title: A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus.
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 confers risk for psychiatric illness.
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Ming
authors.identifier: 0000-0002-8197-6552
authors.initials: M
authors.lastname: Li
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.|Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Andrew E
authors.identifier: 0000-0001-6886-1454
authors.initials: AE
authors.lastname: Jaffe
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Straub
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Joo Heon
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Chao
authors.identifier: 0000-0002-2147-6281
authors.initials: C
authors.lastname: Li
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ohi
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Brady J
authors.initials: BJ
authors.lastname: Maher
authors.affiliation: AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, Cambridge, Massachusetts, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, Cambridge, Massachusetts, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Cross
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Chenoweth
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Daniel J
authors.identifier: 0000-0002-0886-5215
authors.initials: DJ
authors.lastname: Hoeppner
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Huijun
authors.initials: H
authors.lastname: Wei
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: McKay
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American; D000483:Alleles; D001253:Astrocytes / Q000378:metabolism*; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D003598:Cytoskeletal Proteins; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D018598:Minisatellite Repeats; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics*; D044465:White People; D055815:Young Adult
chemical_list: C000619378:BORCS7 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D008780:Methyltransferases; C505756:AS3MT protein, human