We investigate whether number of episodes (NoEs) meaningfully reflect genetic risk and genetic heterogeneity for five primary disorders—Drug Use Disorder (DUD), Alcohol Use Disorder (AUD), Major Depression (MD), Bipolar Disorder (BD), and Schizophrenia (SZ) ascertained from Swedish population registries. We utilize Genetic Risk Ratios (GRR)—defined as the ratio of the genetic risk for secondary disorders to the genetic risk for the primary disorder—derived from Family Genetic Risk Scores (FGRS). For all five primary disorders, genetic risk rose robustly with increasing NoEs. For both AUD and DUD, the GRR for all six secondary disorders—selected to have a likely genetic relationship with the particular primary disorder—declined with increasing NoEs so that cases of AUD and DUD with high versus low NoEs had both a higher genetic risk and a purer genetic signal. With MD, genetic risk maximized at an intermediate NoEs. While the GRRs for AUD and DUD in MD cases dropped sharply with increasing NoEs, GRR for BD increased. For BD, genetic risk rose sharply with increasing NoEs while for all secondary disorders the GRRs showed a mixture of modest increases and decreases. Like AUD and DUD, but even more markedly, selecting BD cases with high rates of recurrence would produce a sample with a high overall genetic risk and a relatively homogeneous genetic signal. For SZ, genetic risk rose moderately with increases in NoEs. GRRs for other non-affective psychoses (ONAP) and autism spectrum disorder (ASD) fell quite slowly with increasing NoEs, and more rapidly for other secondary disorders. Cases of SZ with high recurrence rates had a high genetic risk and a relatively pure signal, albeit with contributions from ONAP and ASD. In summary, NOEs are a robust index of genetic risk and genetic heterogeneity across our primary disorders with important inter-disorder differences.

我们调查了发作次数 （NoE） 是否有意义地反映了五种主要疾病的遗传风险和遗传异质性——药物使用障碍 （DUD）、酒精使用障碍 （AUD）、重度抑郁症 （MD）、双相情感障碍 （BD） 和精神分裂症 （SZ） 从瑞典人口登记处确定。我们使用遗传风险比 （GRR）——定义为继发性疾病的遗传风险与原发性疾病的遗传风险之比——来自家族遗传风险评分 （FGRS）。对于所有五种原发性疾病，遗传风险都随着 NoEs 的增加而强劲上升。对于 AUD 和 DUD，所有六种继发性疾病的 GRR（选择与特定原发性疾病可能具有遗传关系）都随着 NoEs 的增加而下降，因此高 NoEs 与低 NoEs 的 AUD 和 DUD 病例具有更高的遗传风险和更纯净的遗传信号。对于 MD，遗传风险在中间 NoE 时最大。虽然 MD 病例中 AUD 和 DUD 的 GRR 随着 NoE 的增加而急剧下降，但 BD 的 GRR 增加。对于 BD，遗传风险随着 NoEs 的增加而急剧上升，而对于所有继发性疾病，GRR 表现出适度增加和减少的混合。与 AUD 和 DUD 类似，但更明显的是，选择复发率高的 BD 病例将产生具有较高总体遗传风险和相对同质遗传信号的样本。对于 SZ，遗传风险随着 NoE 的增加而适度上升。其他非情感性精神病 （ONAP） 和自闭症谱系障碍 （ASD） 的 GRR 随着 NoE 的增加而下降得相当缓慢，而其他继发性疾病的 GRR 下降得更快。复发率高的 SZ 病例具有较高的遗传风险和相对纯的信号，尽管有来自 ONAP 和 ASD 的贡献。 总之，NOE 是我们原发性疾病中遗传风险和遗传异质性的稳健指标，具有重要的疾病间差异。