Contribution of common and rare variants to schizophrenia risk in east and south asian ancestries

Schizophrenia genetic studies have largely focused on European ancestries, leaving genetic variants in other populations underexplored and potentially increasing health disparities. Recent studies have somewhat rectified this for common variants in East Asian ancestries, but rare variants remain largely uncharacterized in non-European populations. We present the first large-scale schizophrenia sequencing study that examines both common and rare variants in East and South Asian populations, using an innovative, cost-effective sequencing technology. We developed Blended Genome Exome (BGE), a novel sequencing method merging low-pass whole genome and deep whole exome sequencing. Using the PCR-free library spiked into TWIST exome capture, BGE sequences the exome content at a deep depth (∼40x) and the genome content at a low depth (2-4x). This cost-effective technology accomplishes both sequencing tasks in a single experiment, outperforming arrays in non-European ancestries by removing the need to pre-select ancestry-biased variants of interest. We performed BGE sequencing on large samples of both Chinese (n=17,392) and Pakistan (n=5,181) ancestry, equally split between cases and controls. We performed rigorous processing and quality control followed by association analyses to find schizophrenia-associated genetic variants. We analyzed the exome regions (WES) following the strategy described in the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) study. Due to its high missing rate, low-pass whole-genome sequencing (WGS) requires special considerations. We used GLIMPSE, a newly developed tool to refine and impute genotype likelihoods for low-pass WGS efficiently. We found BGE outperformed all genotyping arrays for common variants, even dense ones such as the Omni2.5, and has sufficient sensitivity to capture ultra-rare coding variants that were shown to play a key role in schizophrenia. Combining with existing schizophrenia common and rare variant resources, we expect to identify novel genetic loci associated with schizophrenia in East and South Asian ancestries. This study provides insight into the contribution of common and rare variants to schizophrenia risk in East and South Asia ancestries through a new sequencing technology and a large-scale sample.