Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Jonathan P Bradfield; Rachel L Kember; Anna Ulrich; Zhanna Balkiyarova; Akram Alyass; Izzuddin M Aris; Joshua A Bell; K Alaine Broadaway; Zhanghua Chen; Jin-Fang Chai; Neil M Davies; Dietmar Fernandez-Orth; Mariona Bustamante; Ruby Fore; Amitavo Ganguli; Anni Heiskala; Jouke-Jan Hottenga; Carmen Íñiguez; Sayuko Kobes; Jaakko Leinonen; Estelle Lowry; Leo-Pekka Lyytikainen; Anubha Mahajan; Niina Pitkänen; Theresia M Schnurr; Christian Theil Have; David P Strachan; Elisabeth Thiering; Suzanne Vogelezang; Kaitlin H Wade; Carol A Wang; Andrew Wong; Louise Aas Holm; Alessandra Chesi; Catherine Choong; Miguel Cruz; Paul Elliott; Steve Franks; Christine Frithioff-Bøjsøe; W James Gauderman; Joseph T Glessner; Vicente Gilsanz; Kendra Griesman; Robert L Hanson; Marika Kaakinen; Heidi Kalkwarf; Andrea Kelly; Torben Hansen; Jens-Christian Holm; Thorkild I A Sørensen; Struan F A Grant; Diana L Cousminer; Early Growth Genetics Consortium

doi:10.1186/s13059-023-03136-z

Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Jonathan P Bradfield, Rachel L Kember, Anna Ulrich, Zhanna Balkiyarova, Akram Alyass, Izzuddin M Aris, Joshua A Bell, K Alaine Broadaway, Zhanghua Chen, Jin-Fang Chai, Neil M Davies, Dietmar Fernandez-Orth, Mariona Bustamante, Ruby Fore, Amitavo Ganguli, Anni Heiskala, Jouke-Jan Hottenga, Carmen Íñiguez, Sayuko Kobes, Jaakko LeinonenEstelle Lowry, Leo-Pekka Lyytikainen, Anubha Mahajan, Niina Pitkänen, Theresia M Schnurr, Christian Theil Have, David P Strachan, Elisabeth Thiering, Suzanne Vogelezang, Kaitlin H Wade, Carol A Wang, Andrew Wong, Louise Aas Holm, Alessandra Chesi, Catherine Choong, Miguel Cruz, Paul Elliott, Steve Franks, Christine Frithioff-Bøjsøe, W James Gauderman, Joseph T Glessner, Vicente Gilsanz, Kendra Griesman, Robert L Hanson, Marika Kaakinen, Heidi Kalkwarf, Andrea Kelly, Torben Hansen, Jens-Christian Holm, Thorkild I A Sørensen, Struan F A Grant^*, Diana L Cousminer^*, Early Growth Genetics Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.

RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.

CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

Original language	English
Article number	22
Journal	Genome Biology
Volume	25
Number of pages	19
ISSN	1474-7596
DOIs	https://doi.org/10.1186/s13059-023-03136-z
Publication status	Published - 2024

Bibliographical note

Keywords

Adult
Adolescent
Humans
Child
Child, Preschool
Genome-Wide Association Study
Diabetes Mellitus, Type 2
Puberty/genetics
Phenotype
Body Height/genetics
Outcome Assessment, Health Care
Longitudinal Studies

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Bradfield, J. P., Kember, R. L., Ulrich, A., Balkiyarova, Z., Alyass, A., Aris, I. M., Bell, J. A., Broadaway, K. A., Chen, Z., Chai, J.-F., Davies, N. M., Fernandez-Orth, D., Bustamante, M., Fore, R., Ganguli, A., Heiskala, A., Hottenga, J.-J., Íñiguez, C., Kobes, S., ... Early Growth Genetics Consortium (2024). Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes. Genome Biology, 25, Article 22. https://doi.org/10.1186/s13059-023-03136-z

Bradfield, JP, Kember, RL, Ulrich, A, Balkiyarova, Z, Alyass, A, Aris, IM, Bell, JA, Broadaway, KA, Chen, Z, Chai, J-F, Davies, NM, Fernandez-Orth, D, Bustamante, M, Fore, R, Ganguli, A, Heiskala, A, Hottenga, J-J, Íñiguez, C, Kobes, S, Leinonen, J, Lowry, E, Lyytikainen, L-P, Mahajan, A, Pitkänen, N, Schnurr, TM, Have, CT, Strachan, DP, Thiering, E, Vogelezang, S, Wade, KH, Wang, CA, Wong, A, Holm, LA, Chesi, A, Choong, C, Cruz, M, Elliott, P, Franks, S, Frithioff-Bøjsøe, C, Gauderman, WJ, Glessner, JT, Gilsanz, V, Griesman, K, Hanson, RL, Kaakinen, M, Kalkwarf, H, Kelly, A, Hansen, T , Holm, J-C , Sørensen, TIA, Grant, SFA, Cousminer, DL & Early Growth Genetics Consortium 2024, 'Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes', Genome Biology, vol. 25, 22. https://doi.org/10.1186/s13059-023-03136-z

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title = "Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes",

abstract = "BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single {"}optimal{"} pubertal growth pattern.",

keywords = "Adult, Adolescent, Humans, Child, Child, Preschool, Genome-Wide Association Study, Diabetes Mellitus, Type 2, Puberty/genetics, Phenotype, Body Height/genetics, Outcome Assessment, Health Care, Longitudinal Studies",

author = "Bradfield, {Jonathan P} and Kember, {Rachel L} and Anna Ulrich and Zhanna Balkiyarova and Akram Alyass and Aris, {Izzuddin M} and Bell, {Joshua A} and Broadaway, {K Alaine} and Zhanghua Chen and Jin-Fang Chai and Davies, {Neil M} and Dietmar Fernandez-Orth and Mariona Bustamante and Ruby Fore and Amitavo Ganguli and Anni Heiskala and Jouke-Jan Hottenga and Carmen {\'I}{\~n}iguez and Sayuko Kobes and Jaakko Leinonen and Estelle Lowry and Leo-Pekka Lyytikainen and Anubha Mahajan and Niina Pitk{\"a}nen and Schnurr, {Theresia M} and Have, {Christian Theil} and Strachan, {David P} and Elisabeth Thiering and Suzanne Vogelezang and Wade, {Kaitlin H} and Wang, {Carol A} and Andrew Wong and Holm, {Louise Aas} and Alessandra Chesi and Catherine Choong and Miguel Cruz and Paul Elliott and Steve Franks and Christine Frithioff-B{\o}js{\o}e and Gauderman, {W James} and Glessner, {Joseph T} and Vicente Gilsanz and Kendra Griesman and Hanson, {Robert L} and Marika Kaakinen and Heidi Kalkwarf and Andrea Kelly and Torben Hansen and Jens-Christian Holm and S{\o}rensen, {Thorkild I A} and Grant, {Struan F A} and Cousminer, {Diana L} and {Early Growth Genetics Consortium}",

note = "{\textcopyright} 2023. The Author(s).",

year = "2024",

doi = "10.1186/s13059-023-03136-z",

language = "English",

volume = "25",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

AU - Bradfield, Jonathan P

AU - Kember, Rachel L

AU - Ulrich, Anna

AU - Balkiyarova, Zhanna

AU - Alyass, Akram

AU - Aris, Izzuddin M

AU - Bell, Joshua A

AU - Broadaway, K Alaine

AU - Chen, Zhanghua

AU - Chai, Jin-Fang

AU - Davies, Neil M

AU - Fernandez-Orth, Dietmar

AU - Bustamante, Mariona

AU - Fore, Ruby

AU - Ganguli, Amitavo

AU - Heiskala, Anni

AU - Hottenga, Jouke-Jan

AU - Íñiguez, Carmen

AU - Kobes, Sayuko

AU - Leinonen, Jaakko

AU - Lowry, Estelle

AU - Lyytikainen, Leo-Pekka

AU - Mahajan, Anubha

AU - Pitkänen, Niina

AU - Schnurr, Theresia M

AU - Have, Christian Theil

AU - Strachan, David P

AU - Thiering, Elisabeth

AU - Vogelezang, Suzanne

AU - Wade, Kaitlin H

AU - Wang, Carol A

AU - Wong, Andrew

AU - Holm, Louise Aas

AU - Chesi, Alessandra

AU - Choong, Catherine

AU - Cruz, Miguel

AU - Elliott, Paul

AU - Franks, Steve

AU - Frithioff-Bøjsøe, Christine

AU - Gauderman, W James

AU - Glessner, Joseph T

AU - Gilsanz, Vicente

AU - Griesman, Kendra

AU - Hanson, Robert L

AU - Kaakinen, Marika

AU - Kalkwarf, Heidi

AU - Kelly, Andrea

AU - Hansen, Torben

AU - Holm, Jens-Christian

AU - Sørensen, Thorkild I A

AU - Grant, Struan F A

AU - Cousminer, Diana L

AU - Early Growth Genetics Consortium

PY - 2024

Y1 - 2024

N2 - BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

AB - BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

KW - Adult

KW - Adolescent

KW - Humans

KW - Child

KW - Child, Preschool

KW - Genome-Wide Association Study

KW - Diabetes Mellitus, Type 2

KW - Puberty/genetics

KW - Phenotype

KW - Body Height/genetics

KW - Outcome Assessment, Health Care

KW - Longitudinal Studies

U2 - 10.1186/s13059-023-03136-z

DO - 10.1186/s13059-023-03136-z

M3 - Journal article

C2 - 38229171

SN - 1474-7596

VL - 25

JO - Genome Biology

JF - Genome Biology

M1 - 22

ER -