| Title: |
Rare genetic variants confer a high risk of ADHD and implicate neuronal biology |
| Authors: |
Demontis, Ditte; Duan, Jinjie; Hsu, Yu-Han H.; Pintacuda, Greta; Grove, Jakob; Nielsen, Trine Tollerup; Thirstrup, Janne; Martorana, Makayla; Botts, Travis; Satterstrom, F. Kyle; Bybjerg-Grauholm, Jonas; Tsai, Jason H. Y.; Glerup, Simon; Hoogman, Martine; Buitelaar, Jan; Klein, Marieke; Ziegler, Georg C.; Jacob, Christian; Grimm, Oliver; Bayas, Maximilian; Kobayashi, Nene F.; Kittel-Schneider, Sarah; Lesch, Klaus-Peter; Franke, Barbara; Reif, Andreas; Agerbo, Esben; Werge, Thomas; Nordentoft, Merete; Mors, Ole; Mortensen, Preben Bo; Lage, Kasper; Daly, Mark J.; Neale, Benjamin M.; Borglum, Anders D. |
| Contributors: |
Institute for Molecular Medicine Finland |
| Publisher Information: |
Nature Research |
| Publication Year: |
2025 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Drosophila-melanogaster; Genome; Disorder; Program; Sample; Model; Biomedicine; Genetics; developmental biology; physiology |
| Description: |
Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a large genetic component(1). It affects around 5% of children and 2.5% of adults(2), and is associated with several severe outcomes(3, 4, 5, 6, 7, 8, 9, 10-11). Common genetic variants associated with the disorder have been identified(12,13), but the role of rare variants in ADHD is mostly unknown. Here, by analysing rare coding variants in exome-sequencing data from 8,895 individuals with ADHD and 53,780 control individuals, we identify three genes (MAP1A, ANO8 and ANK2; P < 3.07 x 10(-6); odds ratios 5.55-15.13) that are implicated in ADHD. The protein-protein interaction networks of these three genes were enriched for rare-variant risk genes of other neurodevelopmental disorders, and for genes involved in cytoskeleton organization, synapse function and RNA processing. Top associated rare-variant risk genes showed increased expression across pre- and postnatal brain developmental stages and in several neuronal cell types, including GABAergic (gamma-aminobutyric-acid-producing) and dopaminergic neurons. Deleterious variants were associated with lower socioeconomic status and lower levels of education in individuals with ADHD, and a decrease of 2.25 intelligence quotient (IQ) points per rare deleterious variant in a sample of adults with ADHD (n = 962). Individuals with ADHD and intellectual disability showed an increased load of rare variants overall, whereas other psychiatric comorbidities had an increased load only for specific gene sets associated with those comorbidities. This suggests that psychiatric comorbidity in ADHD is driven mainly by rare variants in specific genes, rather than by a general increased load across constrained genes. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
D.D. was supported by the Novo Nordisk Foundation (NNF20OC0065561, NNF21SA0072102, NNF23OC0083657), the Lundbeck Foundation (R344-2020-1060) and the European Union (EU)'s Horizon 2020 research and innovation programme under grant agreement 965381(TIMESPAN). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) (1R01MH124851-01 to A.D.B.), the EU's Horizon Europe programme under grant agreement 101057385 (R2D2-MH to A.D.B.) and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing (iSEQ), Aarhus University, Denmark (grant to A.D.B.). K.-P.L. was supported by ERA-NET NEURON under grant 01EW1902 (DECODE!), the EU's Horizon 2020 research and innovation programme under grants 728018 (Eat2beNICE), 101086453 (Aqua-Synapse) and 953327, the Deutsche Forschungsgemeinschaft (DFG KFO 125, SFB 581, SFB TRR 58 and GRK 1253) and the Bundesministerium fuer Bildung und Forschung (BMBF 01GV0605). For the Dutch IMpACT sample, we acknowledge support from the European College of Neuropsychopharmacology network 'ADHD Across the Lifespan'. M.H. was supported by the Netherlands Organisation for Scientific Research (NWO; grants Veni 91619115 and Vidi 09150172210069). B.F. was supported by funding from the EU's Horizon 2020 programme (H2020/2014-2020) under grant agreement 847879 (PRIME) and the NIMH/NIH under award number R01MH124851. M.K. was supported by personal grants from the Dutch Research Council (NWO/ZonMW; Rubicon grant 45219212 and Veni grant 09150162010073). K.L. was supported by the Stanley Center for Psychiatric Research, the US NIMH (U01MH121499), the Simons Foundation Autism Research Initiative (award 735604), the Lundbeck Foundation (R350-2020-963) and the Novo Nordisk Foundation (NNF21SA0072102). S.G. was supported by the Lundbeck Foundation 'ADHD of Mice and Men' (R108-2012-10957). J.G. was supported by NIH (1R01NS131433-01). G.P. was supported by the Simons Foundation Autism Research Initiative (SFARI) Bridge to Independence (BTI) award (00002804). We thank the Broad Institute for generating high-quality sequence data supported by funds from the National Human Genome Research Institute (NHGRI) (grant U54 HG003067) with E. Lander as PI. One of the datasets used in this manuscript was obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000990. We thank the Center for the Development of Therapeutics at the Broad Institute for assisting with immunofluorescence imaging.; https://hdl.handle.net/10138/606759; 105021519310; 001615499000001 |
| Availability: |
https://hdl.handle.net/10138/606759 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.983E4B08 |
| Database: |
BASE |