NIAAA Postmortem Prefrontal Cortex eQTL and mQTL Study

Mapping expression and methylation quantitative trait loci (eQTLs and mQTLs) using genome-wide genotype, transcriptome, and DNA methylome data can provide an unbiased approach to identify novel functional variants. One critical issue of the eQTL/mQTL analysis is that the role of genetic variants in regulating gene expression (or DNA methylation) can be tissue- or cell-specific. To unravel causal variants from disease-associated loci, it would be necessary to map eQTLs and mQTLs in both patients and controls. Those eQTLs and mQTLs in patients are more likely to be causal variants for the disease. Identification of disease- and tissue-specific eQTLs and mQTLs will help disentangle the role of the specific tissue in disease development as well. In the present study, we mapped eQTLs and mQTLs in postmortem prefrontal cortex of patients with alcoholism or alcohol use disorder (AUD) and matched control subjects by integrative analyses of genome-wide SNP genotype, mRNA transcriptome, and DNA methylome data. As AUD is comorbid with schizophrenia (SCZ), bipolar disorder (BIP), major depressive disorder (MDD), and attention deficit/hyperactivity disorder (ADHD), we further examined the co-localization of PFC eQTLs/mQTLs and GWAS-identified SNPs (mainly noncoding SNPs) that were associated with AUD as well as comorbid SCZ, BIP, MDD, and ADHD. Our study demonstrated the enrichment of PFC eQTLs/mQTLs in the above psychiatric disorder-associated genetic variants identified by genome-wide association studies (GWAS).]]>
Half of the subjects (16 males and 8 females) were diagnosed with alcoholism [alcohol abuse (n = 15) or dependence (n = 9)], but they did not use illegal drugs of abuse or were not diagnosed with major psychotic disorders (such as schizophrenia and bipolar disorder), according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV). The other half of the subjects (16 males and 8 females) were sex- and age-matched healthy controls, who were free of alcohol or drug abuse or dependence or major psychotic disorders.]]>
In 2011, postmortem prefrontal cortex (PFC) tissue samples (n = 48) were obtained from the New South Wales Tissue Resource Centre (NSW TRC) at the University of Sydney after the Tissue Transfer Agreement was approved. In 2012, PFC mRNA transcriptomes of 46 subjects were profiled using the Illumina HumanHT-12 v4 Expression BeadChip. The transcriptome data has been deposited in the NCBI GEO database (Accession Number: GSE49376). In 2012, the genome-wide DNA methylation (or DNA methylome) was profiled using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, CA, USA), following the Illumina Infinium HD Methylation protocol. The DNA methylome data has been deposited in the NCBI GEO database (Accession Number: GSE49393). In 2013, 48 DNA samples were genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip (Illumina, San Diego, CA, USA) following the Illumina Infinium HD Array Super, Manual Protocol. ]]>