title: Functional variants in DPYSL2 sequence increase risk of schizophrenia and suggest a link to mTOR signaling.
abstract: Numerous linkage and association studies by our group and others have implicated DPYSL2 at 8p21.2 in schizophrenia. Here we explore DPYSL2 for functional variation that underlies these associations. We sequenced all 14 exons of DPYSL2 as well as 27 conserved noncoding regions at the locus in 137 cases and 151 controls. We identified 120 variants, eight of which we genotyped in an additional 729 cases and 1542 controls. Several were significantly associated with schizophrenia, including a three single-nucleotide polymorphism (SNP) haplotype in the proximal promoter, two SNPs in intron 1, and a polymorphic dinucleotide repeat in the 5'-untranslated region that alters sequences predicted to be involved in translational regulation by mammalian target of rapamycin signaling. The 3-SNP promoter haplotype and the sequence surrounding one of the intron 1 SNPs direct tissue-specific expression in the nervous systems of Zebrafish in a pattern consistent with the two endogenous dpysl2 paralogs. In addition, two SNP haplotypes over the coding exons and 3' end of DPYSL2 showed association with opposing sex-specific risks. These data suggest that these polymorphic, schizophrenia-associated sequences function as regulatory elements for DPYSL2 expression. In transient transfection assays, the high risk allele of the polymorphic dinucleotide repeat diminished reporter expression by 3- to 4-fold. Both the high- and low-risk alleles respond to allosteric mTOR inhibition by rapamycin until, at high drug levels, allelic differences are eliminated. Our results suggest that reduced transcription and mTOR-regulated translation of certain DPYSL2 isoforms increase the risk for schizophrenia.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Xuan
authors.initials: X
authors.lastname: Pham
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Lilei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Burzynski
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: David M
authors.initials: DM
authors.lastname: McGaughey
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Shan
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Paula
authors.initials: P
authors.lastname: Wolyniec
authors.affiliation: Department of Epidemiology, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Margaret D
authors.initials: MD
authors.lastname: Fallin
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Pierce
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McCallion
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Pulver
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
authors.affiliation: Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine and, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 dvalle@jhmi.edu.
authors.forename: David
authors.initials: D
authors.lastname: Valle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005091:Exons; D005260:Female; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013702:Temporal Lobe / Q000378:metabolism; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: CRMP2; RNA translation; brain development; gene regulation; mTOR