Overs Bronwyn J, Roberts Gloria, Ridgway Kate, Toma Claudio, Hadzi-Pavlovic Dusan, Wilcox Holly C, Hulvershorn Leslie A, Nurnberger John I, Schofield Peter R, Mitchell Philip B, Fullerton Janice M
Neuroscience Research Australia, Randwick, New South Wales, Australia.
School of Psychiatry, University of New South Wales, Kensington, New South Wales, Australia.
Am J Med Genet B Neuropsychiatr Genet. 2021 Dec;186(8):485-507. doi: 10.1002/ajmg.b.32879. Epub 2021 Nov 2.
Bipolar disorder (BD) is associated with a 20-30-fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRSs)-a quantitative index of genomic risk-and variability in brain structures implicated in SA. Participants (n = 206; aged 12-30 years) were unrelated individuals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives ("high risk"), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRSs were computed using genome-wide association data for SA in BD (SA-in-BD), SA in major depressive disorder (SA-in-MDD) (Mullins et al., 2019, The American Journal of Psychiatry, 176(8), 651-660), and risky behavior (Karlsson Linnér et al., 2019, Nature Genetics, 51(2), 245-257). Structural magnetic resonance imaging processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction. SA-in-MDD and SA-in-BD PRSs negatively predicted parahippocampal thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRSs inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the "high risk" group. SA-in-MDD and SA-in-BD PRSs positively predicted cuneus structure, irrespective of group. This study demonstrated associations between PRSs for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRSs, in conjunction with a range of biological, phenotypic, environmental, and experiential data in high risk populations, may inform predictive models for suicidal behaviors.
与普通人群相比，双相情感障碍（BD）患者的自杀风险增加了20至30倍。BD患者的一级亲属表现出包括自杀行为在内的精神病理学发生率升高。由于缺乏自杀未遂（SA）的可靠生物标志物，我们研究了自杀相关多基因风险评分（PRSs）（一种基因组风险的定量指标）与SA相关脑结构变异性之间的关联。参与者（n = 206；年龄在12至30岁之间）为欧洲血统的无血缘关系个体，分为三组：41例BD患者、96名BD亲属（“高风险”）和69名对照。基因分型采用PsychArray，随后进行插补。使用BD中SA的全基因组关联数据（BD中的SA）、重度抑郁症中SA的数据（MDD中的SA）（Mullins等人，2019年，《美国精神病学杂志》，176(8)，651 - 660）以及危险行为的数据（Karlsson Linnér等人，2019年，《自然遗传学》，51(2)，245 - 257）计算了三个PRSs。结构磁共振成像处理采用FreeSurfer v5.3.0。使用从自杀神经影像学文献中确定的32个感兴趣区域构建一般线性模型，并进行错误发现率校正。MDD中的SA和BD中的SA的PRSs对海马旁回厚度有负向预测作用，后者的关联因组群成员身份而有所改变。BD中的SA和危险行为的PRSs分别对喙侧和尾侧前扣带回结构有反向预测作用，后者的效应由“高风险”组驱动。MDD中的SA和BD中的SA的PRSs对楔叶结构有正向预测作用，与组群无关。这项研究证明了自杀相关表型的PRSs与SA相关脑区的结构变异性之间的关联。未来结合高风险人群的一系列生物学、表型、环境和经验数据对扩展PRSs进行探索，可能为自杀行为的预测模型提供信息。
