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 & 97 others 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

Research output: Contribution to journalArticle

90 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 languageEnglish
Article numberddv472
Pages (from-to)389-403
Number of pages15
JournalHuman Molecular Genetics
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2016

Fingerprint

Genome-Wide Association Study
Body Mass Index
Alleles
Genetic Loci
Pediatric Obesity
Single Nucleotide Polymorphism
Meta-Analysis
Joints
Genome

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Felix, J. F., Bradfield, J. P., Monnereau, C., Van Der Valk, R. J. P., Stergiakouli, E., Chesi, 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. [ddv472]. https://doi.org/10.1093/hmg/ddv472

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

In: Human Molecular Genetics, Vol. 25, No. 2, ddv472, 15.01.2016, p. 389-403.

Research output: Contribution to journalArticle

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, ddv472, pp. 389-403. https://doi.org/10.1093/hmg/ddv472
Felix JF, Bradfield JP, Monnereau C, Van Der Valk RJP, Stergiakouli E, Chesi A et al. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. Human Molecular Genetics. 2016 Jan 15;25(2):389-403. ddv472. https://doi.org/10.1093/hmg/ddv472
Felix, Janine F. ; Bradfield, Jonathan P. ; Monnereau, Claire ; Van Der Valk, Ralf J P ; Stergiakouli, Evie ; Chesi, Alessandra ; Gaillard, Romy ; Feenstra, Bjarke ; Thiering, Elisabeth ; Kreiner-Møller, Eskil ; Mahajan, Anubha ; Niina Pitkänen, Pitkänen ; Joro, Raimo ; Cavadino, Alana ; Huikari, Ville ; Franks, Steve ; Groen-Blokhuis, Maria M. ; Cousminer, Diana L. ; Marsh, Julie A. ; Lehtimäki, Terho ; Curtin, John A. ; Vioque, Jesus ; Ahluwalia, Tarunveer S. ; Myhre, Ronny ; Price, Thomas S. ; Natalia Vilor-Tejedor, Vilor-Tejedor ; Yengo, Loïc ; Grarup, Niels ; Ntalla, Ioanna ; Ang, Wei ; Atalay, Mustafa ; Bisgaard, Hans ; Blakemore, Alexandra I. ; Bonnefond, Amelie ; Carstensen, Lisbeth ; Eriksson, Johan ; Flexeder, Claudia ; Franke, Lude ; Geller, Frank ; Geserick, Mandy ; Hartikainen, Anna Liisa ; Haworth, Claire M A ; Hirschhorn, Joel N. ; Hofman, Albert ; Holm, Jens Christian ; Horikoshi, Momoko ; Hottenga, Jouke Jan ; Huang, Jinyan ; Kadarmideen, Haja N. ; Kähönen, Mika ; Kiess, Wieland ; Lakka, Hanna Maaria ; Lakka, Timo A. ; Lewin, Alexandra M. ; Liang, Liming ; Lyytikäinen, Leo Pekka ; Ma, Baoshan ; Magnus, Per ; McCormack, Shana E. ; McMahon, George ; Mentch, Frank D. ; Middeldorp, Christel M. ; Murray, Clare S. ; Pahkala, Katja ; Pers, Tune H. ; Pfäffle, Roland ; Postma, Dirkje S. ; Power, Christine ; Simpson, Angela ; Sengpiel, Verena ; Tiesler, Carla M T ; Torrent, Maties ; Uitterlinden, André G. ; Van Meurs, Joyce B. ; Vinding, Rebecca ; Waage, Johannes ; Wardle, Jane ; Zeggini, Eleftheria ; Zemel, Babette S. ; Dedoussis, George V. ; Pedersen, Oluf ; Froguel, Philippe ; Sunyer, Jordi ; Plomin, Robert ; Jacobsson, Bo ; Hansen, Torben ; Gonzalez, Juan R. ; Custovic, Adnan ; Raitakari, Olli T. ; Pennell, Craig E. ; Elisabeth Widén, Widén ; Boomsma, Dorret I. ; Koppelman, Gerard H. ; Sebert, Sylvain ; Järvelin, Marjo Riitta ; Hyppönen, Elina ; McCarthy, Mark I. ; Lindi, Virpi ; Harri, Niinikoski ; Körner, Antje ; Bønnelykke, Klaus ; Heinrich, Joachim ; Melbye, Mads ; Rivadeneira, Fernando ; Hakonarson, Hakon ; Ring, Susan M. ; Smith, George Davey ; Sørensen, Thorkild I A ; Timpson, Nicholas J. ; Grant, Struan F A ; Jaddoe, Vincent W V ; Kalkwarf, Heidi J. ; Lappe, Joan M. ; Gilsanz, Vicente ; Oberfield, Sharon E. ; Shepherd, John A. ; Kelly, Andrea. / Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 2. pp. 389-403.
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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.",
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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.

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DO - 10.1093/hmg/ddv472

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