Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2-189) 60% female; mean age = 42.58 years, range = 18-97 years, sd = 15.75 years] with no exclusion criteria for any given psychiatric disorder. We observed that total esterified cholesterol measured at the time of psychiatric assessment shared a significant genetic overlap with risk for suicide attempt (ρ_g = -0.64, p = 1.24 × 10^-04). We also found that total unesterified cholesterol measured around 20 years prior to assessment varied as a function of genetic proximity to an affected individual (h² = 0.21, se = 0.10, p = 8.73 × 10^-04; β_suicide = -0.70, se = 0.25, p = 8.90 × 10^-03). Finally, we found that the relationship between total unesterified cholesterol and suicide risk was significantly mediated by ABCA-1-specific cholesterol efflux capacity (β_{suicide-efflux} = -0.45, p = 0.039; β_{efflux-cholexterol} = -0.34, p < 0.0001; β_indirect = -0.15, p = 0.044). These findings suggest that the relatively well-delineated process of cholesterol metabolism and associated molecular pathways will be informative for understanding the neurobiological underpinnings of risk for suicide attempt.

中文翻译：

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解开胆固醇和自杀风险之间的遗传重叠。

自杀是主要的公共卫生问题。每年全球有100万人死于自杀，其中还有更多的自杀企图。因此，必须确定有力且可靠的自杀风险指标或生物标志物，以便可以识别处于危险中的人并尽快提供适当的干预措施。先前的工作揭示了循环胆固醇水平低与自杀风险之间的关系，暗示胆固醇水平是这样一种潜在的生物标志物，但这种关系的基础因素仍然未知。在本研究中，我们将双变量多基因和相关系数分析相结合，然后在大量来自扩展家谱的墨西哥裔美国人样本中进行了调解分析[N = 1897; 96个血统书（平均大小= 19.17个人，范围= 2-189）60％女；平均年龄= 42.58岁，范围= 18-97岁，标准差= 15.75岁]，对于任何给定的精神疾病均无排除标准。我们观察到，在精神病学评估时测得的总酯化胆固醇与自杀未遂风险有显着的遗传重叠（ρ_g  = -0.64，p = 1.24×10 ^-04）。我们还发现，评估前20年左右测得的未酯化胆固醇总量随与患病个体遗传接近程度的变化而变化（h ²  = 0.21，se = 0.10，p = 8.73×10 ^-04；β_自杀 = -0.70，se = 0.25，p = 8.90×10 ^-03）。最后，我们发现总未酯化胆固醇与自杀风险之间的关系是由ABCA-1特异性胆固醇外排能力显着介导的（β_自杀外排 = -0.45，p = 0.039；β_{外排-胆固醇} = -0.34，p <0.0001 ;β_间接 ＝ -0.15，p ＝ 0.044）。这些发现表明，胆固醇代谢和相关分子途径的相对较好的描述将有助于理解自杀未遂风险的神经生物学基础。