Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases

Manav Kapoor,Michael J Chao,Bernice Porjesz,Emma C Johnson,Howard J Edenberg,Arpana Agrawal,Gloriia Novikova,Dongbing Lai,John I Nürnberger ,Yunlong Liu,Jacquelyn L Meyers,Tatiana Foroud,Edoardo Marcora,Jessica Schulman,Alison Goate

doi:10.1038/s41467-021-25392-y

Abstract

Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.

Highlights

Collaborative Study on the Genetics of Alcoholism (COGA)*, Tatiana Foroud 3,5, Howard J
While alcohol use disorder (AUD) and problematic alcohol use (PAU) appear to be consistently associated with increased genetic liability for other psychiatric disorders and positively with liability to educational achievement, drinks per week (DPW) is genetically uncorrelated with most psychiatric disorders but correlated negatively with educational achievement and cardio-metabolic disease[10,11,12,13,14]
The large meta-analysis of AUD genome-wide association study (GWAS) summary statistics (N = 48,545 AUD cases and 187,065 controls) from the Million Veterans Program (MVP)[19], the Psychiatric Genetics consortium (PGC-SUD)[12] and the Collaborative Studies on Genetics of Alcoholism (COGA)[20] identified 1157 SNPs (31 independent lead SNPs) within or near 79 genes at 10 independent loci associated with AUD (Supplementary Figs. 1–4)

Summary

Introduction

Collaborative Study on the Genetics of Alcoholism (COGA)*, Tatiana Foroud 3,5, Howard J. Several recent studies have integrated GWAS data with expression QTLs (eQTLs) using co-localization or integration methods to identify causal variants and genes associated with schizophrenia, Alzheimer’s disease, and many other complex disorders[13,15,16,18]. Using multi-tissue chromatin (ROADMAP and ENTEX) data[22], we observed a significant enrichment of promoter-specific epigenetic markers (H3K4me1/me3) in the fetal and the adult (germinal matrix, frontal-cortex) brain (P < 5 × 10−8) (Fig. 2; Supplementary Data 2 and 3) for the SNPs associated with AUD and DPW, respectively.

Results

Conclusion