PUBLICATION
Functional Variants in DPYSL2 Sequence Increase Schizophrenia Risk and Suggest a Link to mTOR Signaling
- Authors
- Liu, Y., Pham, X., Zhang, L., Chen, P.L., Burzynski, G., McGaughey, D.M., He, S., McGrath, J.A., Wolyniec, P., Fallin, M.D., Pierce, M.S., McCallion, A.S., Pulver, A.E., Avramopoulos, D., Valle, D.
- ID
- ZDB-PUB-141125-6
- Date
- 2014
- Source
- G3 (Bethesda) 5(1): 61-72 (Journal)
- Registered Authors
- McCallion, Andy
- Keywords
- CRMP2, RNA translation, brain development, gene regulation, mTOR
- MeSH Terms
-
- Adult
- Aged
- Aged, 80 and over
- Animals
- Cells, Cultured
- Cerebral Cortex/cytology
- Exons
- Female
- HEK293 Cells
- Haplotypes
- Humans
- Intercellular Signaling Peptides and Proteins/genetics*
- Male
- Mice
- Middle Aged
- Nerve Tissue Proteins/genetics*
- Polymorphism, Single Nucleotide
- Schizophrenia/genetics*
- Schizophrenia/metabolism
- Sequence Analysis, DNA
- Signal Transduction
- TOR Serine-Threonine Kinases/metabolism*
- Temporal Lobe/metabolism
- White People/genetics
- Young Adult
- PubMed
- 25416705 Full text @ G3 (Bethesda)
Citation
Liu, Y., Pham, X., Zhang, L., Chen, P.L., Burzynski, G., McGaughey, D.M., He, S., McGrath, J.A., Wolyniec, P., Fallin, M.D., Pierce, M.S., McCallion, A.S., Pulver, A.E., Avramopoulos, D., Valle, D. (2014) Functional Variants in DPYSL2 Sequence Increase Schizophrenia Risk and Suggest a Link to mTOR Signaling. G3 (Bethesda). 5(1):61-72.
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 non-coding 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 3-SNP haplotype in the proximal promoter, two SNPs in intron 1, and a polymorphic dinucleotide repeat in the 5'-UTR which alters sequences predicted to be involved in translational regulation by mTOR 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. Additionally, 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 3-4 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping