Although displaying genetic correlations, psychiatric disorders are clinically defined as categorical entities as they each have distinguishing clinical features and may involve different treatments. Identifying differential genetic variations between these disorders may reveal how the disorders differ biologically and help to guide more personalized treatment. Here we presented a statistical framework and comprehensive analysis to identify genetic markers differentially associated with various psychiatric disorders/traits based on GWAS summary statistics, covering 18 psychiatric traits/disorders and 26 comparisons. We also conducted comprehensive analysis to unravel the genes, pathways and SNP functional categories involved, and the cell types and tissues implicated. We also assessed how well one could distinguish between psychiatric disorders by polygenic risk scores (PRS). SNP-based heritabilities (h²_snp) were significantly larger than zero for most comparisons. Based on current GWAS data, PRS have mostly modest power to distinguish between psychiatric disorders. For example, we estimated that AUC for distinguishing schizophrenia from major depressive disorder (MDD), bipolar disorder (BPD) from MDD and schizophrenia from BPD were 0.694, 0.602 and 0.618, respectively, while the maximum AUC (based on h²_snp) were 0.763, 0.749 and 0.726, respectively. We also uncovered differences in each pair of studied traits in terms of their differences in genetic correlation with comorbid traits. For example, clinically defined MDD appeared to more strongly genetically correlated with other psychiatric disorders and heart disease, when compared to non-clinically defined depression in UK Biobank. Our findings highlight genetic differences between psychiatric disorders and the mechanisms involved. PRS may help differential diagnosis of selected psychiatric disorders in the future with larger GWAS samples.

尽管显示出遗传相关性，但精神疾病在临床上被定义为分类实体，因为它们各自具有不同的临床特征并且可能涉及不同的治疗。识别这些疾病之间的差异遗传变异可能会揭示这些疾病在生物学上的差异，并有助于指导更个性化的治疗。在这里，我们提出了一个统计框架和综合分析来差异识别遗传标记与基于 GWAS 汇总统计的各种精神疾病/特征相关，涵盖 18 种精神特征/疾病和 26 种比较。我们还进行了综合分析，以揭示所涉及的基因、途径和 SNP 功能类别，以及所涉及的细胞类型和组织。我们还评估了通过多基因风险评分 (PRS) 区分精神疾病的能力。基于 SNP 的遗传力 ( h ² _snp) 在大多数比较中显着大于零。根据当前的 GWAS 数据，PRS 在区分精神疾病方面的能力通常不大。例如，我们估计区分精神分裂症与重度抑郁症 (MDD)、双相情感障碍 (BPD) 与 MDD 以及精神分裂症与 BPD 的 AUC 分别为 0.694、0.602 和 0.618，而最大 AUC（基于h ² _snp) 分别为 0.763、0.749 和 0.726。我们还发现了每对研究性状在与共病性状的遗传相关性方面的差异。例如，与英国生物银行中非临床定义的抑郁症相比，临床定义的 MDD 似乎与其他精神疾病和心脏病的遗传相关性更强。我们的研究结果突出了精神疾病及其相关机制之间的遗传差异。PRS 可能有助于将来通过更大的 GWAS 样本对选定的精神疾病进行鉴别诊断。