title: A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder.
abstract: Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.
authors.affiliation: Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA; Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA. Electronic address: jduan@uchicago.edu.
authors.forename: Jubao
authors.initials: J
authors.lastname: Duan
authors.affiliation: Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.affiliation: Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6JJ, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fiorentino
authors.affiliation: Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Leites
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA.
authors.forename: Winton
authors.initials: W
authors.lastname: Moy
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Los Alamos National Laboratory, Los Alamos, NM 87544, USA.
authors.forename: Boian S
authors.initials: BS
authors.lastname: Alexandrov
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anny
authors.initials: A
authors.lastname: Usheva
authors.affiliation: Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA.
authors.forename: Deli
authors.initials: D
authors.lastname: He
authors.affiliation: Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Freda
authors.affiliation: Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6JJ, UK.
authors.forename: Niamh L
authors.initials: NL
authors.lastname: O'Brien
authors.affiliation: Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6JJ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McQuillin
authors.affiliation: Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA; Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Sanders
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Gershon
authors.affiliation: VA Boston Healthcare System, Harvard Medical School, Brockton, MA 02301, USA.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: DeLisi
authors.affiliation: Los Alamos National Laboratory, Los Alamos, NM 87544, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Bishop
authors.affiliation: Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6JJ, UK.
authors.forename: Hugh M D
authors.initials: HM
authors.lastname: Gurling
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Keck School of Medicine at USC, Los Angeles, CA 90033, USA.
authors.forename: Michele T
authors.initials: MT
authors.lastname: Pato
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Levinson
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Keck School of Medicine at USC, Los Angeles, CA 90033, USA.
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Pato
authors.affiliation: Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA; Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Gejman
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001714:Bipolar Disorder / Q000235:genetics*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics*; D005787:Gene Frequency; D017930:Genes, Reporter; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C000595587:MIRN-2682 microRNA, human; C545567:MIRN137 microRNA, human; D035683:MicroRNAs