A low frequency damaging SORCS2 variant identified in a family with ADHD compromises receptor stability and quenches activity
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting 5% of children and 2.5% of adults worldwide. ADHD is considered a polygenic disorder caused by a combination of both common and rare risk variants, each with low individual effect size. The Vps10p domain receptor SorCS2 is involved in neuronal development and synaptic plasticity by modulating brain-derived neurotrophic factor (BDNF) signaling. We here describe the identification and characterization of a heterozygous damaging variant in the SORCS2 gene found in two members of a family with persistent ADHD. The SORCS2 variant results in an arginine to tryptophan substitution in the 10CC region of the extracellular Vps10p domain, leading to aberrant posttranslational receptor processing, subcellular localization and ligand binding. Furthermore, the variant abrogates BDNF signaling in a dominant negative manner. Biochemical analysis of additional rare missense variants from ADHD cohorts suggested that SorCS2 structural stability and function is susceptible to such variation in the Vps10p domain. Our findings provide insights into how low frequency damaging variants in SORCS2 may contribute to the risk of ADHD.
Authors
- Christian Bjerggaard Vægter (ORCID: https://orcid.org/0000-0001-6573-146X)
- Camilla Gustafsen (ORCID: https://orcid.org/0000-0002-3349-4639)
- Søren Thirup (ORCID: https://orcid.org/0000-0002-0061-7137)
- Ditte Demontis (ORCID: https://orcid.org/0000-0001-9124-2766)
- Sune Skeldal (ORCID: https://orcid.org/0000-0002-3268-289X)
- Stefan E. Johansson (ORCID: https://orcid.org/0000-0002-2298-7008)
- Ditte Olsen (ORCID: https://orcid.org/0000-0002-4200-9543)
- Anders D. Børglum (ORCID: https://orcid.org/0000-0001-8627-7219)
- Barbara Franke (ORCID: https://orcid.org/0000-0003-4375-6572)
- Peder Madsen (ORCID: https://orcid.org/0000-0002-8845-4802)
- Andreas Reif (ORCID: https://orcid.org/0000-0002-0992-634X)
- Jinjie Duan (ORCID: https://orcid.org/0000-0002-3402-302X)
- Jan Haavik (ORCID: https://orcid.org/0000-0001-7865-2808)
- Joachim Vilstrup (ORCID: https://orcid.org/0000-0002-7941-1536)
- Anders Dalby (ORCID: https://orcid.org/0000-0002-2255-1335)
- Simon Glerup (ORCID: https://orcid.org/0000-0002-9686-8124)
- Gesche Neckelmann
- Simon Mølgaard
- Tetyana Zayats (ORCID: https://orcid.org/0000-0003-1927-3255)
- Jonas Lende (ORCID: https://orcid.org/0009-0009-3620-7680)
- Mathias Kaas Ollendorff (ORCID: https://orcid.org/0000-0002-4122-4401)
- Ole Andreas Ahlgreen
- Per M. Knappskog (ORCID: https://orcid.org/0000-0002-8277-4530)
- Sanne Nordestgaard
- Sarah Broholt Dinesen
Institutions
- Broad Institute (US)
- Goethe University Frankfurt (DE)
- Radboud University Nijmegen (NL)
- Aarhus University (DK)
- Haukeland University Hospital (NO)
- Radboud University Medical Center (NL)
- University of Bergen (NO)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2025-09-18
- DOI
- https://doi.org/10.1038/s41380-025-03242-3
- Primary Topic
- Attention Deficit Hyperactivity Disorder
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Aarhus Universitet
- Stiftelsen Kristian Gerhard Jebsen
- Lundbeckfonden
- Novo Nordisk
- Norges Forskningsråd
- H. Lundbeck A/S