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Genetically informed brain morphometric similarities revealing suicide risk in bipolar disorder

Presented During:

Genetics: Transcriptomics, Phenotypes and Disorders

Wednesday, June 25, 2025: 5:45 PM - 7:00 PM

Brisbane Convention & Exhibition Centre

Room: M2 (Mezzanine Level)

Poster No:

399

Submission Type:

Abstract Submission

Authors:

Ting Wang¹, Li Xue¹, Zhongpeng Dai¹, Junneng Shao¹, Wei Zhang¹, Zhijian Yao², Qing Lu¹

Institutions:

¹School of Biological Sciences & Medical Engineering, Southeast University, NanJing, Jiangsu, ²Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University, NanJing, Jiangsu

First Author:

Ting Wang
School of Biological Sciences & Medical Engineering, Southeast University
NanJing, Jiangsu

Co-Author(s):

Li Xue
School of Biological Sciences & Medical Engineering, Southeast University
NanJing, Jiangsu

Zhongpeng Dai
School of Biological Sciences & Medical Engineering, Southeast University
NanJing, Jiangsu

Junneng Shao
School of Biological Sciences & Medical Engineering, Southeast University
NanJing, Jiangsu

Wei Zhang
School of Biological Sciences & Medical Engineering, Southeast University
NanJing, Jiangsu

Zhijian Yao
Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University
NanJing, Jiangsu

Qing Lu
School of Biological Sciences & Medical Engineering, Southeast University
NanJing, Jiangsu

Introduction:

Suicide in bipolar disorder (BD) with high heritability (Turecki, G., 2019; Erlangsen, A., 2020) is characterized as a dysconnectivity syndrome (Wang H., 2022; Wang, H., 2020) 3-4. While traditionally focused on single-level biological data, suicide-related imaging-genetic studies are now shifting towards a multidimensional approach to spatial correspondence (Li, J., 2024; Qin, K., 2024). It poses challenges for the exploration of multifaceted reliable genetic landscape responsible for reproducible neuroanatomical alterations by suicidal effects. Beyond the exploration of macro-micro-coupling, more tangible and compelling proof-of-principle with paired measures of multi-biological characteristics is also urgently needed to develop personalized risk assessments in clinic (Wang, J., 2024).

Methods:

Totally, 96 healthy controls and two independent BD cohorts consisted of patients with at least one suicide attempt or without any suicide attempt history during the current depressive episode (SA and NSA) were recruited from the Affiliated Brain Hospital of Nanjing Medical University (discovery cohort: 63 BD-SAs \ 72 BD-NSAs) and the Nanjing Drum Tower Hospital (replication cohort: 23 BD-SAs \ 23 BD-NSAs). Anatomically informed suicidal effect was quantified by morphometric similarity network (MSN) (Seidlitz, J., 2018) combining surface area, cortical thickness, gray matter volume, Gaussian curvature, and mean curvature extracted from sMRI (Figure 1a). 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 (Figure 1b-c). Molecularly informed MSN deficits was orthogonally validated by estimates of multi-locus genetic profile score from 6 potential suicide-related SNPs of µ-opioid receptor gene (OPRM1) in patients (46 BD-SAs \ 55 BD-NSAs) utilizing a mediation analysis by structural equation modeling (Figure 1d). Furthermore, the reproducible patterns of suicide-relevant MSN changes and related transcriptional profiles were validated in replication study (Figure 1e).

·Study Overview

Results:

Reproducible suicide-relevant MSN alterations were identified in entorhinal and left lateral occipital cortices (Figure 2b). Transcriptomic molecular factor, opioid receptor was consistently suggested to be responsible for its alterations, coupled with its capability of being rooted in above spatial correspondence by excitatory neurons. MSN deficits of entorhinal cortex positively mediated the effects of genetic risks of opioid receptor on suicide attempted (portion of mediated = 61.3%, β = 6.99e-2, p = 1.96e-2; 95% CI = [3.34e-2 , 0.11], Figure 2d).

·Molecular fingerprint validation by targeted SNP genotyping.

Conclusions:

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

Disorders of the Nervous System:

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Genetics:

Genetic Association Studies ²

Modeling and Analysis Methods:

Multivariate Approaches

Neuroanatomy, Physiology, Metabolism and Neurotransmission:

Cortical Anatomy and Brain Mapping

Physiology, Metabolism and Neurotransmission:

Neurophysiology of Imaging Signals

Keywords:

Affective Disorders

Cortex

Morphometrics

Neurotransmitter

Psychiatric Disorders

STRUCTURAL MRI

^1|2Indicates the priority used for review

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Provide references using APA citation style.

Erlangsen, A., Appadurai, V., Wang, Y., Turecki, G., Mors, O., Werge, T., ... & Agerbo, E. (2020). Genetics of suicide attempts in individuals with and without mental disorders: a population-based genome-wide association study. Molecular Psychiatry, 25(10), 2410-2421.
Li, J., Wang, D., Xia, J., Zhang, C., Meng, Y., Xu, S., ... & Liao, W. (2024). Divergent suicidal symptomatic activations converge on somato-cognitive action network in depression. Molecular Psychiatry, 1-10.
Qin, K., Li, H., Zhang, H., Yin, L., Wu, B., Pan, N., ... & Jia, Z. (2024). Transcriptional patterns of brain structural covariance network abnormalities associated with suicidal thoughts and behaviors in major depressive disorder. Biological Psychiatry.
Seidlitz, J., Váša, F., Shinn, M., Romero-Garcia, R., Whitaker, K. J., Vértes, P. E., ... & Bullmore, E. T. (2018). Morphometric similarity networks detect microscale cortical organization and predict inter-individual cognitive variation. Neuron, 97(1), 231-247.
Turecki, G., Brent, D. A., Gunnell, D., O’Connor, R. C., Oquendo, M. A., Pirkis, J., & Stanley, B. H. (2019). Suicide and suicide risk. Nature reviews Disease primers, 5(1), 74.
Wang, H., Zhu, R., Dai, Z., Tian, S., Shao, J., Wang, X., ... & Lu, Q. (2020). Aberrant functional connectivity and graph properties in bipolar II disorder with suicide attempts. Journal of affective disorders, 275, 202-209.
Wang H, Zhu R, Tian S, et al. Dynamic connectivity alterations in anterior cingulate cortex associated with suicide attempts in bipolar disorders with a current major depressive episode. J Psychiatr Res. 2022 May;149:307-314. doi: 10.1016/j.jpsychires.2022.03.010.
Wang, J., & He, Y. (2024). Toward individualized connectomes of brain morphology. Trends in Neurosciences.

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