Abstract
Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.
Highlights
All other summary statistics and supporting data are available in Supplementary Information
E. et al Natural genetic variation caused by small insertions and deletions in the human genome
Summary
Confirmation of prior results: Higher genome-wide burden of rare SVs in schizophrenia cases has been repeatedly observed in studies using SNP arrays[8,18] (i.e., rare, large SVs with MAF < 0.01 and size > 100 kb). Following Wainschtein et al.’s approach[14], we estimated schizophrenia heritability from our WGS data using 1151 cases and 911 controls (post-QC subjects and pairwise genetic relatedness < 0.05), and 17,364,971 sequence variants (post-QC autosomal SNV/indels observed ≥ 3 times or MAF ≥ 0.0007). Our estimates of SNP- and WGS-heritability had large standard errors This was due to limited sample size and case-control study design (i.e. not continuous trait as height or body mass). The still missing heritability of schizophrenia may be only misplaced, in precisely the blind spots of SNP arrays as has been anticipated for over a decade[44]
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