Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia

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 ultrarare 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.

FIREcaller: Detecting frequently interacting regions from Hi-C data

“…We demonstrate its utilities through applications to multiple Hi-C datasets and integrative analyses with E-P interactions, histone modifications and gene expression. We confirmed that FIREs are tissue/cell-type-specific, enriched of tissue/cell-type-specific enhancers, and are near tissue/cell type-specifically expressed genes, informative for prioritizing variants identified from genome-wide association studies (GWAS), consistent with other published works [14] , [16] , [17] , [18] , [19] , [3] . In addition to the identification of FIREs and super-FIREs, our FIREcaller also allows the detection of differential FIREs and visualization of results.…”

FIREcaller: Detecting Frequently Interacting Regions from Hi-C Data

“…We demonstrate its utilities through applications to multiple Hi-C datasets and integrative analyses with E-P interactions, histone modifications and gene expression. We confirmed that FIREs are tissue/cell-type-specific, enriched of tissue/cell-type-specific enhancers, and are near tissue/cell type-specifically expressed genes, informative for prioritizing variants identified from genome-wide association studies (GWAS), consistent with other published works [14,[16][17][18][19]43]. In addition to the identification of FIREs and super-FIREs, our FIREcaller also allows the detection of differential FIREs and visualization of results.…”

“…Since the discovery of FIREs, we have collaborated with multiple groups to further demonstrate their value in various applications, resulting in multiple recent preprints and publications [16][17][18][19]. For example, in an analysis of adult and fetal cortex Hi-C datasets, FIREs and super-FIREs recapitulated key functions of tissue-specificity, such as neurogenesis in fetal cortex and core neuronal functions in adult cortex [19].…”

Long-Read Sequencing Improves the Detection of Structural Variations Impacting Complex Non-Coding Elements of the Genome

“…Structural genomic variants (SVs) such as copy-number variations (CNVs) (deletions and duplications), inversions, and rearrangements account for a large portion of genetic diversity among individuals [ 1 ]. In the last two decades, SVs were found to be strongly associated with numerous medical conditions, and notably in neurodevelopmental disorders [ 2 ] such as autism [ 3 ], schizophrenia [ 4 ], and epilepsy [ 5 , 6 ]. Short-read based next-generation sequencing technologies aid in the construction of complex genome assemblies, as well as identification and annotation of critical SVs [ 5 ].…”