Common polygenic variation and risk for childhood-onset schizophrenia

K Ahn,Y Y Shugart,S S An,J L Rapoport

doi:10.1038/mp.2014.158

Abstract

Childhood-onset schizophrenia (COS) is a rare and severe form of the disorder, with more striking abnormalities with respect to prepsychotic developmental disorders and abnormities in the brain development compared with later-onset schizophrenia. We previously documented that COS patients, compared with their healthy siblings and with adult-onset patients (AOS), carry significantly more rare chromosomal copy number variations, spanning large genomic regions (>100 kb) (Ahn et al. 2014). Here, we interrogated the contribution of common polygenic variation to the genetic susceptibility for schizophrenia. We examined the association between a direct measure of genetic risk of schizophrenia in 130 COS probands and 103 healthy siblings. Using data from the schizophrenia and autism GWAS of the Psychiatric Genomic Consortia, we selected three risk-related sets of single nucleotide polymorphisms from which we conducted polygenic risk score comparisons for COS probands and their healthy siblings. COS probands had higher genetic risk scores of both schizophrenia and autism than their siblings (P<0.05). Given the small sample size, these findings suggest that COS patients have more salient genetic risk than do AOS.

Highlights

With recent advances in genomic microarrays, identifying common genetic variants for complex traits have become a reality through genome-wide association studies (GWAS).[1]
We previously showed that Childhood-onset schizophrenia (COS) patients carry a higher rate of large (4100 kb) and rare (o0.1% in controls) copy number variations that interrupt genes in pathways of neurodevelopment and regulation than do their healthy siblings or adultonset patients (AOS).[12,13]
COS cases, their biological parents, and full siblings (443 individuals) were included in this analysis. This small sample size had under 5% of power to detect any association in 1 M genome-wide scan, calculated in PBAT. Due to this lack of statistical power to conduct genome-wide association tests, we selected the top 80 significant single nucleotide polymorphisms (SNPs) nominated by Psychiatric Genomic Consortium (PGC)-SCZ in order to test any association with COS

Summary

Introduction

With recent advances in genomic microarrays, identifying common genetic variants for complex traits have become a reality through genome-wide association studies (GWAS).[1]. Stratifying by age of onset has been useful across all of medicine and, in particular, for identifying causal genetic variants.[10,11] We previously showed that COS patients carry a higher rate of large (4100 kb) and rare (o0.1% in controls) copy number variations that interrupt genes in pathways of neurodevelopment and regulation than do their healthy siblings or adultonset patients (AOS).[12,13] In addition, we showed an unexpected relationship. In order to further understand the genetic susceptibility for COS, here we examined the contribution of common polygenic variation in our COS samples. Because COS shows a high rate of prepsychotic neurodevelopmental dysfunction,[14] we examined polygenic risk for autism in our COS sample

Methods

Results

Conclusion