Evaluating the role of common risk variation in the recurrence risk of schizophrenia in multiplex schizophrenia families

Abstract

Multiplex families have higher recurrence risk of schizophrenia compared to the families of sporadic cases, but the source of this increased recurrence risk is unknown. We used schizophrenia genome-wide association study data (N = 156,509) to construct polygenic risk scores (PRS) in 1005 individuals from 257 multiplex schizophrenia families, 2114 ancestry-matched sporadic cases, and 2205 population controls, to evaluate whether increased PRS can explain the higher recurrence risk of schizophrenia in multiplex families compared to ancestry-matched sporadic cases. Using mixed-effects logistic regression with family structure modeled as a random effect, we show that SCZ PRS in familial cases does not differ significantly from sporadic cases either with, or without family history (FH) of psychotic disorders (All sporadic cases p = 0.90, FH+ cases p = 0.88, FH− cases p = 0.82). These results indicate that increased burden of common schizophrenia risk variation as indexed by current SCZ PRS, is unlikely to account for the higher recurrence risk of schizophrenia in multiplex families. In the absence of elevated PRS, segregation of rare risk variation or environmental influences unique to the families may explain the increased familial recurrence risk. These findings also further validate a genetically influenced psychosis spectrum, as shown by a continuous increase of common SCZ risk variation burden from unaffected relatives to schizophrenia cases in multiplex families. Finally, these results suggest that common risk variation loading are unlikely to be predictive of schizophrenia recurrence risk in the families of index probands, and additional components of genetic risk must be identified and included in order to improve recurrence risk prediction.

Relationship between polygenic risk scores and symptom dimensions of schizophrenia and schizotypy in multiplex families with schizophrenia

“…We have previously shown that members of the Irish Study of High-Density Schizophrenia Families (ISHDSF) 16 have an increased PRS for SCZ, bipolar disorder (BIP) and major depressive disorder (MDD) compared with population controls. 17 , 18 In this study, we sought to examine the differential relationship between PRSs for these three major psychiatric disorders, and quantitative measurement of symptom severity in the ISHDSF sample.…”