Chan Io Ieong, Wu Anise M S
Department of Public Health and Medicinal Administration, Faculty of Health Science, University of Macau, Macao, China.
Centre for Cognitive and Brain Sciences, Institute of Collaborative Innovation, University of Macau, Macao, China.
Biol Psychiatry Glob Open Sci. 2024 Feb 18;4(3):100294. doi: 10.1016/j.bpsgos.2024.100294. eCollection 2024 May.
Previous evidence informed by the toxic stress model suggests that higher cortisol causes anxiety and major depression, but clinical success is lacking. To clarify the role of cortisol, we used Mendelian randomization to estimate its associations with anxiety, major depression, and neuroticism, leveraging the largest available genome-wide association studies including from the Psychiatric Genomics Consortium, the UK Biobank, and FinnGen.
After meta-analyzing 2 genome-wide association studies on morning plasma cortisol ( = 32,981), we selected single nucleotide polymorphisms (SNPs) at < 5 × 10 and < 0.3 in the gene region encoding proteins that influence cortisol bioavailability. We applied these SNPs to summary genetic associations with the outcomes considered ( = 17,310-449,484), and systolic blood pressure as a positive outcome, using inverse-variance weighted meta-analysis accounting for correlation. Sensitivity analyses addressing SNP correlation and confounding by childhood maltreatment and follow-up analyses using only SNPs that colocalized with expression were conducted.
Cortisol was associated with anxiety (pooled odds ratio [OR] 1.16 per cortisol score; 95% CI, 1.04 to 1.31), but not major depression (pooled OR 1.02, 95% CI, 0.95 to 1.10) or neuroticism (β -0.025; 95% CI, -0.071 to 0.022). Sensitivity analyses yielded similar estimates. Cortisol was positively associated with systolic blood pressure, as expected. Using rs9989237 and rs2736898, selected using colocalization, cortisol was associated with anxiety in the UK Biobank (OR 1.32; 95% CI, 1.01 to 1.74) but not with major depression in FinnGen (OR 1.14; 95% CI, 0.95 to 1.37).
Cortisol was associated with anxiety and may be a potential target for prevention. Other targets may be more relevant to major depression and neuroticism.
先前基于毒性应激模型的证据表明，较高的皮质醇水平会导致焦虑和重度抑郁症，但缺乏临床成功案例。为了阐明皮质醇的作用，我们利用孟德尔随机化方法来估计其与焦虑、重度抑郁症和神经质的关联，所依据的是现有最大规模的全基因组关联研究，包括来自精神疾病基因组学联盟、英国生物银行和芬兰基因研究项目的数据。
在对两项关于早晨血浆皮质醇的全基因组关联研究（n = 32,981）进行荟萃分析后，我们在编码影响皮质醇生物利用度的蛋白质的基因区域中，选择了P值<5×10⁻⁸且r²<0.3的单核苷酸多态性（SNP）。我们将这些SNP应用于与所考虑的结局（n = 17,310 - 449,484）以及收缩压（作为一个阳性结局）的汇总遗传关联分析，采用考虑相关性的逆方差加权荟萃分析方法。进行了敏感性分析，以解决SNP相关性以及童年期虐待造成的混杂问题，并仅使用与皮质醇表达共定位的SNP进行后续分析。
皮质醇与焦虑相关（每皮质醇标准差得分的合并比值比[OR]为1.16；95%置信区间[CI]，1.04至1.31），但与重度抑郁症无关（合并OR为1.02，95%CI，0.95至1.10）或神经质无关（β为 - 0.025；95%CI， - 0.071至0.022）。敏感性分析得出了相似的估计值。正如预期的那样，皮质醇与收缩压呈正相关。利用通过共定位选择的rs9989237和rs2736898，在英国生物银行中皮质醇与焦虑相关（OR为1.32；95%CI，1.01至1.74），但在芬兰基因研究项目中与重度抑郁症无关（OR为1.14；95%CI，0.95至1.37）。
皮质醇与焦虑相关，可能是预防的一个潜在靶点。其他靶点可能与重度抑郁症和神经质更相关。
