A rare functional noncoding variant at the GWAS-Implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder

Duan, Jubao, Shi, Jianxin, Fiorentino, Alessia, Leites, Catherine, Chen, Xiangning, Moy, Winton, Chen, Jingchun, Alexandrov, Boian S., Usheva, Anny, He, Deli, Freda, Jessica, O'Brien, Niamh L., MGS, GPC, McQuillin, Andrew, Sanders, Alan R., Gershon, Elliot S., DeLisi, Lynn E., Bishop, Alan R., Gurling, Hugh M. D., Pato, Michele T., Levinson, Douglas F., Kendler, Kenneth S., Pato, Carlos N., Gejman, Pablo V. and Mowry, Bryan J. (2014) A rare functional noncoding variant at the GWAS-Implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder. American Journal of Human Genetics, 95 6: 744-753. doi:10.1016/j.ajhg.2014.11.001

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Author Duan, Jubao
Shi, Jianxin
Fiorentino, Alessia
Leites, Catherine
Chen, Xiangning
Moy, Winton
Chen, Jingchun
Alexandrov, Boian S.
Usheva, Anny
He, Deli
Freda, Jessica
O'Brien, Niamh L.
MGS
GPC
McQuillin, Andrew
Sanders, Alan R.
Gershon, Elliot S.
DeLisi, Lynn E.
Bishop, Alan R.
Gurling, Hugh M. D.
Pato, Michele T.
Levinson, Douglas F.
Kendler, Kenneth S.
Pato, Carlos N.
Gejman, Pablo V.
Mowry, Bryan J.
Total Author Count Override 375
Title A rare functional noncoding variant at the GWAS-Implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder
Formatted title
A rare functional noncoding variant at the GWAS-Implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2014-12-04
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2014.11.001
Open Access Status
Volume 95
Issue 6
Start page 744
End page 753
Total pages 10
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2015
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2015 Collection
 
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Created: Mon, 16 Feb 2015, 11:31:47 EST by Susan Day on behalf of Queensland Brain Institute