Investigating the source of increased bipolar and major depressive disorder polygenic risk in multiplex schizophrenia families

Psychotic and affective disorders often aggregate in the relatives of probands with schizophrenia (SCZ), and genetic studies show substantial genetic correlation among SCZ, bipolar disorder (BIP) and major depressive disorder (MDD). However, the nature of this genetic overlap in polygenic risk score (PRS) analyses of multiplex families has not been fully dissected. In the current study, we investigated the polygenic risk burden of BIP and MDD in a sample of 257 multiplex SCZ families (N=1,005) and population controls (N=2,205). Furthermore, due to the strong genetic correlation among SCZ, BIP, and MDD, we examined whether increased BIP or MDD PRS in members of multiplex SCZ families can be attributed to latent genetic factors unique to BIP or MDD, or latent genetic factors that each of these two disorders share with SCZ. Our results indicate that members of multiplex SCZ families have an increased PRS for BIP and MDD, however, this observation is largely attributable to latent genetic factors that BIP or MDD share with SCZ, rather than latent genetic factors unique to them. These results provide new insight for cross-disorder PRS analyses of psychiatric disorders, by cautioning that for complete interpretation of observed cross-disorder PRS enrichment, we should account for genetic correlations across psychiatric disorders. Our findings further indicates that members of multiplex SCZ families may have an increased genetic vulnerability to both psychotic and affective disorders, and for full assessment of an individuals genetic risk, familial backgrounds should be taken into consideration.