Polygenic effects on cortical size and ADHD converge on a mid-gestational progenitor-to-neuron transition programme
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Neurodevelopmental and psychiatric conditions have long been hypothesised to emerge from changes in the structure and function of the brain. However, the molecular and cellular mechanisms linking brain structure to these conditions remain unknown. Here, using genetic and structural/diffusion neuroimaging data from 59,283 individuals spanning adults, children and neonates, we identify widespread genetic associations between ADHD, anxiety and depression and multiple phenotypes indexing cortical size and subcortical volume. Multivariate genetic analyses demonstrate that these associations are largely driven by a common cortical size genetic factor and ADHD. Mendelian randomisation indicates that genetically predicted reduced cortical size is causal for ADHD and not vice versa . Using single-nucleus RNA sequencing of the developing cortex, we further demonstrate that although cortical size and ADHD are enriched in different cell types - proliferating progenitors and postmitotic neurons, respectively, they converge on neurogenic genetic programmes active during the transition between the two cell types. This programme peaks at mid-gestation and is localised to the outer subventricular and intermediate zones, the regions where progenitor amplification and early neuronal migration drive human cortical expansion, and is enriched for genes that are differentially expressed in human and macaque developing cortex. Separately, the negative genetic correlation between ADHD and cortical size measures are strongest in cortical regions that have expanded most in humans relative to macaques. Together, these findings identify a novel, spatiotemporally restricted molecular mechanism underlying neurogenesis that is enriched for polygenic effects of both cortical size and ADHD.
Source: medRxiv
Authors: Yuankai He, Amir Ebneabbasi, Koen Rademaker, Elina Jin, Yuanjun Gu, Fani Femi, Clara M.L. Riegis, Bess Pearson, Renato Polimanti, Jakob Grove, Anders D. Børglum, Nadine Parker, Ole Andreassen, Oleksandr Frei, Darren Cameron, Nicholas Bray, Ang Li, Jian Zeng, Naomi Wray, Rafael Romero-Garcia, Timothy Rittman, Simon Baron-Cohen, Melissa Gladstone, Shivaram Avula, Mary-Ellen Lynall, Sarah Rae, Duncan Astle, Richard A.I. Bethlehem, Edward T. Bullmore, Omer Ali Bayraktar, Varun Warrier
Institutions: University of Cambridge, Wellcome Sanger Institute, King's College London, Imperial College London, Yale University, Aarhus University, Lundbeck Foundation, Oslo University Hospital, University of Oslo, Cardiff University, University of Oxford, Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, University of Liverpool, Alder Hey Children's NHS Foundation Trust, University College London
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214035405