biostudies-literatureWang JYoung ScientistsStrategic Priority Research Program of the Chinese Academy of SciencesWestern Light Innovative Research Team of Chinses Academy of SciencesNIA NIH HHSNIDA NIH HHSNIMH NIH HHSNational Nature Science Foundation of ChinaNIHKey Research Project2569-2585https://www.ebi.ac.uk/biostudies/studies/S-EPMC9612800biostudies-literatureUnknown145(7)Recent genome-wide association studies have reported multiple schizophrenia risk loci, yet the functional variants and their roles in schizophrenia remain to be characterized. Here we identify a functional single nucleotide polymorphism (rs2270363: G>A) at the schizophrenia risk locus 16p13.3. rs2270363 lies in the E-box element of the promoter of NMRAL1 and disrupts binding of the basic helix-loop-helix leucine zipper family proteins, including USF1, MAX and MXI1. We validated the regulatory effects of rs2270363 using reporter gene assays and electrophoretic mobility shift assay. Besides, expression quantitative trait loci analysis showed that the risk allele (A) of rs2270363 was significantly associated with elevated NMRAL1 expression in the human brain. Transcription factors knockdown aBrain : a journal of neurologyFunctional variant rs2270363 on 16p13.3 confers schizophrenia risk by regulating NMRAL1.PMC9612800P50 AG005138202001AV070006P50 MH096891202101AS070055P50 MH066392XDPB17R01 MH080405R01 MH097276P01 AG002219R01 MH075916R37 MH057881P50 MH084051F31 AG05138131970561P50 MH084053HHSN271201300031CU2102205R01 MH085542U1904130R01 MH093725Liu JYang JLi JHuang DXiao XLi KWang JLi MLi WLi XLiu YLi YLv LYang YLi SLuo XJChen RfalseFunctional variant rs2270363 on 16p13.3 confers schizophrenia risk by regulating NMRAL1.Recent genome-wide association studies have reported multiple schizophrenia risk loci, yet the functional variants and their roles in schizophrenia remain to be characterized. Here we identify a functional single nucleotide polymorphism (rs2270363: G>A) at the schizophrenia risk locus 16p13.3. rs2270363 lies in the E-box element of the promoter of NMRAL1 and disrupts binding of the basic helix-loop-helix leucine zipper family proteins, including USF1, MAX and MXI1. We validated the regulatory effects of rs2270363 using reporter gene assays and electrophoretic mobility shift assay. Besides, expression quantitative trait loci analysis showed that the risk allele (A) of rs2270363 was significantly associated with elevated NMRAL1 expression in the human brain. Transcription factors knockdown a2022-01-01T00:00:00Z2022 Jul2026-05-03T10:52:52.397Z2024-11-13T05:17:32.511ZS-EPMC96128003509405910.1093/brain/awac020