The Genetic Architecture of the Human Corpus Callosum and its Subregions

Ravi R. Bhatt (), Shruti P. Gadewar (), Ankush Shetty, Iyad Ba Gari, Elizabeth Haddad, Shayan Javid, Abhinaav Ramesh, Elnaz Nourollahimoghadam, Alyssa H. Zhu, Christiaan Leeuw, Paul M. Thompson, Sarah E. Medland and Neda Jahanshad ()
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Ravi R. Bhatt: University of Southern California
Shruti P. Gadewar: University of Southern California
Ankush Shetty: University of Southern California
Iyad Ba Gari: University of Southern California
Elizabeth Haddad: University of Southern California
Shayan Javid: University of Southern California
Abhinaav Ramesh: University of Southern California
Elnaz Nourollahimoghadam: University of Southern California
Alyssa H. Zhu: University of Southern California
Christiaan Leeuw: VU University
Paul M. Thompson: University of Southern California
Sarah E. Medland: QIMR Berghofer Medical Research Institute
Neda Jahanshad: University of Southern California

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The corpus callosum (CC) is the largest set of white matter fibers connecting the two hemispheres of the brain. In humans, it is essential for coordinating sensorimotor responses and performing associative or executive functions. Identifying which genetic variants underpin CC morphometry can provide molecular insights into the CC’s role in mediating cognitive processes. We developed and used an artificial intelligence based tool to extract the midsagittal CC’s total and regional area and thickness in two large public datasets. We performed a genome-wide association study (GWAS) meta-analysis of European participants (combined N = 46,685) with generalization to the non-European participants (combined N = 7040). Post-GWAS analyses implicated prenatal intracellular organization and cell growth patterns, and high heritability in regions of open chromatin. Results suggest programmed cell death mediated by the immune system drives the thinning of the posterior body and isthmus. Genetic overlap, and causal genetic liability, between the CC, cerebral cortex features, and neuropsychiatric disorders such as attention-deficit/hyperactivity, bipolar disorders, and Parkinson’s disease were identified.

Date: 2025
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DOI: 10.1038/s41467-025-64791-3

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