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A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus

Nature Medicine volume 22, pages 649–656 (2016)Cite this article

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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 (AS3MTd2d3), which lacks arsenite methyltransferase activity and is more abundant in individuals with schizophrenia than in controls. Conditional-expression analysis suggests that BORCS7 and AS3MTd2d3 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 AS3MTd2d3 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 AS3MTd2d3 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 confers risk for psychiatric illness.

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Figure 1: eQTL analysis of the 10q24.32 locus SNP rs7085104 and identification of a VNTR in AS3MT.
Figure 2: Characterizations of AS3MT isoforms.
Figure 3: Risk genotype and diagnosis predict AS3MTd2d3 expression.
Figure 4: The VNTR, AS3MTd2d3 expression and AS3MT methylation.
Figure 5: AS3MTd2d3 isoform and BORCS7 expression are induced during human pluripotent stem cell neural specification (a–c).

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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).

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Authors and Affiliations

  1. 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

  2. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

    Andrew E Jaffe

  3. 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

  4. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Brady J Maher & Daniel R Weinberger

  5. AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, Cambridge, Massachusetts, USA

    Nicholas J Brandon & Alan Cross

  6. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Thomas M Hyde & Daniel R Weinberger

  7. McKusick Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Daniel R Weinberger

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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.

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Correspondence to Daniel R Weinberger.

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Supplementary information

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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)

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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

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