Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Meta-Analysis of Transcriptome-Wide Association Studies Across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction

Version 1 : Received: 20 November 2021 / Approved: 22 November 2021 / Online: 22 November 2021 (11:46:13 CET)

A peer-reviewed article of this Preprint also exists.

Ye, Z.; Mo, C.; Ke, H.; Yan, Q.; Chen, C.; Kochunov, P.; Hong, L.E.; Mitchell, B.D.; Chen, S.; Ma, T. Meta-Analysis of Transcriptome-Wide Association Studies across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction. Genes 2022, 13, 37. Ye, Z.; Mo, C.; Ke, H.; Yan, Q.; Chen, C.; Kochunov, P.; Hong, L.E.; Mitchell, B.D.; Chen, S.; Ma, T. Meta-Analysis of Transcriptome-Wide Association Studies across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction. Genes 2022, 13, 37.

Journal reference: Genes 2021, 13, 37
DOI: 10.3390/genes13010037

Abstract

Genome-wide association studies (GWAS) have identified and reproduced thousands of diseases associated loci but many of them are not directly interpretable due to the strong linkage disequilibrium among variants. Transcriptome-wide association studies (TWAS) incorporated expression quantitative trait loci (eQTL) cohorts as reference panel to detect associations with the phenotype at the gene level and were gaining popularity in recent years. For nicotine addiction, several important susceptible genetic variants were identified by GWAS, but TWAS that detected genes associated with nicotine addiction and unveiled the underlying molecular mechanism were still lacking. In this study, we used eQTL data from the Genotype-Tissue Expression (GTEx) consortium as reference panel to conduct tissue specific TWAS on cigarettes per day (CPD) over 13 brain tissues in two large cohorts: UK Biobank (UKBB; N=142,202) and the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN; N=143,210), and then meta-analyzed the results across tissues while considering the heterogeneity across tissues. We identified three major clusters of genes with different meta-patterns across tissues consistent in both cohorts, including homogenous genes associated with CPD in all brain tissues, partially homogeneous genes associated with CPD in cortex, cerebellum and hippocampus tissues, and lastly the tissue-specific genes associated with CPD in only few specific brain tissues. Downstream enrichment analyses on each gene cluster identified unique biological pathways associated with CPD and provided important biological insights into the regulatory mechanism of nicotine dependence in the brain.

Keywords

genome-wide association study; transcriptome-wide association study; meta-analysis; expression quantitative trait loci; nicotine addiction

Subject

LIFE SCIENCES, Genetics

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