TY  - JOUR
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.
AU  - Jami, E.S.*
AU  - Hammerschlag, A.R.*
AU  - Ip, H.F.*
AU  - Allegrini, A.G.*
AU  - Benyamin, B.*
AU  - Border, R.*
AU  - Diemer, E.W.*
AU  - Jiang, C.*
AU  - Karhunen, V.*
AU  - Lu, Y.*
AU  - Lu, Q.*
AU  - Mallard, T.T.*
AU  - Mishra, P.P.*
AU  - Nolte, I.M.*
AU  - Palviainen, T.*
AU  - Peterson, R.E.*
AU  - Sallis, H.M.*
AU  - Shabalin, A.A.*
AU  - Tate, A.E.*
AU  - Thiering, E.
AU  - Vilor-Tejedor, N.*
AU  - Wang, C.*
AU  - Zhou, A.*
AU  - Adkins, D.E.*
AU  - Alemany, S.*
AU  - Ask, H.*
AU  - Chen, Q.*
AU  - Corley, R.P.*
AU  - Ehli, E.A.*
AU  - Evans, L.M.*
AU  - Havdahl, A.*
AU  - Hagenbeek, F.A.*
AU  - Hakulinen, C.*
AU  - Henders, A.K.*
AU  - Hottenga, J.J.*
AU  - Korhonen, T.*
AU  - Mamun, A.*
AU  - Marrington, S.*
AU  - Neumann, A.*
AU  - Rimfeld, K.*
AU  - Rivadeneira, F.*
AU  - Silberg, J.L.*
AU  - van Beijsterveldt, C.E.*
AU  - Vuoksimaa, E.*
AU  - Whipp, A.M.*
AU  - Tong, X.*
AU  - Andreassen, O.A.*
AU  - Boomsma, D.I.*
AU  - Brown, S.A.*
AU  - Burt, S.A.*
AU  - Copeland, W.C.*
AU  - Dick, D.M.*
AU  - Harden, K.P.*
AU  - Harris, K.M.*
AU  - Hartman, C.A.*
AU  - Heinrich, J.
AU  - Hewitt, J.K.*
AU  - Hopfer, C.J.*
AU  - Hyppönen, E.*
AU  - Jarvelin, M.R.*
AU  - Kaprio, J.*
AU  - Keltikangas-Järvinen, L.*
AU  - Klump, K.L.*
AU  - Krauter, K.*
AU  - Kuja-Halkola, R.*
AU  - Larsson, H.*
AU  - Lehtimäki, T.*
AU  - Lichtenstein, P.*
AU  - Lundstrom, S.*
AU  - Maes, H.H.*
AU  - Magnus, P.*
AU  - Munafò, M.R.*
AU  - Najman, J.M.*
AU  - Njølstad, P.R.*
AU  - Oldehinkel, A.J.*
AU  - Pennell, C.E.*
AU  - Plomin, R.*
AU  - Reichborn-Kjennerud, T.*
AU  - Reynolds, C.*
AU  - Rose, R.J.*
AU  - Smolen, A.*
AU  - Snieder, H.*
AU  - Stallings, M.C.*
AU  - Standl, M.
AU  - Sunyer, J.*
AU  - Tiemeier, H.*
AU  - Wadsworth, S.J.*
AU  - Wall, T.L.*
AU  - Whitehouse, A.J.O.*
AU  - Williams, G.M.*
AU  - Ystrøm, E.*
AU  - Nivard, M.G.*
AU  - Bartels, M.*
AU  - Middeldorp, C.M.*
C1  - 64813
C2  - 52393
SP  - 934-945
TI  - Genome-wide association meta-analysis of childhood and adolescent internalising symptoms.
JO  - J. Am. Acad. Child Adolesc. Psychiatry
VL  - 61
IS  - 7
PY  - 2022
SN  - 0890-8567
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. METHOD: Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. RESULTS: SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. CONCLUSION: The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.
AU  - Middeldorp, C.M.*
AU  - Hammerschlag, A.R.*
AU  - Ouwens, K.G.*
AU  - Groen-Blokhuis, M.M.*
AU  - St Pourcain, B.*
AU  - Greven, C.U.*
AU  - Pappa, I.*
AU  - EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium (Tiesler, C.M.
AU  - Standl, M.
AU  - Thiering, E.
AU  - Heinrich, J.)
AU  - Ang, W.*
AU  - Nolte, I.M.*
AU  - Vilor-Tejedor, N.*
AU  - Bacelis, J.*
AU  - Ebejer, J.L.*
AU  - Zhao, H.*
AU  - Davies, G.E.*
AU  - Ehli, E.A.*
AU  - Evans, D.M*
AU  - Fedko, I.O.*
AU  - Guxens, M.*
AU  - Hottenga, J.J.*
AU  - Hudziak, J.J.*
AU  - Jugessur, A.*
AU  - Kemp, J.P.*
AU  - Krapohl, E.*
AU  - Martin, N.G.*
AU  - Murcia, M.*
AU  - Myhre, R.*
AU  - Ormel, J.*
AU  - Ring, S.M.*
AU  - Stergiakouli, E.*
AU  - Stoltenberg, C.*
AU  - Timpson, N.J.*
AU  - Trzaskowski, M.*
AU  - van der Most, P.J.*
AU  - Wang, C.*
AU  - Nyholt, D.R.*
AU  - Medland, S.E.*
AU  - Neale, B.M.*
AU  - Jacobsson, B.*
AU  - Sunyer, J.*
AU  - Hartman, C.A.*
AU  - Whitehouse, A.J.*
AU  - Pennell, C.E.*
AU  - Plomin, R.*
AU  - Davey Smith, G.*
AU  - Tiemeier, H.*
AU  - Posthuma, D.*
AU  - Boomsma, D.I.*
C1  - 49547
C2  - 30482
CY  - New York
SP  - 896-905.e6
TI  - A Genome-wide association meta-analysis of attention-deficit/hyperactivity disorder symptoms in population-based pediatric cohorts.
JO  - J. Am. Acad. Child Adolesc. Psychiatry
VL  - 55
IS  - 10
PB  - Elsevier Science Inc
PY  - 2016
SN  - 0890-8567
ER  -