The genetic basis for schizophrenia has long been studied since the first major study was released over 70 years ago, with twin, family and adoption studies all strongly showing a genetic basis for the disease. However, the inheritance of schizophrenia is complex with twin heritability around 81%.
Most research into the genetics of schizophrenia has focused on understanding the role of genes in the heritability and development of the disease, identifying large rare structural variants and common variants from well-established genes implicated in exome sequencing. Whole genome sequencing (WGS) is expensive but could provide a better understanding of the genetic variants affecting schizophrenia
Last week, the largest whole genome sequencing study of schizophrenia was published in Nature. It analysed high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls.
The study suggested that an ultra-rare structural variant that affects the boundaries of topologically associated domains (TADs) increased the risk for schizophrenia. TADs are distinct regions of the genome with strict boundaries between them that keep the domains from interacting with the genes in neighbouring TADs. Shifting or changing these boundaries allows interactions between genes and elements that would not normally interact and can lead to dysregulation of gene expression.
The extremely rare structural variants affecting TAD boundaries in the brain occurred significantly more often in people with schizophrenia than without it. Jin Szatkiewicz, the co-author of the paper, suggested future mechanistic studies could determine the precise functional effects of the variants and a possible investigation would use patient-derived cells with the TAD-affecting mutations to figure out what happened at the molecular level.