Genome-wide association meta-analysis of childhood and adolescent internalising symptoms
Authors: Jami Eshim S , Hammerschlag Anke R , Ip Hill F , Allegrini Andrea G , Benyamin Beben , Border Richard , Diemer Elizabeth W , Jiang Chang , Karhunen Ville , Lu Yi , Lu Qing , Mallard Travis T , Mishra Pashupati P , Nolte Ilja M , Palviainen Teemu , Peterson Roseann E , Sallis Hannah M , Shabalin Andrey A , Tate Ashley E , Thiering Elisabeth , Vilor-Tejedor Natàlia , Wang Carol , Zhou Ang , Adkins Daniel E , Alemany Silvia , Ask Helga , Chen Qi , Corley Robin P , Ehli Erik A , Evans Luke M , Havdahl Alexandra , Hagenbeek Fiona A , Hakulinen Christian , Henders Anjali K , Hottenga Jouke Jan , Korhonen Tellervo , Mamun Abdullah , Marrington Shelby , Neumann Alexander , Rimfeld Kaili , Rivadeneira Fernando , Silberg Judy L , van Beijsterveldt Catharina E , Vuoksimaa Eero , Whipp Alyce M , Xiaoran Tong , Andreassen Ole A , Boomsma Dorret , Brown Sandra A , Burt S Alexandra , Copeland William , Costello Elizabeth J , Dick Danielle M , Eaves Lindon J , Harden K Paige , Harris Kathleen Mullan , Hartman Catharina A , Heinrich Joachim , Hewitt John K , Hopfer Christian , Hypponen Elina , Jarvelin Marjo-Riitta , Kaprio Jaakko , Keltikangas-Järvinen Liisa , Klump Kelly L , Krauter Kenneth , Kuja-Halkola Ralf , Larsson Henrik , Lehtimäki Terho , Lichtenstein Paul , Lundstrom Sebastian , Maes Hermine H , Magnus Per , Munafò Marcus R , Najman Jake M , Njølstad Pål R , Oldehinkel Albertine J , Pennell Craig E , Plomin Robert , Reichborn-Kjennerud Ted , Reynolds Chandra , Rose Richard J , Smolen Andrew , Snieder Harold , Stallings Michael , Standl Marie , Sunyer Jordi , Tiemeier Henning , Wadsworth Sally , Wall Tamara L , Whitehouse Andrew J O , Williams Gail M , Ystrom Eivind , Nivard Michel G , Bartels Meike , Middeldorp Christel M 
Published: September 2020

Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low 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 internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising 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. The pattern of genetic correlations suggests that childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalising 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.