Prefrontal cortex eQTLs/mQTLs enriched in genetic variants associated with alcohol use disorder and other diseases

Abstract

Aim: This study aimed to investigate the function of genome-wide association study (GWAS)-identified variants associated with alcohol use disorder (AUD)/comorbid psychiatric disorders. Materials & methods: Genome-wide genotype, transcriptome and DNA methylome data were obtained from postmortem prefrontal cortex (PFC) of 48 Caucasians (24 AUD cases/24 controls). Expression/methylation quantitative trait loci (eQTL/mQTL) were identified and their enrichment in GWAS signals for the above disorders were analyzed. Results: PFC cis-eQTLs (923 from cases+controls, 27 from cases and 98 from controls) and cis-mQTLs (9,932 from cases+controls, 264 from cases and 695 from controls) were enriched in GWAS-identified genetic variants for the above disorders. Cis-eQTLs from AUD cases were mapped to morphine addiction-related genes. Conclusion: PFC cis-eQTLs/cis-mQTLs influence gene expression/DNA methylation patterns, thus increasing the disease risk.

Keywords::

• alcohol use disorder
• enrichment analysis
• expression quantitative trait loci
• genome-wide association study
• human prefrontal cortex
• methylation quantitative trait loci

Acknowledgments

The transcriptome and DNA methylome data were generated at the Yale Center for Genome Analysis (YCGA). The authors thank AM Lacobelle and C Robinson from the Psychiatric Genetic Laboratory at the VA Connecticut Healthcare System for helping with the Illumina HumanCoreExome BeadChip assay. The authors are also grateful to the Australian Brain Donor Programs New South Wales Tissue Resource Centre (NSWTRC) for providing alcoholic and control brain tissues for this study. The NSWTRC is supported by the University of Sydney, the National Health and Medical Research Council of Australia and the National Institute on Alcohol Abuse and Alcoholism. We also thank the deceased subjects’ next of kin for providing consent for the studies.

Financial & competing interests disclosure

This work was supported by grants (R01AA025080 [H Zhang] and R21AA023068 [H Zhang]) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. Postmortem brain tissue samples from the NSWTRC (Tissue Transfer Agreement No.: PID0191) – which has ethics approval from the Sydney Local Health Network and The University of Sydney – were de-identified. Deceased subjects’ next of kin provided informed written consent for the studies.

Data sharing statement

The genotype data have been deposited in the NCBI dbGaP database (Accession Number: phs001981.v1.p1). The DNA methylome data have been deposited in the NCBI GEO database (Accession Number: GSE49393). The transcriptome data have been deposited in the NCBI GEO database (Accession Number: GSE49376).

Additional information

Funding

This work was supported by grants (R01AA025080 [H Zhang] and R21AA023068 [H Zhang]) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.