Cross-ancestry genetic architecture reveals shared biological pathways of major psychiatric disorders, 2026, Feng et al

[forestglip]

Cross-ancestry genetic architecture reveals shared biological pathways of major psychiatric disorders

Spoiler: Authors

Feng, Yu; Jia, Ningning; Huang, Peng; Hu, Shaohua; Yang, Sheng

Abstract
Psychiatric disorders, including bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ), share substantial genetic overlap. We conducted a cross-ancestry multivariate genome-wide association study (GWAS) integrating European and East Asian populations to uncover shared genetic underpinnings.

Our analyses identified 403 loci associated with shared polygenic liability to psychiatric disorders, including 88 novel regions. Cross-ancestry fine-mapping highlighted robust shared signals, notably at VRK2 (rs7596038), consistently significant across ancestries. Gene prioritization revealed 90 high-confidence candidate genes enriched in neurodevelopmental pathways.

Single-nucleus RNA sequencing implicated excitatory neurons and astrocytes as key cellular contexts, emphasizing NCAM1–FGFR1 and NEGR1–NEGR1 signaling pathways.

Mendelian randomization analyses provided causal evidence linking shared genetic liability to structural brain alterations, particularly in regions crucial for emotion and cognition. Polygenic risk scores derived from shared genetic liability substantially enhanced predictive accuracy for BD and SCZ, demonstrating strong trans-ancestry validity.

These results advance understanding of shared genetic architecture in psychiatric disorders, highlighting potential therapeutic targets and emphasizing the critical importance of diverse ancestry studies in precision psychiatry.

Web | DOI | PDF | Molecular Psychiatry | Paywall

 

[forestglip]

Cross-ancestry fine-mapping highlighted robust shared signals, notably at VRK2 (rs7596038)

NEGR1–NEGR1 signaling pathways.

NEGR1 was at the 10th most significant locus and VRK2 was at the 25th most significant locus in DecodeME. The loci plots can be seen in this post: https://www.s4me.info/threads/initi...2025-decodeme-collaboration.45490/post-635001

 

[forestglip]

Here is the VRK2 variant they highlighted in the text, rs7596038 (2-58156685-C-T), highlighted over the DecodeME data:

It doesn't look to be within the main ME/CFS locus.

Though it's interesting that there are two loci with somewhat significant lead variants in ME/CFS around this area. Maybe both affect VRK2 or the other gene here FANCL.

 

[SNT Gatchaman]

NCAM1 encodes CD56. Wikipedia summarises with —

Neural cell adhesion molecule (NCAM), also called CD56, is […] expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discovery site, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is mostly associated with, but not limited to, natural killer cells. CD56 has been detected on other lymphoid cells, including gamma delta (γδ) Τ cells and activated CD8+ T cells, as well as on dendritic cells. NCAM has been implicated as having a role in cell–cell adhesion, neurite outgrowth, synaptic plasticity, and learning and memory.