Expression quantitative trait loci (eQTLs) in microRNA genes are enriched for schizophrenia and bipolar disorder association signals

Abstract

Background Schizophrenia (SZ) and bipolar disorder (BD) have substantial negative impact on the quality of human life. Both, microRNA (miRNA) expression profiling in SZ and BD postmortem brains [and genome-wide association studies (GWAS)] have implicated miRNAs in disease etiology. Here, we aim to determine whether significant GWAS signals observed in the Psychiatric Genetic Consortium (PGC) are enriched for miRNAs. Method A two-stage approach was used to determine whether association signals from PGC affect miRNAs: (i) statistical assessment of enrichment using a Simes test and sum of squares test (SST) and (ii) biological evidence that quantitative trait loci (eQTL) mapping to known miRNA genes affect their expression in an independent sample of 78 postmortem brains from the Stanley Medical Research Institute. Results A total of 2567 independent single nucleotide polymorphisms (SNPs) (R2 > 0.8) were mapped locally, within 1 Mb, to all known miRNAs (miRBase v. 21). We show robust enrichment for SZ- and BD-related SNPs with miRNAs using Simes (SZ: p ≤ 0.0023, BD: p ≤ 0.038), which remained significant after adjusting for background inflation in SZ (empirical p = 0.018) and approached significance in BD (empirical p = 0.07). At a false discovery rate of 10%, we identified a total of 32 eQTLs to influence miRNA expression; 11 of these overlapped with BD. Conclusions Our approach of integrating PGC findings with eQTL results can be used to generate specific hypotheses regarding the role of miRNAs in SZ and BD.

A polymorphism in miR‐1262 regulatory region confers the risk of lung cancer in Chinese population

“…Genetic variants in miRNA regulome may affect miRNA transcription and regulation of targeted genes, and finally contribute to the development of complex traits and diseases. Some GWAS‐based studies have comprehensively investigated the associations of single nucleotide polymorphisms (SNPs) in miRNA regulome with human traits and diseases . Bulik‐Sullivan et al .…”

“…Williamson et al . revealed that SNPs associated with miRNA expression were enriched in the significant GWAS signals of some special diseases …”

“…Some GWAS-based studies have comprehensively investigated the associations of single nucleotide polymorphisms (SNPs) in miRNA regulome with human traits and diseases. [17][18][19][20][21] Bulik-Sullivan et al systematically cataloged trait/disease-associated SNPs in miRNA promoter regions and identified a variant in the promoter of the miRNA let-7 linked with human height variation. 17 Williamson et al revealed that SNPs associated with miRNA expression were enriched in the significant GWAS signals of some special diseases.…”

“…17 Williamson et al revealed that SNPs associated with miRNA expression were enriched in the significant GWAS signals of some special diseases. 20 Recently, large-scale efforts such as the Encyclopedia of DNA Elements (ENCODE) have made available data for identifying functional non-coding elements in human genome. For example, the histone markers H3K4me3 and H3K4me1 represent the active promoter and enhancer element, respectively.…”

From Linkage Studies to Epigenetics: What We Know and What We Need to Know in the Neurobiology of Schizophrenia

“…So, a statistical and computational approach correlates data from genetic patterns of all markers with the expression of all measured genes (Michaelson et al, 2009 ). With regard to schizophrenia, this approach allowed to find several new risk loci in blood samples (3p21 and 10q24 and SNPs in two calcium-channels subunits genes; Cross-Disorder Group of the Psychiatric Genomics, 2013 ) and also was recently used to evaluate the potential role of microRNA in its etiology (Williamson et al, 2015 ) or the genetic pleiotropy between immune and psychiatric disorders (Andreassen et al, 2015 ; Wang Q. et al, 2015 ).…”