Molecular regulatory mechanisms of schizophrenia-associated functional non-coding variants

Genome-wide association studies (GWAS) have identified over 300 risk loci for schizophrenia (SCZ). However, given the vast majority of risk variants identified from GWAS are localized in non-coding regions, identification of functional risk variants from the risk loci and elucidating their molecular regulatory mechanisms remain major challenges. Here, we leverage a functional genomics approach to systematically identify functional variants from the reported risk loci. By integrating chromatin immunoprecipitation sequencing (ChIP-Seq) and position weight matrix (PWM) data, we identified 249 functional variants (located in 99 loci) that affect the binding of transcription factors (TFs). Expression quantitative trait loci (eQTL) annotation showed that 207 TF binding-affecting SNPs are significantly associated with gene expression in the human brain. For 92 loci where functional variants have not been identified by functional genomics, we conducted fine-mapping and applied motifbreakR to identify potential causal or functional variants. Notably, regulatory effects of 35 identified functional variants were validated by the published massively parallel reporter assays (MPRAs). Expression analysis showed dysregulation of genes whose expression levels are associated with functional variants in SCZ cases compared with controls. Our study identifies the functional variants from the reported risk loci and elucidates the molecular regulatory mechanisms of SCZ-associated functional non-coding variants, providing an important starting point to translate the genetic findings into disease biology and potential therapeutic targets.