Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, PR China; China National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, PR China.
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, PR China.
J Affect Disord. 2022 Jul 15;309:242-251. doi: 10.1016/j.jad.2022.04.097. Epub 2022 Apr 26.
Large-scale studies have shown that bipolar I disorder (BD-I) and bipolar II disorder (BD-II) have differences in genetic association with schizophrenia (SCZ) and major depressive disorder (MDD). However, the underlying shared genetic architectures between BD subtypes and both SCZ and MDD remain largely unknown.
We applied univariate and bivariate causal mixture models (MiXeR) to estimate the polygenicity and polygenic overlaps on large GWASs summary statistics of BD-I (n = 25,060), BD-II (n = 6781), SCZ (n = 69,369) and MDD (n = 170,756). Then, conjunctional false discovery rate approach was used to identify specific shared genetic loci between BD subtypes and both SCZ and MDD.
Univariate MiXeR revealed that BD-II was substantially more polygenic (22.37 K causal variants) as compared to BD-I, SCZ and MDD (7.87-12.43 K causal variants). Bivariate MiXeR revealed substantial polygenic overlaps between BD-I and SCZ (Dice-coefficient = 0.83) and between BD-I and MDD (Dice-coefficient = 0.76), which are beyond the genetic correlation (rg = 0.71 and 0.36). Conjunctional FDR analysis identified 236 distinct shared loci between BD-I and BD-II (2 loci), BD-I and SCZ (227 loci), BD-I and MDD (19 loci), BD-II and SCZ (1 locus), and BD-II and MDD (3 loci). Most of these shared loci have concordant effect directions among BD subtypes, SCZ and MDD.
The bivariate MiXeR model was not applied for the BD-II because of insufficient power and inadequate model fit.
These findings provide evidence for extensive polygenic effects across BD subtypes, SCZ and MDD, which further our understanding of the potential genetic basis for the comorbid symptoms across these disorders.
大规模研究表明，双相情感障碍 I 型（BD-I）和双相情感障碍 II 型（BD-II）在与精神分裂症（SCZ）和重度抑郁症（MDD）的遗传关联上存在差异。然而，BD 亚型与 SCZ 和 MDD 之间潜在的共同遗传结构在很大程度上仍然未知。
我们应用单变量和双变量因果混合模型（MiXeR）来估计 BD-I（n=25060）、BD-II（n=6781）、SCZ（n=69369）和 MDD（n=170756）的大型 GWAS 汇总统计数据的多基因性和多基因重叠。然后，采用联合假发现率方法来识别 BD 亚型与 SCZ 和 MDD 之间的特定共同遗传位点。
单变量 MiXeR 显示，BD-II 的多基因性明显高于 BD-I、SCZ 和 MDD（22.37 K 个因果变异）（7.87-12.43 K 个因果变异）。双变量 MiXeR 显示，BD-I 与 SCZ（Dice 系数=0.83）和 BD-I 与 MDD（Dice 系数=0.76）之间存在大量的多基因重叠，这超出了遗传相关性（rg=0.71 和 0.36）。联合 FDR 分析确定了 236 个独特的共同位点存在于 BD-I 和 BD-II（2 个位点）、BD-I 和 SCZ（227 个位点）、BD-I 和 MDD（19 个位点）、BD-II 和 SCZ（1 个位点）和 BD-II 和 MDD（3 个位点）之间。这些共同的位点中的大多数在 BD 亚型、SCZ 和 MDD 之间具有一致的效应方向。
由于功率不足和模型拟合不足，BD-II 未应用双变量 MiXeR 模型。
这些发现为 BD 亚型、SCZ 和 MDD 之间广泛的多基因效应提供了证据，进一步加深了我们对这些疾病共病症状潜在遗传基础的理解。
