, John A. Shepherd, Andrea Kelly

Australian Centre For Precision Health

Research output: Contribution to journal › Article › peer-review

245 Citations (Scopus)

Abstract

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown.We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores.We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10^-8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10^-10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

Original language	English
Pages (from-to)	389-403
Number of pages	15
Journal	Human molecular genetics
Volume	25
Issue number	2
DOIs	https://doi.org/10.1093/hmg/ddv472
Publication status	Published or Issued - 15 Jan 2016

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/ddv472

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Felix, J. F., Bradfield, J. P., Monnereau, C., Van Der Valk, R. J. P., Stergiakouli, E., Chesi, A., Gaillard, R., Feenstra, B., Thiering, E., Kreiner-Møller, E., Mahajan, A., Niina Pitkänen, P., Joro, R., Cavadino, A., Huikari, V., Franks, S., Groen-Blokhuis, M. M., Cousminer, D. L., Marsh, J. A., ... Kelly, A. (2016). Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. Human molecular genetics, 25(2), 389-403. https://doi.org/10.1093/hmg/ddv472

@article{147a746548024420a8b5a7cfa3e9fa1e,

title = "Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index",

abstract = "A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown.We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores.We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10-8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10-10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.",

author = "Felix, {Janine F.} and Bradfield, {Jonathan P.} and Claire Monnereau and {Van Der Valk}, {Ralf J P} and Evie Stergiakouli and Alessandra Chesi and Romy Gaillard and Bjarke Feenstra and Elisabeth Thiering and Eskil Kreiner-M{\o}ller and Anubha Mahajan and {Niina Pitk{\"a}nen}, Pitk{\"a}nen and Raimo Joro and Alana Cavadino and Ville Huikari and Steve Franks and Groen-Blokhuis, {Maria M.} and Cousminer, {Diana L.} and Marsh, {Julie A.} and Terho Lehtim{\"a}ki and Curtin, {John A.} and Jesus Vioque and Ahluwalia, {Tarunveer S.} and Ronny Myhre and Price, {Thomas S.} and {Natalia Vilor-Tejedor}, Vilor-Tejedor and Lo{\"i}c Yengo and Niels Grarup and Ioanna Ntalla and Wei Ang and Mustafa Atalay and Hans Bisgaard and Blakemore, {Alexandra I.} and Amelie Bonnefond and Lisbeth Carstensen and Johan Eriksson and Claudia Flexeder and Lude Franke and Frank Geller and Mandy Geserick and Hartikainen, {Anna Liisa} and Haworth, {Claire M A} and Hirschhorn, {Joel N.} and Albert Hofman and Holm, {Jens Christian} and Momoko Horikoshi and Hottenga, {Jouke Jan} and Jinyan Huang and Kadarmideen, {Haja N.} and Mika K{\"a}h{\"o}nen and Wieland Kiess and Lakka, {Hanna Maaria} and Lakka, {Timo A.} and Lewin, {Alexandra M.} and Liming Liang and Lyytik{\"a}inen, {Leo Pekka} and Baoshan Ma and Per Magnus and McCormack, {Shana E.} and George McMahon and Mentch, {Frank D.} and Middeldorp, {Christel M.} and Murray, {Clare S.} and Katja Pahkala and Pers, {Tune H.} and Roland Pf{\"a}ffle and Postma, {Dirkje S.} and Christine Power and Angela Simpson and Verena Sengpiel and Tiesler, {Carla M T} and Maties Torrent and Uitterlinden, {Andr{\'e} G.} and {Van Meurs}, {Joyce B.} and Rebecca Vinding and Johannes Waage and Jane Wardle and Eleftheria Zeggini and Zemel, {Babette S.} and Dedoussis, {George V.} and Oluf Pedersen and Philippe Froguel and Jordi Sunyer and Robert Plomin and Bo Jacobsson and Torben Hansen and Gonzalez, {Juan R.} and Adnan Custovic and Raitakari, {Olli T.} and Pennell, {Craig E.} and {Elisabeth Wid{\'e}n}, Wid{\'e}n and Boomsma, {Dorret I.} and Koppelman, {Gerard H.} and Sylvain Sebert and J{\"a}rvelin, {Marjo Riitta} and Elina Hypp{\"o}nen and McCarthy, {Mark I.} and Virpi Lindi and Niinikoski Harri and Antje K{\"o}rner and Klaus B{\o}nnelykke and Joachim Heinrich and Mads Melbye and Fernando Rivadeneira and Hakon Hakonarson and Ring, {Susan M.} and Smith, {George Davey} and S{\o}rensen, {Thorkild I A} and Timpson, {Nicholas J.} and Grant, {Struan F A} and Jaddoe, {Vincent W V} and Kalkwarf, {Heidi J.} and Lappe, {Joan M.} and Vicente Gilsanz and Oberfield, {Sharon E.} and Shepherd, {John A.} and Andrea Kelly",

note = "Publisher Copyright: {\textcopyright} The Author 2015. Published by Oxford University Press.",

year = "2016",

month = jan,

day = "15",

doi = "10.1093/hmg/ddv472",

language = "English",

volume = "25",

pages = "389--403",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "2",

}

Felix, JF, Bradfield, JP, Monnereau, C, Van Der Valk, RJP, Stergiakouli, E, Chesi, A, Gaillard, R, Feenstra, B, Thiering, E, Kreiner-Møller, E, Mahajan, A, Niina Pitkänen, P, Joro, R, Cavadino, A, Huikari, V, Franks, S, Groen-Blokhuis, MM, Cousminer, DL, Marsh, JA, Lehtimäki, T, Curtin, JA, Vioque, J, Ahluwalia, TS, Myhre, R, Price, TS, Natalia Vilor-Tejedor, V-T, Yengo, L, Grarup, N, Ntalla, I, Ang, W, Atalay, M, Bisgaard, H, Blakemore, AI, Bonnefond, A, Carstensen, L, Eriksson, J, Flexeder, C, Franke, L, Geller, F, Geserick, M, Hartikainen, AL, Haworth, CMA, Hirschhorn, JN, Hofman, A, Holm, JC, Horikoshi, M, Hottenga, JJ, Huang, J, Kadarmideen, HN, Kähönen, M, Kiess, W, Lakka, HM, Lakka, TA, Lewin, AM, Liang, L, Lyytikäinen, LP, Ma, B, Magnus, P, McCormack, SE, McMahon, G, Mentch, FD, Middeldorp, CM, Murray, CS, Pahkala, K, Pers, TH, Pfäffle, R, Postma, DS, Power, C, Simpson, A, Sengpiel, V, Tiesler, CMT, Torrent, M, Uitterlinden, AG, Van Meurs, JB, Vinding, R, Waage, J, Wardle, J, Zeggini, E, Zemel, BS, Dedoussis, GV, Pedersen, O, Froguel, P, Sunyer, J, Plomin, R, Jacobsson, B, Hansen, T, Gonzalez, JR, Custovic, A, Raitakari, OT, Pennell, CE, Elisabeth Widén, W, Boomsma, DI, Koppelman, GH, Sebert, S, Järvelin, MR, Hyppönen, E, McCarthy, MI, Lindi, V, Harri, N, Körner, A, Bønnelykke, K, Heinrich, J, Melbye, M, Rivadeneira, F, Hakonarson, H, Ring, SM, Smith, GD, Sørensen, TIA, Timpson, NJ, Grant, SFA, Jaddoe, VWV, Kalkwarf, HJ, Lappe, JM, Gilsanz, V, Oberfield, SE, Shepherd, JA & Kelly, A 2016, 'Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index', Human molecular genetics, vol. 25, no. 2, pp. 389-403. https://doi.org/10.1093/hmg/ddv472

TY - JOUR

T1 - Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

AU - Felix, Janine F.

AU - Bradfield, Jonathan P.

AU - Monnereau, Claire

AU - Van Der Valk, Ralf J P

AU - Stergiakouli, Evie

AU - Chesi, Alessandra

AU - Gaillard, Romy

AU - Feenstra, Bjarke

AU - Thiering, Elisabeth

AU - Kreiner-Møller, Eskil

AU - Mahajan, Anubha

AU - Niina Pitkänen, Pitkänen

AU - Joro, Raimo

AU - Cavadino, Alana

AU - Huikari, Ville

AU - Franks, Steve

AU - Groen-Blokhuis, Maria M.

AU - Cousminer, Diana L.

AU - Marsh, Julie A.

AU - Lehtimäki, Terho

AU - Curtin, John A.

AU - Vioque, Jesus

AU - Ahluwalia, Tarunveer S.

AU - Myhre, Ronny

AU - Price, Thomas S.

AU - Natalia Vilor-Tejedor, Vilor-Tejedor

AU - Yengo, Loïc

AU - Grarup, Niels

AU - Ntalla, Ioanna

AU - Ang, Wei

AU - Atalay, Mustafa

AU - Bisgaard, Hans

AU - Blakemore, Alexandra I.

AU - Bonnefond, Amelie

AU - Carstensen, Lisbeth

AU - Eriksson, Johan

AU - Flexeder, Claudia

AU - Franke, Lude

AU - Geller, Frank

AU - Geserick, Mandy

AU - Hartikainen, Anna Liisa

AU - Haworth, Claire M A

AU - Hirschhorn, Joel N.

AU - Hofman, Albert

AU - Holm, Jens Christian

AU - Horikoshi, Momoko

AU - Hottenga, Jouke Jan

AU - Huang, Jinyan

AU - Kadarmideen, Haja N.

AU - Kähönen, Mika

AU - Kiess, Wieland

AU - Lakka, Hanna Maaria

AU - Lakka, Timo A.

AU - Lewin, Alexandra M.

AU - Liang, Liming

AU - Lyytikäinen, Leo Pekka

AU - Ma, Baoshan

AU - Magnus, Per

AU - McCormack, Shana E.

AU - McMahon, George

AU - Mentch, Frank D.

AU - Middeldorp, Christel M.

AU - Murray, Clare S.

AU - Pahkala, Katja

AU - Pers, Tune H.

AU - Pfäffle, Roland

AU - Postma, Dirkje S.

AU - Power, Christine

AU - Simpson, Angela

AU - Sengpiel, Verena

AU - Tiesler, Carla M T

AU - Torrent, Maties

AU - Uitterlinden, André G.

AU - Van Meurs, Joyce B.

AU - Vinding, Rebecca

AU - Waage, Johannes

AU - Wardle, Jane

AU - Zeggini, Eleftheria

AU - Zemel, Babette S.

AU - Dedoussis, George V.

AU - Pedersen, Oluf

AU - Froguel, Philippe

AU - Sunyer, Jordi

AU - Plomin, Robert

AU - Jacobsson, Bo

AU - Hansen, Torben

AU - Gonzalez, Juan R.

AU - Custovic, Adnan

AU - Raitakari, Olli T.

AU - Pennell, Craig E.

AU - Elisabeth Widén, Widén

AU - Boomsma, Dorret I.

AU - Koppelman, Gerard H.

AU - Sebert, Sylvain

AU - Järvelin, Marjo Riitta

AU - Hyppönen, Elina

AU - McCarthy, Mark I.

AU - Lindi, Virpi

AU - Harri, Niinikoski

AU - Körner, Antje

AU - Bønnelykke, Klaus

AU - Heinrich, Joachim

AU - Melbye, Mads

AU - Rivadeneira, Fernando

AU - Hakonarson, Hakon

AU - Ring, Susan M.

AU - Smith, George Davey

AU - Sørensen, Thorkild I A

AU - Timpson, Nicholas J.

AU - Grant, Struan F A

AU - Jaddoe, Vincent W V

AU - Kalkwarf, Heidi J.

AU - Lappe, Joan M.

AU - Gilsanz, Vicente

AU - Oberfield, Sharon E.

AU - Shepherd, John A.

AU - Kelly, Andrea

PY - 2016/1/15

Y1 - 2016/1/15

N2 - A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown.We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores.We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10-8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10-10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

AB - A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown.We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores.We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10-8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10-10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

UR - http://www.scopus.com/inward/record.url?scp=84960812216&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddv472

DO - 10.1093/hmg/ddv472

M3 - Article

C2 - 26604143

AN - SCOPUS:84960812216

SN - 0964-6906

VL - 25

SP - 389

EP - 403

JO - Human molecular genetics

JF - Human molecular genetics

IS - 2

ER -

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

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