Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity

Diana L Cousminer; Diane J Berry; Nicholas J Timpson; Xiao Wei Emmiline Ang; Elisabeth Thiering; Enda Byrne; H Rob Taal; Ville Huikari; Jonathan P Bradfield; Marjan Kerkhof; Maria M Groen-Blokhuis; Eskil Kreiner-Møller; Marcella Marinelli; Claus Holst; Jaakko T Leinonen; John R B Perry; Ida Surakka; Olli Pietiläinen; Johannes Kettunen; Verneri Anttila; Marika Kaakinen; Ulla Sovio; Anneli Pouta; Shikta Das; Vasiliki Lagou; Chris Power; Inga Prokopenko; David M Evans; John P Kemp; Beate St Pourcain; Sue Ring; Aarno Palotie; Eero Kajantie; Clive Osmond; Terho Lehtimäki; Jorma S Viikari; Mika Kähönen; Nicole M Warrington; Stephen J Lye; Lyle J Palmer; Carla M T Tiesler; Claudia Flexeder; Grant W Montgomery; Sarah E Medland; Albert Hofman; Hakon Hakonarson; Mònica Guxens; Meike Bartels; Thorkild I A Sørensen; Hans Bisgaard; The ReproGen Consortium

doi:10.1093/hmg/ddt104

Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity

Diana L Cousminer, Diane J Berry, Nicholas J Timpson, Xiao Wei Emmiline Ang, Elisabeth Thiering, Enda Byrne, H Rob Taal, Ville Huikari, Jonathan P Bradfield, Marjan Kerkhof, Maria M Groen-Blokhuis, Eskil Kreiner-Møller, Marcella Marinelli, Claus Holst, Jaakko T Leinonen, John R B Perry, Ida Surakka, Olli Pietiläinen, Johannes Kettunen, Verneri AnttilaMarika Kaakinen, Ulla Sovio, Anneli Pouta, Shikta Das, Vasiliki Lagou, Chris Power, Inga Prokopenko, David M Evans, John P Kemp, Beate St Pourcain, Sue Ring, Aarno Palotie, Eero Kajantie, Clive Osmond, Terho Lehtimäki, Jorma S Viikari, Mika Kähönen, Nicole M Warrington, Stephen J Lye, Lyle J Palmer, Carla M T Tiesler, Claudia Flexeder, Grant W Montgomery, Sarah E Medland, Albert Hofman, Hakon Hakonarson, Mònica Guxens, Meike Bartels, Thorkild I A Sørensen, Hans Bisgaard, The ReproGen Consortium

111 Citationer (Scopus)

Abstract

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growthfactors.Although little is knownabout the underlying genetics,growthvariabilityduring puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associatedwith pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlyingmechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth andmaturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 3 10^-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Originalsprog	Engelsk
Tidsskrift	Human Molecular Genetics
Vol/bind	22
Udgave nummer	13
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/ddt104
Status	Udgivet - 1 jul. 2013

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Cousminer, D. L., Berry, D. J., Timpson, N. J., Ang, X. W. E., Thiering, E., Byrne, E., Taal, H. R., Huikari, V., Bradfield, J. P., Kerkhof, M., Groen-Blokhuis, M. M., Kreiner-Møller, E., Marinelli, M., Holst, C., Leinonen, J. T., Perry, J. R. B., Surakka, I., Pietiläinen, O., Kettunen, J., ... The ReproGen Consortium (2013). Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity. Human Molecular Genetics, 22(13). https://doi.org/10.1093/hmg/ddt104

Cousminer, DL, Berry, DJ, Timpson, NJ, Ang, XWE, Thiering, E, Byrne, E, Taal, HR, Huikari, V, Bradfield, JP, Kerkhof, M, Groen-Blokhuis, MM, Kreiner-Møller, E, Marinelli, M, Holst, C, Leinonen, JT, Perry, JRB, Surakka, I, Pietiläinen, O, Kettunen, J, Anttila, V, Kaakinen, M, Sovio, U, Pouta, A, Das, S, Lagou, V, Power, C, Prokopenko, I, Evans, DM, Kemp, JP, St Pourcain, B, Ring, S, Palotie, A, Kajantie, E, Osmond, C, Lehtimäki, T, Viikari, JS, Kähönen, M, Warrington, NM, Lye, SJ, Palmer, LJ, Tiesler, CMT, Flexeder, C, Montgomery, GW, Medland, SE, Hofman, A, Hakonarson, H, Guxens, M, Bartels, M, Sørensen, TIA, Bisgaard, H & The ReproGen Consortium 2013, 'Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity', Human Molecular Genetics, bind 22, nr. 13. https://doi.org/10.1093/hmg/ddt104

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title = "Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity",

abstract = "The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growthfactors.Although little is knownabout the underlying genetics,growthvariabilityduring puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associatedwith pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlyingmechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth andmaturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 3 10-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.",

author = "Cousminer, {Diana L} and Berry, {Diane J} and Timpson, {Nicholas J} and Ang, {Xiao Wei Emmiline} and Elisabeth Thiering and Enda Byrne and Taal, {H Rob} and Ville Huikari and Bradfield, {Jonathan P} and Marjan Kerkhof and Groen-Blokhuis, {Maria M} and Eskil Kreiner-M{\o}ller and Marcella Marinelli and Claus Holst and Leinonen, {Jaakko T} and Perry, {John R B} and Ida Surakka and Olli Pietil{\"a}inen and Johannes Kettunen and Verneri Anttila and Marika Kaakinen and Ulla Sovio and Anneli Pouta and Shikta Das and Vasiliki Lagou and Chris Power and Inga Prokopenko and Evans, {David M} and Kemp, {John P} and {St Pourcain}, Beate and Sue Ring and Aarno Palotie and Eero Kajantie and Clive Osmond and Terho Lehtim{\"a}ki and Viikari, {Jorma S} and Mika K{\"a}h{\"o}nen and Warrington, {Nicole M} and Lye, {Stephen J} and Palmer, {Lyle J} and Tiesler, {Carla M T} and Claudia Flexeder and Montgomery, {Grant W} and Medland, {Sarah E} and Albert Hofman and Hakon Hakonarson and M{\`o}nica Guxens and Meike Bartels and S{\o}rensen, {Thorkild I A} and Hans Bisgaard and S{\o}rensen, {Thorkild I.A.}",

year = "2013",

month = jul,

day = "1",

doi = "10.1093/hmg/ddt104",

language = "English",

volume = "22",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "13",

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TY - JOUR

T1 - Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity

AU - Cousminer, Diana L

AU - Berry, Diane J

AU - Timpson, Nicholas J

AU - Ang, Xiao Wei Emmiline

AU - Thiering, Elisabeth

AU - Byrne, Enda

AU - Taal, H Rob

AU - Huikari, Ville

AU - Bradfield, Jonathan P

AU - Kerkhof, Marjan

AU - Groen-Blokhuis, Maria M

AU - Kreiner-Møller, Eskil

AU - Marinelli, Marcella

AU - Holst, Claus

AU - Leinonen, Jaakko T

AU - Perry, John R B

AU - Surakka, Ida

AU - Pietiläinen, Olli

AU - Kettunen, Johannes

AU - Anttila, Verneri

AU - Kaakinen, Marika

AU - Sovio, Ulla

AU - Pouta, Anneli

AU - Das, Shikta

AU - Lagou, Vasiliki

AU - Power, Chris

AU - Prokopenko, Inga

AU - Evans, David M

AU - Kemp, John P

AU - St Pourcain, Beate

AU - Ring, Sue

AU - Palotie, Aarno

AU - Kajantie, Eero

AU - Osmond, Clive

AU - Lehtimäki, Terho

AU - Viikari, Jorma S

AU - Kähönen, Mika

AU - Warrington, Nicole M

AU - Lye, Stephen J

AU - Palmer, Lyle J

AU - Tiesler, Carla M T

AU - Flexeder, Claudia

AU - Montgomery, Grant W

AU - Medland, Sarah E

AU - Hofman, Albert

AU - Hakonarson, Hakon

AU - Guxens, Mònica

AU - Bartels, Meike

AU - Sørensen, Thorkild I A

AU - Bisgaard, Hans

AU - The ReproGen Consortium

PY - 2013/7/1

Y1 - 2013/7/1

N2 - The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growthfactors.Although little is knownabout the underlying genetics,growthvariabilityduring puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associatedwith pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlyingmechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth andmaturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 3 10-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

AB - The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growthfactors.Although little is knownabout the underlying genetics,growthvariabilityduring puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associatedwith pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlyingmechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth andmaturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 3 10-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

U2 - 10.1093/hmg/ddt104

DO - 10.1093/hmg/ddt104

M3 - Journal article

SN - 0964-6906

VL - 22

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 13

ER -

Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity

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