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

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.

SUBMITTER: Duan J

PROVIDER: S-EPMC4259974 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Duan Jubao J Shi Jianxin J Fiorentino Alessia A Leites Catherine C Chen Xiangning X Moy Winton W Chen Jingchun J Alexandrov Boian S BS Usheva Anny A He Deli D Freda Jessica J O'Brien Niamh L NL McQuillin Andrew A Sanders Alan R AR Gershon Elliot S ES DeLisi Lynn E LE Bishop Alan R AR Gurling Hugh M D HM Pato Michele T MT Levinson Douglas F DF Kendler Kenneth S KS Pato Carlos N CN Gejman Pablo V PV

American journal of human genetics 20141126 6

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 varia ...[more]

PMID: 25434007

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Project description:BACKGROUND:A challenge of understanding the mechanisms underlying cognition including neurodevelopmental and neuropsychiatric disorders is mainly given by the potential severity of cognitive disorders for the quality of life and their prevalence. However, the field has been focused predominantly on protein coding variation until recently. Given the importance of tightly controlled gene expression for normal brain function, the goal of the study was to assess the functional variation including non-coding variation in human genome that is likely to play an important role in cognitive functions. To this end, we organized and utilized available genome-wide datasets from genomic, transcriptomic and association studies into a comprehensive data corpus. We focused on genomic regions that are enriched in regulatory activity-overlapping transcriptional factor binding regions and repurpose our data collection especially for identification of the regulatory SNPs (rSNPs) that showed associations both with allele-specific binding and allele-specific expression. We matched these rSNPs to the nearby and distant targeted genes and then selected the variants that could implicate the etiology of cognitive disorders according to Genome-Wide Association Studies (GWAS). Next, we use DeSeq 2.0 package to test the differences in the expression of the certain targeted genes between the controls and the patients that were diagnosed bipolar affective disorder and schizophrenia. Finally, we assess the potential biological role for identified drivers of cognition using DAVID and GeneMANIA. RESULTS:As a result, we selected fourteen regulatory SNPs locating within the loci, implicated from GWAS for cognitive disorders with six of the variants unreported previously. Grouping of the targeted genes according to biological functions revealed the involvement of processes such as 'posttranscriptional regulation of gene expression', 'neuron differentiation', 'neuron projection development', 'regulation of cell cycle process' and 'protein catabolic processes'. We identified four rSNP-targeted genes that showed differential expression between patient and control groups depending on brain region: NRAS-in schizophrenia cohort, CDC25B, DDX21 and NUCKS1-in bipolar disorder cohort. CONCLUSIONS:Overall, our findings are likely to provide the keys for unraveling the mechanisms that underlie cognitive functions including major depressive disorder, bipolar disorder and schizophrenia etiopathogenesis.

Project description:Genome-wide association studies (GWASs) have reported numerous genetic variations associated with schizophrenia, but knowledge regarding relevant molecular mechanisms is limited. Many genes undergo sophisticated alternative splicing in the brain, and aberrations of this process may contribute to the pathogenesis of schizophrenia. To examine modulated alternative splicing by genetic risk variant of schizophrenia, we performed genome-wide screening to identify schizophrenia risk single nucleotide polymorphisms that were associated with mRNA expression of alternative splicing junctions, especially previously unannotated junctions. Among the 14,465 schizophrenia risk SNPs, 17,107 splicing QTLs (sQTLs) for previously unannotated splicing junctions were identified in two independent brain RNA-Seq datasets (BrainSeq and CommonMind Consortium). Functional predictions using the deep neural network SpliceAI found 7 likely causal risk SNPs, among which a synonymous SNP rs3935873 in DOC2A at 16p11.2 GWAS locus showed the highest score and was significantly associated with elevated mRNA expression of a previously uncharacterized alternatively spliced DOC2AMutant isoform. In vitro minigene assays confirmed the selective regulatory effect of rs3935873 on the expression of DOC2AMutant rather than the wild-type DOC2AFull, suggesting its putatively causal role in the splicing of DOC2A. The SNP rs3935873 was significantly associated with hippocampal volume, and overexpressing DOC2AMutant in the hippocampus lead to multiple schizophrenia-like behavioral phenotypes, including aberrant prepulse inhibition (PPI), which are distinct from the mice overexpressing DOC2AFull. Both DOC2AMutant and DOC2AFull overexpression led to increased number of synapses, whereas DOC2AMutant reduced synaptic vesicle densities and postsynaptic density (PSD) width. Mechanistically, DOC2AMutant had distinct three-dimensional structure compared with DOC2AFull, and specifically-bound proteins were involved in the “regulation of actin cytoskeleton” and “Hippo signaling pathways”. Taken together, this study provides a splicing mechanism for the prominent 16p11.2 locus schizophrenia association, suggesting that sQTL analyses with previously uncharacterized isoforms could provide novel insights into the molecular mechanisms underlying GWAS associations.

Dataset Information

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

Publications

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

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