Genetically Informed Disassortative Brain Morphometric Similarities Revealing Suicide Risk in Bipolar Disorder

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

Anatomically informed suicidal effects quantified with morphometric similarity network (MSN) upon structural magnetic resonance imaging were evaluated in 2 independent BD cohorts that consisted of patients with suicide attempt (SA) and without SA (NSA) (discovery: 63 BD-SAs and 72 BD-NSAs with 6 potential suicide-related single nucleotide polymorphisms [SNPs] examined in 46 BD-SAs and 55 BD-NSAs; replication: 23 BD-SAs and 23 BD-NSAs) and 119 healthy control participants. In the discovery study, transcriptomic and neurotransmitter correlates of suicide-relevant MSN deficits were examined by partial least squares regression using the 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 using a multilevel mediation analysis. A reproducible pattern of genetically decoding suicide-relevant MSN changes was validated in the replication study.

The μ opioid receptor was consistently suggested to be responsible for reproducible suicide-relevant MSN alterations identified in entorhinal and left lateral occipital cortices. MSN deficits of the entorhinal cortex positively mediated the effects of genetic risks of OPRM1 on SA (portion mediated = 61.3%; β = 6.99 × 10^-2; p = .02; 95% CI, 3.34 × 10^-2 to 0.11).

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