title: DEGS2 polymorphism associated with cognition in schizophrenia is associated with gene expression in brain.
abstract: A genome-wide association study of cognitive deficits in patients with schizophrenia in Japan found association with a missense genetic variant (rs7157599, Asn8Ser) in the delta(4)-desaturase, sphingolipid 2 (DEGS2) gene. A replication analysis using Caucasian samples showed a directionally consistent trend for cognitive association of a proxy single-nucleotide polymorphism (SNP), rs3783332. Although the DEGS2 gene is expressed in human brain, it is unknown how DEGS2 expression varies during human life and whether it is affected by psychiatric disorders and genetic variants. To address these questions, we examined DEGS2 messenger RNA using next-generation sequencing in postmortem dorsolateral prefrontal cortical tissue from a total of 418 Caucasian samples including patients with schizophrenia, bipolar disorder and major depressive disorder. DEGS2 is expressed at very low levels prenatally and increases gradually from birth to adolescence and consistently expressed across adulthood. Rs3783332 genotype was significantly associated with the expression across all subjects (F3,348=10.79, P=1.12 × 10(-)(3)), particularly in control subjects (F1,87=13.14, P=4.86 × 10(-4)). Similar results were found with rs715799 genotype. The carriers of the risk-associated minor allele at both loci showed significantly lower expression compared with subjects homozygous for the non-risk major allele and this was a consistent finding across all diagnostic groups. DEGS2 expression showed no association with diagnostic status after correcting for multiple testing (P>0.05). Our findings demonstrate that a SNP showing genome-wide association study significant association with cognition in schizophrenia is also associated with regulation of DEGS2 expression, implicating a molecular mechanism for the clinical association.
authors: 1] Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA [2] Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: K
authors: K
authors: Ohi
authors: Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors: G
authors: G
authors: Ursini
authors: Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors: M
authors: 0000000281976552
authors: M
authors: Li
authors: Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors: J H
authors: JH
authors: Shin
authors: Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors: T
authors: T
authors: Ye
authors: Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors: Q
authors: Q
authors: Chen
authors: Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors: R
authors: R
authors: Tao
authors: Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors: J E
authors: JE
authors: Kleinman
authors: 1] Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA [2] Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA [3] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: T M
authors: TM
authors: Hyde
authors: 1] Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan [2] Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
authors: R
authors: 0000000259414238
authors: R
authors: Hashimoto
authors: 1] Department of Clinical Genetics, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA [2] Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA [3] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA [4] Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA [5] Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: D R
authors: DR
authors: Weinberger
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D012565:Schizophrenic Psychology; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C000604035:DEGS2 protein, human; D044943:Fatty Acid Desaturases