Polygenic effects on cortical size and ADHD converge on a mid-gestational progenitor-to-neuron transition programme
- 1University of Cambridge
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.
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BibTeX
@misc{he2026polygenic,
title = {{Polygenic effects on cortical size and ADHD converge on a mid-gestational progenitor-to-neuron transition programme}},
author = {Y. He and A. Ebneabbasi and K. Rademaker and E. Z. Jin and Y. Gu and F. Femi and C. M. L. Riegis and B. Pearson and R. Polimanti and J. Grove and A. Borglum and N. Parker and O. Andreassen and O. Frei and D. Cameron and N. J. Bray and A. Li and J. Zeng and N. R. Wray and R. Romero-Garcia and T. Rittman and S. Baron-Cohen and M. J. Gladstone and S. Avula and M.-E. Lynall and S. Rae and D. Astle and R. A. I. Bethlehem and E. T. Bullmore and O. A. Bayraktar and V. Warrier},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.26363544},
url = {https://www.medrxiv.org/content/10.64898/2026.09.21.26363544v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Polygenic effects on cortical size and ADHD converge on a mid-gestational progenitor-to-neuron transition programme
AU - Y. He
AU - A. Ebneabbasi
AU - K. Rademaker
AU - E. Z. Jin
AU - Y. Gu
AU - F. Femi
AU - C. M. L. Riegis
AU - B. Pearson
AU - R. Polimanti
AU - J. Grove
AU - A. Borglum
AU - N. Parker
AU - O. Andreassen
AU - O. Frei
AU - D. Cameron
AU - N. J. Bray
AU - A. Li
AU - J. Zeng
AU - N. R. Wray
AU - R. Romero-Garcia
AU - T. Rittman
AU - S. Baron-Cohen
AU - M. J. Gladstone
AU - S. Avula
AU - M.-E. Lynall
AU - S. Rae
AU - D. Astle
AU - R. A. I. Bethlehem
AU - E. T. Bullmore
AU - O. A. Bayraktar
AU - V. Warrier
PY - 2026
DA - 2026/09/21
PB - medRxiv
DO - 10.64898/2026.09.21.26363544
UR - https://www.medrxiv.org/content/10.64898/2026.09.21.26363544v1
AB - 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.
ER -