Bipolar disorder (BD) has high clinical heterogeneity, frequent psychiatric comorbidities, and elevated suicide risk. To determine genetic differences between common clinical sub-phenotypes of BD, we performed a systematic polygenic risk score (PRS) analysis using multiple PRSs from a range of psychiatric, personality, and lifestyle traits to dissect differences in BD sub-phenotypes in two BD cohorts: the Mayo Clinic BD Biobank (N = 968) and Genetic Association Information Network (N = 1001). Participants were assessed for history of psychosis, early-onset BD, rapid cycling (defined as four or more episodes in a year), and suicide attempts using questionnaires and the Structured Clinical Interview for DSM-IV. In a combined sample of 1969 bipolar cases (45.5% male), those with psychosis had higher PRS for SCZ (OR = 1.3 per S.D.; p = 3e-5) but lower PRSs for anhedonia (OR = 0.87; p = 0.003) and BMI (OR = 0.87; p = 0.003). Rapid cycling cases had higher PRS for ADHD (OR = 1.23; p = 7e-5) and MDD (OR = 1.23; p = 4e-5) and lower BD PRS (OR = 0.8; p = 0.004). Cases with a suicide attempt had higher PRS for MDD (OR = 1.26; p = 1e-6) and anhedonia (OR = 1.22; p = 2e-5) as well as lower PRS for educational attainment (OR = 0.87; p = 0.003). The observed novel PRS associations with sub-phenotypes align with clinical observations such as rapid cycling BD patients having a greater lifetime prevalence of ADHD. Our findings confirm that genetic heterogeneity contributes to clinical heterogeneity of BD and consideration of genetic contribution to psychopathologic components of psychiatric disorders may improve genetic prediction of complex psychiatric disorders.

双相情感障碍 (BD) 具有高度的临床异质性、频繁的精神共病和升高的自杀风险。为了确定 BD 常见临床亚表型之间的遗传差异，我们使用来自一系列精神、性格和生活方式特征的多个 PRS 进行了系统的多基因风险评分 (PRS) 分析，以剖析两个 BD 队列中 BD 亚表型的差异：Mayo Clinic BD Biobank ( N  = 968) 和遗传协会信息网络 ( N = 1001）。使用问卷和 DSM-IV 的结构化临床访谈对参与者的精神病史、早发性 BD、快速循环（定义为一年中四次或更多次发作）和自杀企图进行了评估。在 1969 名双相患者（45.5% 男性）的合并样本中，精神病患者 SCZ 的 PRS 较高（每个 SD 的 OR = 1.3；p  = 3e-5），但快感缺乏的 PRS较低（OR = 0.87；p  = 0.003）和BMI（OR = 0.87；p  = 0.003）。快速循环病例的 ADHD（OR = 1.23；p  = 7e-5）和 MDD（OR = 1.23；p  = 4e-5）的 PRS 较高，而 BD PRS 较低（OR = 0.8；p  = 0.004）。有自杀企图的病例对 MDD 的 PRS 较高（OR = 1.26；p = 1e-6) 和快感缺失 (OR = 1.22; p  = 2e-5) 以及较低的受教育程度 PRS (OR = 0.87; p  = 0.003)。观察到的新型 PRS 与亚表型的关联与临床观察一致，例如快速循环的 BD 患者具有更高的 ADHD 终生患病率。我们的研究结果证实，遗传异质性有助于 BD 的临床异质性，考虑遗传对精神疾病的精神病理学成分的贡献可能会改善对复杂精神疾病的遗传预测。