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PQG Working Group
March 28, 2023 @ 1:00 pm - 2:00 pm
Enhanced Interpretation of Schizophrenia GWAS of Diverse Ancestry with Brain Regulatory Architecture of Matched Population
Previous genetic studies of schizophrenia focused on disproportionate majority of European Population. GWAS of non-European populations highlighted the importance of generalizability of genetic studies. Yet, the scarcity of expression quantitative trait loci (eQTL) data of non-European population brains restricted our understanding of how population genetic diversity is involved in the risk of schizophrenia. In this study, we analyzed genotype and RNA-seq of African Americans (AA, n= 158) and Europeans (EUR, n= 408) from the PsychENCODE consortium and East Asians (EAS, n= 217) from the Chinese Human Brain Bank. In our study, 198,769 cis-eQTLs involving 1,276 genes (~10% of all eGenes) and 288,143 SNPs are uniquely captured in the non-EUR populations. We identified 534 eQTLs involving ten genes that have opposite eQTL effects across populations. TAS2R31 is a bitter taste receptor gene, and its opposite eQTLs in EAS and EUR were replicated using independent datasets. We next used the brain eQTLs to explain SCZ GWAS from diverse ancestries and observed that eQTLs better explained SCZ GWAS in the matched population. After prioritizing risk genes via transcriptome-wide association analysis and colocalization in the matched populations. Fourteen novel SCZ candidate genes were identified based on EAS population eQTL with EAS SCZ GWAS. Lastly, using deconvoluted eQTLs of the three populations, we fine-mapped more potential causal variants and risk genes at the major subtypes of brain cells. This characterization of brain regulatory architecture across diverse populations highlighted the importance of studying brain eQTL from non-EUR populations and provides a comprehensive resource for novel insights into schizophrenia.
