University of Oulu

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 & Adolescent Psychiatry, 61(7), 934–945.

Genome-wide association meta-analysis of childhood and adolescent internalizing symptoms

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Author: Jami, Eshim S.1,2; Hammerschlag, Anke R.1,3,4; Ip, Hill F.1;
Allegrini, Andrea G.2,5; Benyamin, Beben6,7; Border, Richard8; Diemer, Elizabeth W.9,10; Jiang, Chang11,12; Karhunen, Ville13; Lu, Yi14; Lu, Qing11; Mallard, Travis T.15; Mishra, Pashupati P.16,17; Nolte, Ilja M.18; Palviainen, Teemu19; Peterson, Roseann E.20; Sallis, Hannah M.21,22,23; Shabalin, Andrey A.24; Tate, Ashley E.14; Thiering, Elisabeth25,26; Vilor-Tejedor, Natalia1,9,10,27,28,29,30; Wang, Carol31; Zhou, Ang6; Adkins, Daniel E.24; Alemany, Silvia29,30,32; Ask, Helga33; Chen, Qi14; Corley, Robin P.8; Ehli, Erik A.34,35; Evans, Luke M.8; Havdahl, Alexandra33; Hagenbeek, Fiona A.1,3; Hakulinen, Christian36; Henders, Anjali K.37; Hottenga, Jouke Jan1; Korhonen, Tellervo19; Mamun, Abdullah38; Marrington, Shelby39; Neumann, Alexander9,40; Rimfeld, Kaili5; Rivadeneira, Fernando9; Silberg, Judy L.20; van Beijsterveldt, Catharina E.1; Vuoksimaa, Eero19; Whipp, Alyce M.19; Tong, Xiaoran11,12; Andreassen, Ole A.41,42; Boomsma, Dorret, I1; Brown, Sandra A.43; Burt, S. Alexandra11; Copeland, William44; Dick, Danielle M.45; Harden, K. Paige15; Harris, Kathleen Mullan46; Hartman, Catharina A.18; Heinrich, Joachim25,26,47; Hewitt, John K.8; Hopfer, Christian48; Hypponen, Elina6,7; Järvelin, Marjo-Riitta49,50,51; Kaprio, Jaakko19; Keltikangas-Jarvinen, Liisa36; Klump, Kelly L.11; Krauter, Kenneth52; Kuja-Halkola, Ralf14; Larsson, Henrik14; Lehtimaki, Terho16,17; Lichtenstein, Paul14; Lundstrom, Sebastian53; Maes, Hermine H.20,54; Magnus, Per55; Munafo, Marcus R.21,22,56,57; Najman, Jake M.39; Njolstad, Pal R.58,59; Oldehinkel, Albertine J.18; Pennell, Craig E.31; Plomin, Robert5; Reichborn-Kjennerud, Ted33; Reynolds, Chandra60,61; Rose, Richard J.60,61; Smolen, Andrew8; Snieder, Harold18; Stallings, Michael8; Standl, Marie25; Sunyer, Jordi29,30,32,62; Tiemeier, Henning9,10; Wadsworth, Sally J.8; Wall, Tamara L.43; Whitehouse, Andrew J. O.63; Williams, Gail M.39; Ystrom, Eivind33,64; Nivard, Michel G.1; Bartels, Meike1,3; Middeldorp, Christel M.1,4,65
Organizations: 1Vrije Univ Amsterdam, Amsterdam, Netherlands.
2UCL, London, England.
3Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
4Univ Queensland, Child Hlth Res Ctr, Brisbane, Qld, Australia.
5Kings Coll London, Social Genet & Dev Psychiat Ctr, London, England.
6Univ South Australia, Adelaide, SA, Australia.
7South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
8Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA.
9Erasmus MC, Rotterdam, Netherlands.
10Harvard TH Chan Sch Publ Hlth, Boston, MA USA.
11Michigan State Univ, E Lansing, MI 48824 USA.
12Univ Florida, Gainesville, FL USA.
13Imperial Coll London, London, England.
14Karolinska Inst, Stockholm, Sweden.
15Univ Texas Austin, Austin, TX 78712 USA.
16Tampere Univ, Tampere, Finland.
17Fimlab Labs, Tampere, Finland.
18Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands.
19Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.
20Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA.
21Univ Bristol, Sch Psychol Sci, Bristol, Avon, England.
22Univ Bristol, Med Res Council MRC Integrat Epidemiol Unit, Bristol, Avon, England.
23Univ Bristol, Ctr Acad Mental Hlth, Populat Hlth Sci, Bristol, Avon, England.
24Univ Utah, Salt Lake City, UT USA.
25Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.
26Ludwig Maximilians Univ Munchen, Munich, Germany.
27Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Barcelona, Spain.
28BBRC Pasqual Maragall Fdn, BarcelonaBeta Brain Res Ctr, Barcelona, Spain.
29Univ Pompeu Fabra UPF, Barcelona, Spain.
30Barcelona Inst Global Hlth, SGlobal, Barcelona, Spain.
31Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia.
32CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain.
33Norwegian Inst Publ Hlth, Oslo, Norway.
34Avera McKennan Hosp, Avera Inst Human Genet, Sioux Falls, SD USA.
35Univ Hlth Ctr, Sioux Falls, SD USA.
36Univ Helsinki, Helsinki, Finland.
37Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia.
38Univ Queensland, Inst Social Sci Res, Brisbane, Qld, Australia.
39Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia.
40Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ, Canada.
41Univ Oslo, NORMENT Ctr, Inst Clin Med, Oslo, Norway.
42Oslo Univ Hosp, Oslo, Norway.
43Univ Calif San Diego, La Jolla, CA 92093 USA.
44Univ Vermont, Burlington, VT USA.
45Virginia Commonwealth Univ, Richmond, VA USA.
46Univ North Carolina Chapel Hill, Carolina Populat Ctr, Chapel Hill, NC USA.
47Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.
48Univ Colorado, Aurora, CO USA.
49MRC-PHE Centre for Environment and Health, Imperial College London, United Kingdom
50the Center for Life Course Health Research, University of Oulu, Oulu, Finland
51Oulu University Hospital, Oulu, Finland
52Univ Colorado, Boulder, CO 80309 USA.
53Univ Gothenburg, Gothenburg, Sweden.
54Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA.
55Norwegian Inst Publ Hlth, Ctr Fertil & Hlth, Oslo, Norway.
56Univ Hosp Bristol NHS Fdn Trust, NIHR Biomed Res Ctr, Bristol, Avon, England.
57Univ Bristol, Bristol, Avon, England.
58Univ Bergen, Ctr Diabet Res, Bergen, Norway.
59Haukeland Hosp, Bergen, Norway.
60Univ Calif Riverside, Riverside, CA 92521 USA.
61Indiana Univ, Bloomington, IN USA.
62IMIM Hosp del Mar Med Res Inst, Barcelona, Spain.
63Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia.
64Univ Oslo, PROMENTA Res Ctr, Oslo, Norway.
65Childrens Hlth Queensland Hosp & Hlth Serv, Child & Youth Mental Hlth Serv, Brisbane, Qld, Australia.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.6 MB)
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Language: English
Published: Elsevier, 2022
Publish Date: 2022-09-09


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 and adolescents between 3 and 18 years of age. 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 polymorphism (SNP) heritability (1.66%, 95% CI = 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% CI = 3.08%–8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being 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 among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

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Series: Journal of the American Academy of Child & Adolescent Psychiatry
ISSN: 0890-8567
ISSN-E: 1527-5418
ISSN-L: 0890-8567
Volume: 61
Issue: 7
Pages: 934 - 945
DOI: 10.1016/j.jaac.2021.11.035
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3124 Neurology and psychiatry
Funding: The study was supported by the Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe (CAPICE) project. CAPICE has received funding from the European Union's Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions e MSCA-ITN-2016 e Innovative Training Networks, under grant agreement number 721567. Cohort-specific acknowledgements and funding information are described in Supplement 1, available online.
Dataset Reference: The summary statistics for the overall meta-analysis can be downloaded from the GWAS Catalog (Study Accession: GCST90054778). Other summary statistics are available from the corresponding author upon request.
Copyright information: © 2022 American Academy of Child and Adolescent Psychiatry. This is an open access article under the CC BY license (