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ABSTRACT Genome-wide association studies (GWASs) have reported many single nucleotide polymorphisms (SNPs) associated with psychiatric disorders, but knowledge is lacking regarding molecular

mechanisms. Here we show that risk alleles spanning multiple genes across the 10q24.32 schizophrenia-related locus are associated in the human brain selectively with an increase in the

expression of both BLOC-1 related complex subunit 7 (_BORCS7_) and a previously uncharacterized, human-specific arsenite methyltransferase (_AS3MT_) isoform (_AS3MT_d2d3), which lacks

arsenite methyltransferase activity and is more abundant in individuals with schizophrenia than in controls. Conditional-expression analysis suggests that _BORCS7_ and _AS3MT_d2d3 signals

are largely independent. GWAS risk SNPs across this region are linked with a variable number tandem repeat (VNTR) polymorphism in the first exon of _AS3MT_ that is associated with the

expression of _AS3MT_d2d3 in samples from both Caucasians and African Americans. The VNTR genotype predicts promoter activity in luciferase assays, as well as DNA methylation within the

_AS3MT_ gene. Both _AS3MT_d2d3 and _BORCS7_ are expressed in adult human neurons and astrocytes, and they are upregulated during human stem cell differentiation toward neuronal fates. Our

results provide a molecular explanation for the prominent 10q24.32 locus association, including a novel and evolutionarily recent protein that is involved in early brain development and

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Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS A MISSENSE VARIANT IN _NDUFA6_ CONFERS SCHIZOPHRENIA RISK BY AFFECTING YY1 BINDING AND _NAGA_ EXPRESSION

Article 30 April 2021 INTEGRATIVE ANALYSES PRIORITIZE _GNL3_ AS A RISK GENE FOR BIPOLAR DISORDER Article 21 August 2020 THE MOLECULAR PATHOLOGY OF SCHIZOPHRENIA: AN OVERVIEW OF EXISTING

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_Nat. Genet._ 29, 306–309 (2001). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank A. Deep-Soboslay (Lieber Institute for Brain Development) for her tireless

efforts in clinical diagnosis and demographic characterization; R. Zielke, R.D. Vigorito and R.M. Johnson (National Institute of Child Health and Human Development Brain and Tissue Bank for

Developmental Disorders at the University of Maryland) for their provision of fetal, pediatric and adolescent brain tissue specimens; X. Xiao (Johns Hopkins Bloomberg School of Public

Health) for her technical assistance. This work was supported by funding from the Lieber Institute for Brain Development and the Maltz Research Laboratories, and from a Senior Investigator

grant from the Brain Behavior Research Foundation (J.E.K.). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the US National

Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and the NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick, Inc.

(SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis and

Coordinating Center (LDACC) were funded through a contract (HHSN268201000029C) to the Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel

Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants

DA006227 & DA033684, and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago

(MH090951, MH090937, MH101820, MH101825), the University of North Carolina at Chapel Hill (MH090936 & MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington

University St. Louis (MH101810) and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from dbGaP accession number

phs000424.v6.p1 on October 6, 2015. Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche, Ltd. and

NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and

MH06692. Brain tissue for the study was obtained from the following brain-bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer's

Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: P. Sklar, J. Buxbaum (Icahn School

of Medicine at Mount Sinai), B. Devlin, D. Lewis (University of Pittsburgh), R. Gur, C.-G. Hahn (University of Pennsylvania), K. Hirai, H. Toyoshiba (Takeda Pharmaceuticals Company, Ltd.),

E. Domenici, L. Essioux (F. Hoffman-La Roche, Ltd.), L. Mangravite, M. Peters (Sage Bionetworks), T. Lehner, B. Lipska (NIMH). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Lieber Institute

for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA Ming Li, Andrew E Jaffe, Richard E Straub, Ran Tao, Joo Heon Shin, Yanhong Wang, Qiang Chen, Chao Li, Yankai

Jia, Kazutaka Ohi, Brady J Maher, Joshua G Chenoweth, Daniel J Hoeppner, Huijun Wei, Thomas M Hyde, Ronald McKay, Joel E Kleinman & Daniel R Weinberger * Department of Mental Health,

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA Andrew E Jaffe * Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore,

Maryland, USA Brady J Maher, Thomas M Hyde, Joel E Kleinman & Daniel R Weinberger * Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA Brady J Maher 

& Daniel R Weinberger * AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, Cambridge, Massachusetts, USA Nicholas J Brandon & Alan Cross * Department

of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA Thomas M Hyde & Daniel R Weinberger * McKusick Nathans Institute of Genetic Medicine, Johns Hopkins School of

Medicine, Baltimore, Maryland, USA Daniel R Weinberger Authors * Ming Li View author publications You can also search for this author inPubMed Google Scholar * Andrew E Jaffe View author

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inPubMed Google Scholar CONTRIBUTIONS M.L. and D.R.W. designed the study and interpreted the results. M.L., A.E.J., R.T., J.H.S., C.L., Y.J., K.O. and R.E.S. carried out RNA-seq analysis.

T.M.H. and J.E.K. organized and carried out subject recruitment, phenotype analysis and biological-material collection. M.L., Q.C. and A.E.J. performed genotyping and imputation. M.L.

conducted _in vitro_ functional assays, molecular cloning, cell line experiments, western blot, immunofluorescence and preparation of recombinant proteins, and M.L. and D.R.W. analyzed those

data. M.L., R.T. and C.L. performed RT-qPCR. B.J.M., D.J.H., N.J.B. and A.C. contributed to design and analysis of protein-expression experiments. M.L., Y.W., J.G.C. and R.M. performed the

iPSC experiments. H.W. carried out enzymatic assay analysis. M.L. and D.R.W. drafted the manuscript, and all authors contributed to the final version of the paper. CORRESPONDING AUTHOR

Correspondence to Daniel R Weinberger. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES

Supplementary Figures 1–15 and Supplementary Tables 1–13 (PDF 4154 kb) SUPPLEMENTARY DATASET 1 Demographic characteristics of individuals in RNA-sequencing and the paths to RNA-sequencing

.bam file and expression metrics (CSV 372 kb) SOURCE DATA SOURCE DATA TO FIG. 1 SOURCE DATA TO FIG. 2 SOURCE DATA TO FIG. 3 SOURCE DATA TO FIG. 4 SOURCE DATA TO FIG. 5 RIGHTS AND PERMISSIONS

Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Li, M., Jaffe, A., Straub, R. _et al._ A human-specific _AS3MT_ isoform and _BORCS7_ are molecular risk factors in the 10q24.32

schizophrenia-associated locus. _Nat Med_ 22, 649–656 (2016). https://doi.org/10.1038/nm.4096 Download citation * Received: 08 August 2015 * Accepted: 05 April 2016 * Published: 09 May 2016

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