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

Abstract Importance Multiplex schizophrenia families have higher recurrence risk of schizophrenia compared to the families of singleton cases in the population, but the source of increased familial recurrence risk is unknown. Determining the source of this observation is essential, as it will define the relative focus on common versus rare genetic variation in case-control and family studies of schizophrenia. Objective To evaluate the role of common risk variation in the recurrence risk of schizophrenia, by comparing the polygenic risk scores in familial versus ancestry matched singleton cases of schizophrenia. Design We used the latest genome-wide association study data of schizophrenia (N=166,464) to construct polygenic risk scores in multiplex family members, singleton cases and controls. To account for the high degree of relatedness in the samples, analyses were carried out using a mixed effects logistic regression model with the family structure modeled as a random effect. Setting Population and family based. Participants We used a large, homogenous sample of 1,005 individuals from 257 families from the Irish Study of High-Density Schizophrenia Families, 2,224 singleton cases and 2,284 population controls all from the population of the island of Ireland. Exposures Polygenic risk scores, diagnostic categories, familial or singleton case status. Main outcomes and measures The primary outcomes were the mixed effects logistic regression results generated from comparison between different groups. Results Polygenic risk scores in singleton cases did not differ significantly from familial cases (p=0.49), rejecting the hypothesis that an increased burden of common risk variation can account for the higher recurrence risk of schizophrenia in multiplex families. Conclusions and relevance This study suggests that a higher burden of common schizophrenia risk variation cannot account for the increased familial recurrence risk of schizophrenia in multiplex families. In the absence of elevated polygenic risk scores in multiplex schizophrenia families, segregation of rare variation in the genome and environmental exposures unique to the families may explain the increased multiplex familial recurrence risk of schizophrenia. These findings also further validate the concept of a genetically influenced psychosis spectrum in multiplex schizophrenia families as shown by a continuous increase of common risk variation burden from unaffected relatives to familial cases of schizophrenia in the families.