Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes
van der Laan CM, Ip HF, Schipper M, Hottenga JJ, St Pourcain B, Zayats T, Pool R, Krapohl EML, Brikell I, Soler Artigas M, Cabana-Domínguez J, Nolte IM, Bolhuis K, Palviainen T, Zafarmand H, Gordon S, Aliev F, Burt SA, Wang CA, Saunders G, Karhunen V, Adkins DE, Border R, Peterson RE, Prinz JA, Thiering E, Vilor-Tejedor N, Ahluwalia TS, Allegrini A, Rimfeld K, Chen Q, Lu Y, Martin J, Bosch R, Ramos-Quiroga JA, Neumann A, Ensink J, Grasby KL, Morosoli JJ, Tong X, Marrington S, Scott JG, Shabalin AA, Corley R, Evans LM, Sugden K, Alemany S, Sass L, Vinding R, Ehli EA, Hagenbeek FA, Derks EM, Larsson H, Snieder H, Cecil C, Whipp AM, Korhonen T, Vuoksimaa E, Rose RJ, Uitterlinden AG, Haavik J, Harris JR, Helgeland Ø, Johansson S, Knudsen GPS, Njolstad PR, Lu Q, Rodriguez A, Henders AK, Mamun A, Najman JM, Brown S, Hopfer C, Krauter K, Reynolds CA, Smolen A, Stallings M, Wadsworth S, Wall TL, Eaves L, Silberg JL, Miller A, Havdahl A, Llop S, Lopez-Espinosa MJ, Bønnelykke K, Sunyer J, Arseneault L, Standl M, Heinrich J, Boden J, Pearson J, Horwood J, Kennedy M, Poulton R, Maes HH, Hewitt J, Copeland WE, Middeldorp CM, Williams GM, Wray N, Järvelin MR, McGue M, Iacono W, Caspi A, Moffitt TE, Whitehouse AJO, Pennell CE, Klump KL, Jiang C, Dick DM, Reichborn-Kjennerud T, Martin NG, Medland SE, Vrijkotte T, Kaprio J, Tiemeier H, Davey Smith G, Hartman CA, Oldehinkel AJ, Casas M, Ribasés M, Lichtenstein P, Lundström S, Plomin R, Bartels M, Nivard MG, Boomsma DI, Llonga N.
Abstract
We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHDSYMP). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHDOVERALL). ADHDSYMP returned no genome-wide significant variants. We show that the combined ADHDOVERALL GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (rg < -0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHDOVERALL outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.
Reference
van der Laan CM, Ip HF, Schipper M, Hottenga JJ, St Pourcain B, Zayats T, Pool R, Krapohl EML, Brikell I, Soler Artigas M, Cabana-Domínguez J, Llonga N, Nolte IM, Bolhuis K, Palviainen T, Zafarmand H, Gordon S, Aliev F, Burt SA, Wang CA, Saunders G, Karhunen V, Adkins DE, Border R, Peterson RE, Prinz JA, Thiering E, Vilor-Tejedor N, Ahluwalia TS, Allegrini A, Rimfeld K, Chen Q, Lu Y, Martin J, Bosch R, Ramos-Quiroga JA, Neumann A, Ensink J, Grasby KL, Morosoli JJ, Tong X, Marrington S, Scott JG, Shabalin AA, Corley R, Evans LM, Sugden K, Alemany S, Sass L, Vinding R, Ehli EA, Hagenbeek FA, Derks EM, Larsson H, Snieder H, Cecil C, Whipp AM, Korhonen T, Vuoksimaa E, Rose RJ, Uitterlinden AG, Haavik J, Harris JR, Helgeland Ø, Johansson S, Knudsen GPS, Njolstad PR, Lu Q, Rodriguez A, Henders AK, Mamun A, Najman JM, Brown S, Hopfer C, Krauter K, Reynolds CA, Smolen A, Stallings M, Wadsworth S, Wall TL, Eaves L, Silberg JL, Miller A, Havdahl A, Llop S, Lopez-Espinosa MJ, Bønnelykke K, Sunyer J, Arseneault L, Standl M, Heinrich J, Boden J, Pearson J, Horwood J, Kennedy M, Poulton R, Maes HH, Hewitt J, Copeland WE, Middeldorp CM, Williams GM, Wray N, Järvelin MR, McGue M, Iacono W, Caspi A, Moffitt TE, Whitehouse AJO, Pennell CE, Klump KL, Jiang C, Dick DM, Reichborn-Kjennerud T, Martin NG, Medland SE, Vrijkotte T, Kaprio J, Tiemeier H, Davey Smith G, Hartman CA, Oldehinkel AJ, Casas M, Ribasés M, Lichtenstein P, Lundström S, Plomin R, Bartels M, Nivard MG, Boomsma DI. Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes. Nat Genet. 2025 Sep 17. doi: 10.1038/s41588-025-02295-y. Epub ahead of print. Erratum in: Nat Genet. 2025 Sep 29. doi: 10.1038/s41588-025-02383-z. PMID: 40962958.
