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

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.

[1]  Shalini Oberdoerffer A conserved role for intragenic DNA methylation in alternative pre-mRNA splicing , 2012, Transcription.

[2]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[3]  Simon C. Potter,et al.  Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia , 2013, Nature Genetics.

[4]  M. Daly,et al.  Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis , 2013, The Lancet.

[5]  Qi Xu,et al.  Common variants on 8p12 and 1q24.2 confer risk of schizophrenia , 2011, Nature Genetics.

[6]  Kerang Zhang,et al.  A cis-Phase Interaction Study of Genetic Variants Within the MAOA Gene in Major Depressive Disorder , 2010, Biological Psychiatry.

[7]  Vikram Patel,et al.  No health without mental health , 2007, The Lancet.

[8]  Paul J. Harrison The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications , 2004, Psychopharmacology.

[9]  Thomas W. Mühleisen,et al.  Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe , 2012, Molecular Psychiatry.

[10]  R. Kahn Faculty Opinions recommendation of A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. , 2009 .

[11]  Matthew E Ritchie,et al.  Using the R Package crlmm for Genotyping and Copy Number Estimation. , 2011, Journal of statistical software.

[12]  J. Suvisaari,et al.  Replication of Association Between Working Memory and Reelin, a Potential Modifier Gene in Schizophrenia , 2010, Biological Psychiatry.

[13]  T M Hyde,et al.  Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression , 2014, Molecular Psychiatry.

[14]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[15]  Zhi Xing,et al.  Effects of selenium on the structure and function of recombinant human S-adenosyl-l-methionine dependent arsenic (+3 oxidation state) methyltransferase in E. coli , 2009, JBIC Journal of Biological Inorganic Chemistry.

[16]  E. Bramon,et al.  Altered effect of dopamine transporter 3'UTR VNTR genotype on prefrontal and striatal function in schizophrenia. , 2009, Archives of general psychiatry.

[17]  C. Dieterich,et al.  A coding-independent function of an alternative Ube3a transcript during neuronal development , 2015, Nature Neuroscience.

[18]  Eric D. Wieben,et al.  Human Arsenic Methyltransferase (AS3MT) Pharmacogenetics , 2006, Journal of Biological Chemistry.

[19]  Y. Hsueh,et al.  GSTO and AS3MT genetic polymorphisms and differences in urinary arsenic concentrations among residents in Bangladesh , 2012, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[20]  Paul J. Harrison,et al.  Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706. , 2014, JAMA psychiatry.

[21]  J. Cowden,et al.  AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility. , 2014, Environmental research.

[22]  A. Allan,et al.  The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review , 2014, Current Environmental Health Reports.

[23]  C. Sabatti,et al.  The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins, and role in neurite outgrowth , 2009, Molecular Psychiatry.

[24]  Daniel R. Weinberger,et al.  Neuregulin 1 Transcripts Are Differentially Expressed in Schizophrenia and Regulated by 5′ SNPs Associated With the Disease , 2006 .

[25]  J. B. Simeonsson,et al.  A NovelS-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol* , 2002, The Journal of Biological Chemistry.

[26]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[27]  Daniel R Weinberger,et al.  Mapping DNA methylation across development, genotype, and schizophrenia in the human frontal cortex , 2015, Nature Neuroscience.

[28]  C. Spencer,et al.  Identification of loci associated with schizophrenia by genome-wide association and follow-up , 2008, Nature Genetics.

[29]  T. Agusa,et al.  Individual Variations in Inorganic Arsenic Metabolism Associated with AS3MT Genetic Polymorphisms , 2011, International journal of molecular sciences.

[30]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[31]  Leonardo Collado-Torres,et al.  Developmental regulation of human cortex transcription and its clinical relevance at base resolution , 2014, Nature Neuroscience.

[32]  Latarsha J. Carithers,et al.  The Genotype-Tissue Expression (GTEx) Project. , 2015, Biopreservation and biobanking.

[33]  Jianxin Shi,et al.  Common variants on chromosome 6p22.1 are associated with schizophrenia , 2009, Nature.

[34]  Pall I. Olason,et al.  Common variants conferring risk of schizophrenia , 2009, Nature.

[35]  J. Ioannidis,et al.  Replication validity of genetic association studies , 2001, Nature Genetics.

[36]  Manuel A. R. Ferreira,et al.  Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4 , 2011, Nature Genetics.

[37]  J. Bonifacino,et al.  BORC, a multisubunit complex that regulates lysosome positioning. , 2015, Developmental cell.

[38]  J. Kleinman,et al.  Critical Factors in Gene Expression in Postmortem Human Brain: Focus on Studies in Schizophrenia , 2006, Biological Psychiatry.

[39]  Working Group,et al.  Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ 4 Psychiatric GWAS Consortium Bipolar Disorder , 2012 .

[40]  M. Gill,et al.  Dysbindin (DTNBP1) and the Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1): Main and Epistatic Gene Effects Are Potential Contributors to Schizophrenia Susceptibility , 2008, Biological Psychiatry.

[41]  Anders D. Børglum,et al.  Genome-wide association study identifies five new schizophrenia loci , 2011, Nature Genetics.