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 - Tong, Xiaoran
AU - Andreassen, Ole A.
AU - Boomsma, Dorret I.
AU - Brown, Sandra A.
AU - Munafò, Marcus R.
PY - 2022/7/31
Y1 - 2022/7/31
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 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.
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 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.
KW - anxiety
KW - depression
KW - genetic epidemiology
KW - molecular genetics
KW - repeated measures
UR - http://www.scopus.com/inward/record.url?scp=85128378571&partnerID=8YFLogxK
U2 - 10.1016/j.jaac.2021.11.035
DO - 10.1016/j.jaac.2021.11.035
M3 - Article
C2 - 35378236
AN - SCOPUS:85128378571
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 -
