title: Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex.
abstract: MicroRNAs (miRNAs) are small non-coding RNAs that act as potent regulators of gene expression. A recent GWAS reported the rs1625579 SNP, located downstream of miR-137, as the strongest new association with schizophrenia [Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:969-76.]. Prior to this GWAS finding, a schizophrenia imaging-genetic study found miR-137 target genes significantly enriched for association with activation in the dorsolateral prefrontal cortex (DLPFC) [Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, et al. Identifying gene regulatory networks in schizophrenia. Neuroimage 2010;53:839-47.]. We investigated the expression levels of miR-137 and three candidate target genes (ZNF804A, CACNA1C, TCF4) in the DLPFC of postmortem brain tissue from 2 independent cohorts: (1) 26 subjects (10 control (CTR), 7 schizophrenia (SZ), 9 bipolar disorder (BD)) collected at the UCI brain bank; and (2) 99 subjects (33 CTR, 35 SZ, 31 BD) obtained from the Stanley Medical Research Institute (SMRI). MiR-137 expression in the DLPFC did not differ between diagnoses. We also explored the relationship between rs1625579 genotypes and miR-137 expression. Significantly lower miR-137 expression levels were observed in the homozygous TT subjects compared to TG and GG subjects in the control group (30% decrease, p-value = 0.03). Moreover, reduced miR-137 levels in TT subjects corresponded to increased levels of the miR-137 target gene TCF4. The miR-137 expression pattern in 9 brain regions was significant for regional effect (ANOVA p-value = 1.83E-12), with amygdala and hippocampus having the highest miR-137 expression level. In conclusion, decreased miR-137 expression is associated with the SZ risk allele of rs1625579, and potential regulation of TCF4, another SZ candidate gene. This study offers additional support for involvement of miR-137 and downstream targets as mechanisms of risk for psychiatric disorders.
authors.affiliation: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guella
authors.forename: Adolfo
authors.initials: A
authors.lastname: Sequeira
authors.forename: Brandi
authors.initials: B
authors.lastname: Rollins
authors.forename: Linda
authors.initials: L
authors.lastname: Morgan
authors.forename: Federica
authors.initials: F
authors.lastname: Torri
authors.forename: Theo G M
authors.initials: TG
authors.lastname: van Erp
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.forename: Jack David
authors.initials: JD
authors.lastname: Barchas
authors.forename: Alan F
authors.initials: AF
authors.lastname: Schatzberg
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watson
authors.forename: Huda
authors.initials: H
authors.lastname: Akil
authors.forename: William E
authors.initials: WE
authors.lastname: Bunney
authors.forename: Steven G
authors.initials: SG
authors.lastname: Potkin
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
authors.forename: Marquis P
authors.initials: MP
authors.lastname: Vawter
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000378:metabolism*; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020864:Calcium Channels, N-Type
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015220:Calcium Channels; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D012333:RNA, Messenger; D000073940:Transcription Factor 4; D014157:Transcription Factors; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C545567:MIRN137 microRNA, human; C532096:TCF4 protein, human; C540527:ZNF804A protein, human
keywords: Bipolar disorder; Gene expression; Schizophrenia; TCF4; miR-137; rs1625579