Genetically informed disassortative brain morphometric similarities revealing suicide risk in bipolar disorder

Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Apr 25:S2451-9022(25)00139-9. doi: 10.1016/j.bpsc.2025.04.011. Online ahead of print.

ABSTRACT

BACKGROUND: Cortical structure alterations in bipolar disorder (BD) have consistently been reported in association with suicide with high heritability. Currently, multifaceted genetic landscape responsible for replicable neuroanatomical alterations with suicidal effects is poorly explored to develop personalized risk assessments in clinic.

METHODS: Anatomically informed suicidal effects quantified with morphometric similarity network (MSN) upon structural MRI was evaluated in two independent BD cohorts consisted of patients with or without suicide attempt (SA and NSA) (discovery: 63 BD-SAs72 BD-NSAs with 6 potential suicide-related SNPs examined in 46 BD-SAs55 BD-NSAs; replication: 23 BD-SAs23 BD-NSAs) and 119 healthy controls. In discovery study, transcriptomic and neurotransmitter correlates of suicide-relevant MSN deficits were examined by partial least squares regression on Allen Human Brain Atlas and dominance analysis on 9 distinct neurotransmitter systems. Molecularly informed MSN deficits were orthogonally validated by estimating genetic risks from targeted SNP genotyping utilizing a multi-level mediation analysis. Reproducible pattern of genetically decoding suicide-relevant MSN changes was validated in replication study.

RESULTS: Opioid receptor was consistently suggested to be responsible for the reproducible suicide-relevant MSN alterations identified in entorhinal and left lateral occipital cortices. MSN deficits of entorhinal cortex positively mediated the effects of genetic risks of OPRM1 on suicide attempted (portion of mediated = 61.3%, β=6.99e-2, p=.02, 95% CI = [3.34e-2, 0.11]).

CONCLUSION: Abnormal cytoarchitecture communities, especially maladaptive changes in neuronal communication between entorhinal cortex and reward circuit regulated by opioid receptors reflected by enhanced morphometric similarities could mediate the effect on increased suicidal tendencies involved in OPRM1 gene variants in BD.

PMID:40288753 | DOI:10.1016/j.bpsc.2025.04.011