Shared genetic architecture between major depression and intrinsic brain functional connectome organization

06/09/2026

AI Summary

Significant genetic overlap between major depression and 148 of 191 intrinsic brain functional connectome traits.
Cross-trait analyses reveal 627 genomic loci, with 193 loci showing evidence of shared causal variants via colocalization.
Gene mapping implicated 1,459 protein-coding genes (390 unique), prioritising 17 high-confidence genes enriched for neurodevelopmental and lipid metabolism pathways.

AI Summary

Although both MD and brain functional connectome architecture are highly heritable, the genetic architecture underlying their relationship remains poorly characterized.

METHODS: We integrated genome-wide association studies of MD with 191 ICA-based resting-state functional connectome traits to investigate their shared genetic architecture.

CONCLUSIONS: This study provides a multi-scale characterization of the shared genetic architecture between MD and intrinsic brain functional connectome organization, revealing that shared genetic signals between MD and brain functional systems are distributed across multiple functional levels and converge at the molecular level.

Basic summary

Prog Neuropsychopharmacol Biol Psychiatry. 2026 Sep 5:111919. doi: 10.1016/j.pnpbp.2026.111919. Online ahead of print.

ABSTRACT

BACKGROUND: Major depression (MD) is increasingly understood as a disorder characterized by widespread abnormalities in intrinsic brain functional network organization. Although both MD and brain functional connectome architecture are highly heritable, the genetic architecture underlying their relationship remains poorly characterized.

METHODS: We integrated genome-wide association studies of MD with 191 ICA-based resting-state functional connectome traits to investigate their shared genetic architecture. These traits captured intrinsic connectome organization across amplitude, functional connectivity, and global connectivity domains. Cross-trait genetic analyses were used to assess pleiotropic overlap between traits. Locus-level and gene-based analyses integrating multi-omics evidence were performed to characterize the biological relevance of shared genetic signals.

RESULTS: We identified significant genetic overlap between MD and 148 of 191 brain functional connectome traits. Cross-trait analyses revealed widespread shared genetic signals organized into 627 genomic loci across amplitude, functional connectivity, and global connectivity measures. Among these, 193 loci showed evidence consistent with shared causal variants based on colocalization analyses. Gene-level integration mapped these loci to 1459 protein-coding genes (390 unique genes). Multi-layer prioritization identified 17 high-confidence genes supported by convergent genomic, transcriptomic, and proteomic evidence, with enrichment in neurodevelopmental and lipid-related metabolism pathways.

PMID:42700945 | DOI:10.1016/j.pnpbp.2026.111919

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