Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
Mol Psychiatry. 2021 Jun;26(6):2457-2470. doi: 10.1038/s41380-020-0689-5. Epub 2020 Mar 16.
Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLiGen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
锂是双相情感障碍（BD）的一线药物，但只有三分之一的患者对药物有最佳反应。由于证据表明抑郁和双相情感障碍之间存在强烈的临床和遗传重叠，我们研究了对 major depression 的多基因易感性是否与 BD 患者对锂治疗的反应有关。使用从接受锂治疗并参加锂遗传学联合会（ConLiGen）研究的 2586 名双相情感障碍患者获得的遗传数据，使用不同 GWAS p 值阈值计算了 major depression（MD）的加权多基因评分（PGS）。用于 PGS 加权的是来自精神疾病基因组学联合会（PGC）的 MD（135458 例病例和 344901 例对照）全基因组关联研究的汇总统计数据。使用 Alda 量表上的测量值，锂治疗反应通过连续评分和分类结果（反应者与非反应者）来定义。使用线性和二元逻辑回归模型分别评估 MD 的 PGS 与锂治疗反应之间的关联。在整个队列以及欧洲和亚洲亚样本中进行了分析。在多民族、欧洲或亚洲人群中，在不同的 p 值阈值下，MD 的 PGS 与锂治疗反应显著相关。与高多基因负荷的患者相比，MD 多基因负荷低的双相情感障碍患者更有可能对锂治疗有良好反应[最低与最高 PGS 四分位数相比，多民族样本：OR=1.54（95%CI：1.18-2.01）和欧洲样本：OR=1.75（95%CI：1.30-2.36)]。虽然我们在亚洲样本中的分析发现了相同方向等效的效应大小：OR=1.71（95%CI：0.61-4.90），但这并不具有统计学意义。使用 PGS 十分位数比较，我们发现 MD 多基因负荷高与锂反应低之间存在类似的关联趋势。我们的研究结果强调了 BD 中锂反应的遗传贡献，并支持 BD 中出现的锂反应生物型的概念。
