Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Eshim S Jami; Anke R Hammerschlag; Hill F Ip; Andrea G Allegrini; Beben Benyamin; Richard Border; Elizabeth W Diemer; Chang Jiang; Ville Karhunen; Yi Lu; Qing Lu; Travis T Mallard; Pashupati P Mishra; Ilja M Nolte; Teemu Palviainen; Roseann E Peterson; Hannah M Sallis; Andrey A Shabalin; Ashley E Tate; Elisabeth Thiering; Natàlia Vilor-Tejedor; Carol Wang; Ang Zhou; Daniel E Adkins; Silvia Alemany; Helga Ask; Qi Chen; Robin P Corley; Erik A Ehli; Luke M Evans; Alexandra Havdahl; Fiona A Hagenbeek; Christian Hakulinen; Anjali K Henders; Jouke Jan Hottenga; Tellervo Korhonen; Abdullah Mamun; Shelby Marrington; Alexander Neumann; Kaili Rimfeld; Fernando Rivadeneira; Judy L Silberg; Catharina E van Beijsterveldt; Eero Vuoksimaa; Alyce M Whipp; Tong Xiaoran; Ole A Andreassen; Dorret I Boomsma; Sandra A Brown; S Alexandra Burt; William Copeland; Danielle M Dick; K Paige Harden; Kathleen Mullan Harris; Catharina A Hartman; Joachim Heinrich; John K Hewitt; Christian Hopfer; Elina Hypponen; Marjo-Riitta Jarvelin; Jaakko Kaprio; Liisa Keltikangas-Järvinen; Kelly L Klump; Kenneth Krauter; Ralf Kuja-Halkola; Henrik Larsson; Terho Lehtimäki; Paul Lichtenstein; Sebastian Lundström; Hermine H Maes; Per Magnus; Marcus R Munafò; Jake M Najman; Pål R Njølstad; Albertine J Oldehinkel; Craig E Pennell; Robert Plomin; Ted Reichborn-Kjennerud; Chandra Reynolds; Richard J Rose; Andrew Smolen; Harold Snieder; Michael Stallings; Marie Standl; Jordi Sunyer; Henning Tiemeier; Sally J Wadsworth; Tamara L Wall; Andrew J O Whitehouse; Gail M Williams; Eivind Ystrøm; Michel G Nivard; Meike Bartels; Christel M Middeldorp

doi:10.1016/j.jaac.2021.11.035

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Eshim S Jami^*, Anke R Hammerschlag, Hill F Ip, Andrea G Allegrini, Beben Benyamin, Richard Border, Elizabeth W Diemer, Chang Jiang, Ville Karhunen, Yi Lu, Qing Lu, Travis T Mallard, Pashupati P Mishra, Ilja M Nolte, Teemu Palviainen, Roseann E Peterson, Hannah M Sallis, Andrey A Shabalin, Ashley E Tate, Elisabeth ThieringNatàlia Vilor-Tejedor, Carol Wang, Ang Zhou, Daniel E Adkins, Silvia Alemany, Helga Ask, Qi Chen, Robin P Corley, Erik A Ehli, Luke M Evans, Alexandra Havdahl, Fiona A Hagenbeek, Christian Hakulinen, Anjali K Henders, Jouke Jan Hottenga, Tellervo Korhonen, Abdullah Mamun, Shelby Marrington, Alexander Neumann, Kaili Rimfeld, Fernando Rivadeneira, Judy L Silberg, Catharina E van Beijsterveldt, Eero Vuoksimaa, Alyce M Whipp, Tong Xiaoran, Ole A Andreassen, Dorret I Boomsma, Sandra A Brown, S Alexandra Burt, William Copeland, Danielle M Dick, K Paige Harden, Kathleen Mullan Harris, Catharina A Hartman, Joachim Heinrich, John K Hewitt, Christian Hopfer, Elina Hypponen, Marjo-Riitta Jarvelin, Jaakko Kaprio, Liisa Keltikangas-Järvinen, Kelly L Klump, Kenneth Krauter, Ralf Kuja-Halkola, Henrik Larsson, Terho Lehtimäki, Paul Lichtenstein, Sebastian Lundström, Hermine H Maes, Per Magnus, Marcus R Munafò, Jake M Najman, Pål R Njølstad, Albertine J Oldehinkel, Craig E Pennell, Robert Plomin, Ted Reichborn-Kjennerud, Chandra Reynolds, Richard J Rose, Andrew Smolen, Harold Snieder, Michael Stallings, Marie Standl, Jordi Sunyer, Henning Tiemeier, Sally J Wadsworth, Tamara L Wall, Andrew J O Whitehouse, Gail M Williams, Eivind Ystrøm, Michel G Nivard, Meike Bartels, Christel M Middeldorp

^*Corresponding author for this work

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

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Abstract

OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence.

METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children aged between 3 and 18. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age and instrument.

RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphisms (SNP) heritability (1.66%, 95% confidence intervals 0.84-2.48%, neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalizing symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range |rg|=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.

CONCLUSION: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Original language	English
Pages (from-to)	934-945
Number of pages	12
Journal	Journal of the American Academy of Child and Adolescent Psychiatry
Volume	61
Issue number	7
Early online date	1-Apr-2022
DOIs	https://doi.org/10.1016/j.jaac.2021.11.035
Publication status	Published - Jul-2022

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Jami, E. S., Hammerschlag, A. R., Ip, H. F., Allegrini, A. G., Benyamin, B., Border, R., Diemer, E. W., Jiang, C., Karhunen, V., Lu, Y., Lu, Q., Mallard, T. T., Mishra, P. P., Nolte, I. M., Palviainen, T., Peterson, R. E., Sallis, H. M., Shabalin, A. A., Tate, A. E., ... Middeldorp, C. M. (2022). Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms. Journal of the American Academy of Child and Adolescent Psychiatry, 61(7), 934-945. https://doi.org/10.1016/j.jaac.2021.11.035

@article{4035ef5f3e294795be7e7489fcf43018,

title = "Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms",

abstract = "OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence.METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children aged between 3 and 18. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age and instrument.RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphisms (SNP) heritability (1.66%, 95% confidence intervals 0.84-2.48%, neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalizing symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range |rg|=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.CONCLUSION: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.",

author = "Jami, {Eshim S} and Hammerschlag, {Anke R} and Ip, {Hill F} and Allegrini, {Andrea G} and Beben Benyamin and Richard Border and Diemer, {Elizabeth W} and Chang Jiang and Ville Karhunen and Yi Lu and Qing Lu and Mallard, {Travis T} and Mishra, {Pashupati P} and Nolte, {Ilja M} and Teemu Palviainen and Peterson, {Roseann E} and Sallis, {Hannah M} and Shabalin, {Andrey A} and Tate, {Ashley E} and Elisabeth Thiering and Nat{\`a}lia Vilor-Tejedor and Carol Wang and Ang Zhou and Adkins, {Daniel E} and Silvia Alemany and Helga Ask and Qi Chen and Corley, {Robin P} and Ehli, {Erik A} and Evans, {Luke M} and Alexandra Havdahl and Hagenbeek, {Fiona A} and Christian Hakulinen and Henders, {Anjali K} and Hottenga, {Jouke Jan} and Tellervo Korhonen and Abdullah Mamun and Shelby Marrington and Alexander Neumann and Kaili Rimfeld and Fernando Rivadeneira and Silberg, {Judy L} and {van Beijsterveldt}, {Catharina E} and Eero Vuoksimaa and Whipp, {Alyce M} and Tong Xiaoran and Andreassen, {Ole A} and Boomsma, {Dorret I} and Brown, {Sandra A} and Burt, {S Alexandra} and William Copeland and Dick, {Danielle M} and Harden, {K Paige} and Harris, {Kathleen Mullan} and Hartman, {Catharina A} and Joachim Heinrich and Hewitt, {John K} and Christian Hopfer and Elina Hypponen and Marjo-Riitta Jarvelin and Jaakko Kaprio and Liisa Keltikangas-J{\"a}rvinen and Klump, {Kelly L} and Kenneth Krauter and Ralf Kuja-Halkola and Henrik Larsson and Terho Lehtim{\"a}ki and Paul Lichtenstein and Sebastian Lundstr{\"o}m and Maes, {Hermine H} and Per Magnus and Munaf{\`o}, {Marcus R} and Najman, {Jake M} and Nj{\o}lstad, {P{\aa}l R} and Oldehinkel, {Albertine J} and Pennell, {Craig E} and Robert Plomin and Ted Reichborn-Kjennerud and Chandra Reynolds and Rose, {Richard J} and Andrew Smolen and Harold Snieder and Michael Stallings and Marie Standl and Jordi Sunyer and Henning Tiemeier and Wadsworth, {Sally J} and Wall, {Tamara L} and Whitehouse, {Andrew J O} and Williams, {Gail M} and Eivind Ystr{\o}m and Nivard, {Michel G} and Meike Bartels and Middeldorp, {Christel M}",

note = "Copyright {\textcopyright} 2022. Published by Elsevier Inc.",

year = "2022",

month = jul,

doi = "10.1016/j.jaac.2021.11.035",

language = "English",

volume = "61",

pages = "934--945",

journal = "Journal of the American Academy of Child and Adolescent Psychiatry",

issn = "0890-8567",

publisher = "ELSEVIER SCIENCE INC",

number = "7",

}

Jami, ES, Hammerschlag, AR, Ip, HF, Allegrini, AG, Benyamin, B, Border, R, Diemer, EW, Jiang, C, Karhunen, V, Lu, Y, Lu, Q, Mallard, TT, Mishra, PP, Nolte, IM, Palviainen, T, Peterson, RE, Sallis, HM, Shabalin, AA, Tate, AE, Thiering, E, Vilor-Tejedor, N, Wang, C, Zhou, A, Adkins, DE, Alemany, S, Ask, H, Chen, Q, Corley, RP, Ehli, EA, Evans, LM, Havdahl, A, Hagenbeek, FA, Hakulinen, C, Henders, AK, Hottenga, JJ, Korhonen, T, Mamun, A, Marrington, S, Neumann, A, Rimfeld, K, Rivadeneira, F, Silberg, JL, van Beijsterveldt, CE, Vuoksimaa, E, Whipp, AM, Xiaoran, T, Andreassen, OA, Boomsma, DI, Brown, SA, Burt, SA, Copeland, W, Dick, DM, Harden, KP, Harris, KM, Hartman, CA, Heinrich, J, Hewitt, JK, Hopfer, C, Hypponen, E, Jarvelin, M-R, Kaprio, J, Keltikangas-Järvinen, L, Klump, KL, Krauter, K, Kuja-Halkola, R, Larsson, H, Lehtimäki, T, Lichtenstein, P, Lundström, S, Maes, HH, Magnus, P, Munafò, MR, Najman, JM, Njølstad, PR, Oldehinkel, AJ, Pennell, CE, Plomin, R, Reichborn-Kjennerud, T, Reynolds, C, Rose, RJ, Smolen, A, Snieder, H, Stallings, M, Standl, M, Sunyer, J, Tiemeier, H, Wadsworth, SJ, Wall, TL, Whitehouse, AJO, Williams, GM, Ystrøm, E, Nivard, MG, Bartels, M & Middeldorp, CM 2022, 'Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms', Journal of the American Academy of Child and Adolescent Psychiatry, vol. 61, no. 7, pp. 934-945. https://doi.org/10.1016/j.jaac.2021.11.035

TY - JOUR

T1 - Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

AU - Jami, Eshim S

AU - Hammerschlag, Anke R

AU - Ip, Hill F

AU - Allegrini, Andrea G

AU - Benyamin, Beben

AU - Border, Richard

AU - Diemer, Elizabeth W

AU - Jiang, Chang

AU - Karhunen, Ville

AU - Lu, Yi

AU - Lu, Qing

AU - Mallard, Travis T

AU - Mishra, Pashupati P

AU - Nolte, Ilja M

AU - Palviainen, Teemu

AU - Peterson, Roseann E

AU - Sallis, Hannah M

AU - Shabalin, Andrey A

AU - Tate, Ashley E

AU - Thiering, Elisabeth

AU - Vilor-Tejedor, Natàlia

AU - Wang, Carol

AU - Zhou, Ang

AU - Adkins, Daniel E

AU - Alemany, Silvia

AU - Ask, Helga

AU - Chen, Qi

AU - Corley, Robin P

AU - Ehli, Erik A

AU - Evans, Luke M

AU - Havdahl, Alexandra

AU - Hagenbeek, Fiona A

AU - Hakulinen, Christian

AU - Henders, Anjali K

AU - Hottenga, Jouke Jan

AU - Korhonen, Tellervo

AU - Mamun, Abdullah

AU - Marrington, Shelby

AU - Neumann, Alexander

AU - Rimfeld, Kaili

AU - Rivadeneira, Fernando

AU - Silberg, Judy L

AU - van Beijsterveldt, Catharina E

AU - Vuoksimaa, Eero

AU - Whipp, Alyce M

AU - Xiaoran, Tong

AU - Andreassen, Ole A

AU - Boomsma, Dorret I

AU - Brown, Sandra A

AU - Burt, S Alexandra

AU - Copeland, William

AU - Dick, Danielle M

AU - Harden, K Paige

AU - Harris, Kathleen Mullan

AU - Hartman, Catharina A

AU - Heinrich, Joachim

AU - Hewitt, John K

AU - Hopfer, Christian

AU - Hypponen, Elina

AU - Jarvelin, Marjo-Riitta

AU - Kaprio, Jaakko

AU - Keltikangas-Järvinen, Liisa

AU - Klump, Kelly L

AU - Krauter, Kenneth

AU - Kuja-Halkola, Ralf

AU - Larsson, Henrik

AU - Lehtimäki, Terho

AU - Lichtenstein, Paul

AU - Lundström, Sebastian

AU - Maes, Hermine H

AU - Magnus, Per

AU - Munafò, Marcus R

AU - Najman, Jake M

AU - Njølstad, Pål R

AU - Oldehinkel, Albertine J

AU - Pennell, Craig E

AU - Plomin, Robert

AU - Reichborn-Kjennerud, Ted

AU - Reynolds, Chandra

AU - Rose, Richard J

AU - Smolen, Andrew

AU - Snieder, Harold

AU - Stallings, Michael

AU - Standl, Marie

AU - Sunyer, Jordi

AU - Tiemeier, Henning

AU - Wadsworth, Sally J

AU - Wall, Tamara L

AU - Whitehouse, Andrew J O

AU - Williams, Gail M

AU - Ystrøm, Eivind

AU - Nivard, Michel G

AU - Bartels, Meike

AU - Middeldorp, Christel M

PY - 2022/7

Y1 - 2022/7

N2 - OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence.METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children aged between 3 and 18. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age and instrument.RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphisms (SNP) heritability (1.66%, 95% confidence intervals 0.84-2.48%, neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalizing symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range |rg|=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.CONCLUSION: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

AB - OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence.METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children aged between 3 and 18. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age and instrument.RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphisms (SNP) heritability (1.66%, 95% confidence intervals 0.84-2.48%, neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalizing symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range |rg|=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.CONCLUSION: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

U2 - 10.1016/j.jaac.2021.11.035

DO - 10.1016/j.jaac.2021.11.035

M3 - Article

C2 - 35378236

SN - 0890-8567

VL - 61

SP - 934

EP - 945

JO - Journal of the American Academy of Child and Adolescent Psychiatry

JF - Journal of the American Academy of Child and Adolescent Psychiatry

IS - 7

ER -