A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

Jonathan P. Bradfield; Suzanne Vogelezang; Janine F. Felix; Alessandra Chesi; Øyvind Helgeland; Momoko Horikoshi; Ville Karhunen; Estelle Lowry; Diana L. Cousminer; Tarunveer S. Ahluwalia; Elisabeth Thiering; Eileen Tai Hui Boh; Mohammad H. Zafarmand; Natalia Vilor-Tejedor; Carol A. Wang; Raimo Joro; Zhanghua Chen; William J. Gauderman; Niina Pitkänen; Esteban J. Parra; Lindsay Fernandez-Rhodes; Akram Alyass; Claire Monnereau; John A. Curtin; Christian T. Have; Shana E. McCormack; Mette Hollensted; Christine Frithioff-Bøjsøe; Adan Valladares-Salgado; Jesus Peralta-Romero; Yik Ying Teo; Marie Standl; Jaakko T. Leinonen; Jens Christian Holm; Triinu Peters; Jesus Vioque; Martine Vrijheid; Angela Simpson; Adnan Custovic; Marc Vaudel; Mickaël Canouil; Virpi Lindi; Mustafa Atalay; Mika Kähönen; Olli T. Raitakari; Barbera D.C. Van Schaik; Robert I. Berkowitz; Shelley A. Cole; V. Saroja Voruganti; Yujie Wang; Heather M. Highland; Anthony G. Comuzzie; Nancy F. Butte; Anne E. Justice; Sheila Gahagan; Estela Blanco; Terho Lehtimäki; Timo A. Lakka; Johannes Hebebrand; Amélie Bonnefond; Niels Grarup; Philippe Froguel; Leo Pekka Lyytikäinen; Miguel Cruz; Sayuko Kobes; Robert L. Hanson; Babette S. Zemel; Anke Hinney; Koon K. Teo; David Meyre; Kari E. North; Frank D. Gilliland; Hans Bisgaard; Mariona Bustamante; Klaus Bonnelykke; Craig E. Pennell; Fernando Rivadeneira; André G. Uitterlinden; Leslie J. Baier; Tanja G.M. Vrijkotte; Joachim Heinrich; Thorkild I.A. Sørensen; Seang Mei Saw; Oluf Pedersen; Torben Hansen; Johan Eriksson; Elisabeth Widén; Mark I. McCarthy; Pål R. Njølstad; Christine Power; Elina Hyppönen; Sylvain Sebert; Christopher D. Brown; Marjo Riitta Järvelin; Nicholas J. Timpson; Stefan Johansson; Hakon Hakonarson; Vincent W.V. Jaddoe; F. A. Struan

doi:10.1093/hmg/ddz161

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

Jonathan P. Bradfield, Suzanne Vogelezang, Janine F. Felix, Alessandra Chesi, Øyvind Helgeland, Momoko Horikoshi, Ville Karhunen, Estelle Lowry, Diana L. Cousminer, Tarunveer S. Ahluwalia, Elisabeth Thiering, Eileen Tai Hui Boh, Mohammad H. Zafarmand, Natalia Vilor-Tejedor, Carol A. Wang, Raimo Joro, Zhanghua Chen, William J. Gauderman, Niina Pitkänen, Esteban J. ParraLindsay Fernandez-Rhodes, Akram Alyass, Claire Monnereau, John A. Curtin, Christian T. Have, Shana E. McCormack, Mette Hollensted, Christine Frithioff-Bøjsøe, Adan Valladares-Salgado, Jesus Peralta-Romero, Yik Ying Teo, Marie Standl, Jaakko T. Leinonen, Jens Christian Holm, Triinu Peters, Jesus Vioque, Martine Vrijheid, Angela Simpson, Adnan Custovic, Marc Vaudel, Mickaël Canouil, Virpi Lindi, Mustafa Atalay, Mika Kähönen, Olli T. Raitakari, Barbera D.C. Van Schaik, Robert I. Berkowitz, Shelley A. Cole, V. Saroja Voruganti, Yujie Wang, Heather M. Highland, Anthony G. Comuzzie, Nancy F. Butte, Anne E. Justice, Sheila Gahagan, Estela Blanco, Terho Lehtimäki, Timo A. Lakka, Johannes Hebebrand, Amélie Bonnefond, Niels Grarup, Philippe Froguel, Leo Pekka Lyytikäinen, Miguel Cruz, Sayuko Kobes, Robert L. Hanson, Babette S. Zemel, Anke Hinney, Koon K. Teo, David Meyre, Kari E. North, Frank D. Gilliland, Hans Bisgaard, Mariona Bustamante, Klaus Bonnelykke, Craig E. Pennell, Fernando Rivadeneira, André G. Uitterlinden, Leslie J. Baier, Tanja G.M. Vrijkotte, Joachim Heinrich, Thorkild I.A. Sørensen, Seang Mei Saw, Oluf Pedersen, Torben Hansen, Johan Eriksson, Elisabeth Widén, Mark I. McCarthy, Pål R. Njølstad, Christine Power, Elina Hyppönen, Sylvain Sebert, Christopher D. Brown, Marjo Riitta Järvelin, Nicholas J. Timpson, Stefan Johansson, Hakon Hakonarson, Vincent W.V. Jaddoe, F. A. Struan

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Abstract

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Original language	English (US)
Pages (from-to)	3327-3338
Number of pages	12
Journal	Human molecular genetics
Volume	28
Issue number	19
DOIs	https://doi.org/10.1093/hmg/ddz161
State	Published - Oct 1 2019

All Science Journal Classification (ASJC) codes

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/ddz161

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Bradfield, J. P., Vogelezang, S., Felix, J. F., Chesi, A., Helgeland, Ø., Horikoshi, M., Karhunen, V., Lowry, E., Cousminer, D. L., Ahluwalia, T. S., Thiering, E., Boh, E. T. H., Zafarmand, M. H., Vilor-Tejedor, N., Wang, C. A., Joro, R., Chen, Z., Gauderman, W. J., Pitkänen, N., ... Struan, F. A. (2019). A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity. Human molecular genetics, 28(19), 3327-3338. https://doi.org/10.1093/hmg/ddz161

@article{734f5eea8e46462c87e216250b3fa8ab,

title = "A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity",

abstract = "Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.",

author = "Bradfield, {Jonathan P.} and Suzanne Vogelezang and Felix, {Janine F.} and Alessandra Chesi and {\O}yvind Helgeland and Momoko Horikoshi and Ville Karhunen and Estelle Lowry and Cousminer, {Diana L.} and Ahluwalia, {Tarunveer S.} and Elisabeth Thiering and Boh, {Eileen Tai Hui} and Zafarmand, {Mohammad H.} and Natalia Vilor-Tejedor and Wang, {Carol A.} and Raimo Joro and Zhanghua Chen and Gauderman, {William J.} and Niina Pitk{\"a}nen and Parra, {Esteban J.} and Lindsay Fernandez-Rhodes and Akram Alyass and Claire Monnereau and Curtin, {John A.} and Have, {Christian T.} and McCormack, {Shana E.} and Mette Hollensted and Christine Frithioff-B{\o}js{\o}e and Adan Valladares-Salgado and Jesus Peralta-Romero and Teo, {Yik Ying} and Marie Standl and Leinonen, {Jaakko T.} and Holm, {Jens Christian} and Triinu Peters and Jesus Vioque and Martine Vrijheid and Angela Simpson and Adnan Custovic and Marc Vaudel and Micka{\"e}l Canouil and Virpi Lindi and Mustafa Atalay and Mika K{\"a}h{\"o}nen and Raitakari, {Olli T.} and {Van Schaik}, {Barbera D.C.} and Berkowitz, {Robert I.} and Cole, {Shelley A.} and Voruganti, {V. Saroja} and Yujie Wang and Highland, {Heather M.} and Comuzzie, {Anthony G.} and Butte, {Nancy F.} and Justice, {Anne E.} and Sheila Gahagan and Estela Blanco and Terho Lehtim{\"a}ki and Lakka, {Timo A.} and Johannes Hebebrand and Am{\'e}lie Bonnefond and Niels Grarup and Philippe Froguel and Lyytik{\"a}inen, {Leo Pekka} and Miguel Cruz and Sayuko Kobes and Hanson, {Robert L.} and Zemel, {Babette S.} and Anke Hinney and Teo, {Koon K.} and David Meyre and North, {Kari E.} and Gilliland, {Frank D.} and Hans Bisgaard and Mariona Bustamante and Klaus Bonnelykke and Pennell, {Craig E.} and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G.} and Baier, {Leslie J.} and Vrijkotte, {Tanja G.M.} and Joachim Heinrich and S{\o}rensen, {Thorkild I.A.} and Saw, {Seang Mei} and Oluf Pedersen and Torben Hansen and Johan Eriksson and Elisabeth Wid{\'e}n and McCarthy, {Mark I.} and Nj{\o}lstad, {P{\aa}l R.} and Christine Power and Elina Hypp{\"o}nen and Sylvain Sebert and Brown, {Christopher D.} and J{\"a}rvelin, {Marjo Riitta} and Timpson, {Nicholas J.} and Stefan Johansson and Hakon Hakonarson and Jaddoe, {Vincent W.V.} and Struan, {F. A.}",

year = "2019",

month = oct,

day = "1",

doi = "10.1093/hmg/ddz161",

language = "English (US)",

volume = "28",

pages = "3327--3338",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "19",

}

Bradfield, JP, Vogelezang, S, Felix, JF, Chesi, A, Helgeland, Ø, Horikoshi, M, Karhunen, V, Lowry, E, Cousminer, DL, Ahluwalia, TS, Thiering, E, Boh, ETH, Zafarmand, MH, Vilor-Tejedor, N, Wang, CA, Joro, R, Chen, Z, Gauderman, WJ, Pitkänen, N, Parra, EJ, Fernandez-Rhodes, L, Alyass, A, Monnereau, C, Curtin, JA, Have, CT, McCormack, SE, Hollensted, M, Frithioff-Bøjsøe, C, Valladares-Salgado, A, Peralta-Romero, J, Teo, YY, Standl, M, Leinonen, JT, Holm, JC, Peters, T, Vioque, J, Vrijheid, M, Simpson, A, Custovic, A, Vaudel, M, Canouil, M, Lindi, V, Atalay, M, Kähönen, M, Raitakari, OT, Van Schaik, BDC, Berkowitz, RI, Cole, SA, Voruganti, VS, Wang, Y, Highland, HM, Comuzzie, AG, Butte, NF, Justice, AE, Gahagan, S, Blanco, E, Lehtimäki, T, Lakka, TA, Hebebrand, J, Bonnefond, A, Grarup, N, Froguel, P, Lyytikäinen, LP, Cruz, M, Kobes, S, Hanson, RL, Zemel, BS, Hinney, A, Teo, KK, Meyre, D, North, KE, Gilliland, FD, Bisgaard, H, Bustamante, M, Bonnelykke, K, Pennell, CE, Rivadeneira, F, Uitterlinden, AG, Baier, LJ, Vrijkotte, TGM, Heinrich, J, Sørensen, TIA, Saw, SM, Pedersen, O, Hansen, T, Eriksson, J, Widén, E, McCarthy, MI, Njølstad, PR, Power, C, Hyppönen, E, Sebert, S, Brown, CD, Järvelin, MR, Timpson, NJ, Johansson, S, Hakonarson, H, Jaddoe, VWV & Struan, FA 2019, 'A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity', Human molecular genetics, vol. 28, no. 19, pp. 3327-3338. https://doi.org/10.1093/hmg/ddz161

TY - JOUR

T1 - A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

AU - Bradfield, Jonathan P.

AU - Vogelezang, Suzanne

AU - Felix, Janine F.

AU - Chesi, Alessandra

AU - Helgeland, Øyvind

AU - Horikoshi, Momoko

AU - Karhunen, Ville

AU - Lowry, Estelle

AU - Cousminer, Diana L.

AU - Ahluwalia, Tarunveer S.

AU - Thiering, Elisabeth

AU - Boh, Eileen Tai Hui

AU - Zafarmand, Mohammad H.

AU - Vilor-Tejedor, Natalia

AU - Wang, Carol A.

AU - Joro, Raimo

AU - Chen, Zhanghua

AU - Gauderman, William J.

AU - Pitkänen, Niina

AU - Parra, Esteban J.

AU - Fernandez-Rhodes, Lindsay

AU - Alyass, Akram

AU - Monnereau, Claire

AU - Curtin, John A.

AU - Have, Christian T.

AU - McCormack, Shana E.

AU - Hollensted, Mette

AU - Frithioff-Bøjsøe, Christine

AU - Valladares-Salgado, Adan

AU - Peralta-Romero, Jesus

AU - Teo, Yik Ying

AU - Standl, Marie

AU - Leinonen, Jaakko T.

AU - Holm, Jens Christian

AU - Peters, Triinu

AU - Vioque, Jesus

AU - Vrijheid, Martine

AU - Simpson, Angela

AU - Custovic, Adnan

AU - Vaudel, Marc

AU - Canouil, Mickaël

AU - Lindi, Virpi

AU - Atalay, Mustafa

AU - Kähönen, Mika

AU - Raitakari, Olli T.

AU - Van Schaik, Barbera D.C.

AU - Berkowitz, Robert I.

AU - Cole, Shelley A.

AU - Voruganti, V. Saroja

AU - Wang, Yujie

AU - Highland, Heather M.

AU - Comuzzie, Anthony G.

AU - Butte, Nancy F.

AU - Justice, Anne E.

AU - Gahagan, Sheila

AU - Blanco, Estela

AU - Lehtimäki, Terho

AU - Lakka, Timo A.

AU - Hebebrand, Johannes

AU - Bonnefond, Amélie

AU - Grarup, Niels

AU - Froguel, Philippe

AU - Lyytikäinen, Leo Pekka

AU - Cruz, Miguel

AU - Kobes, Sayuko

AU - Hanson, Robert L.

AU - Zemel, Babette S.

AU - Hinney, Anke

AU - Teo, Koon K.

AU - Meyre, David

AU - North, Kari E.

AU - Gilliland, Frank D.

AU - Bisgaard, Hans

AU - Bustamante, Mariona

AU - Bonnelykke, Klaus

AU - Pennell, Craig E.

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G.

AU - Baier, Leslie J.

AU - Vrijkotte, Tanja G.M.

AU - Heinrich, Joachim

AU - Sørensen, Thorkild I.A.

AU - Saw, Seang Mei

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Eriksson, Johan

AU - Widén, Elisabeth

AU - McCarthy, Mark I.

AU - Njølstad, Pål R.

AU - Power, Christine

AU - Hyppönen, Elina

AU - Sebert, Sylvain

AU - Brown, Christopher D.

AU - Järvelin, Marjo Riitta

AU - Timpson, Nicholas J.

AU - Johansson, Stefan

AU - Hakonarson, Hakon

AU - Jaddoe, Vincent W.V.

AU - Struan, F. A.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

AB - Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

UR - http://www.scopus.com/inward/record.url?scp=85075111079&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075111079&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddz161

DO - 10.1093/hmg/ddz161

M3 - Article

C2 - 31504550

AN - SCOPUS:85075111079

SN - 0964-6906

VL - 28

SP - 3327

EP - 3338

JO - Human molecular genetics

JF - Human molecular genetics

IS - 19

ER -

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

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