posted on 2024-01-16, 16:54authored byMohammad Ahangari, Amanda E Gentry, Irish Schizophrenia Genomics Consortium, Tan-Hoang Nguyen, Robert Kirkpatrick, Brian C Verrelli, Silviu-Alin Bacanu, Kenneth S Kendler, Bradley T Webb, Brien P Riley, John WaddingtonJohn Waddington, Kieran MurphyKieran Murphy
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.
Funding
R01-MH114593
R01-MH083094
Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z)
Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B)
NIMH grant MH 41953
R01-MH062276
R01-MH068881
T32-MH020030
NARSAD Young Investigator Grant 28599 and K25-AA030072
Science Foundation Ireland (08/IN.1/B1916)
History
Data Availability Statement
GWAS summary statistics for PGC3-SCZ GWAS is publicly available on the PGC website https://www.med.unc.edu/pgc/download-results/
Leave-N-out GWAS summary statistics for PGC3-SCZ GWAS was acquired from the PGC by following the appropriate guidelines and will be shared upon reasonable request.
GWAS summary statistics for LDL is publicly available on the ENGAGE Consortium website
http://diagram-consortium.org/2015_ENGAGE_1KG/
We made use of various freely available software tools in this study:
PRS-CS: https://github.com/getian107/PRScs
PLINK: https://www.cog-genomics.org/plink/2.0/
GMMAT: https://github.com/hanchenphd/GMMAT
LDAK: http://dougspeed.com/ldak/
PLINK2: https://www.cog-genomics.org/plink/2.0/
The custom scripts used in this study are available upon request.
Comments
The original article is available at https://www.nature.com/
Published Citation
Ahangari M. et al. Evaluating the role of common risk variation in the recurrence risk of schizophrenia in multiplex schizophrenia families. Transl Psychiatry. 2022;12(1):291.