Genome-wide analysis reveals genetic overlap between alcohol use behaviors, schizophrenia and bipolar disorder and identifies novel shared risk loci

Addiction. 2021 Sep 2. doi: 10.1111/add.15680. Online ahead of print.

Abstract

Background and aim: Schizophrenia (SCZ) and bipolar disorder (BD) have a high comorbidity of alcohol use disorder (AUD), and both comorbid AUD and excessive alcohol consumption (AC) have been linked to greater illness severity. We aimed to identify genomic loci jointly associated with SCZ, BD, AUD, and AC to gain further insights into their shared genetic architecture.

Design: We analyzed summary data (p-values and z-scores) from genome-wide association studies (GWAS) using conjunctional false discovery rate (conjFDR) analysis, which increases power to discover shared genomic loci. We functionally characterized the identified loci using publicly available biological resources.

Setting: AUD and AC data provided by the Million Veteran Program, derived from the United States Department of Veterans Affairs Healthcare System. SCZ and BD data provided by the Psychiatric Genomics Consortium, based on cohorts from countries in Europe, North America and Australia.

Cases: AUD (34,658 cases, 167,346 controls), AC (n=200,680), SCZ (31,013 cases and 38,918 controls), BD (20,352 cases and 31,358 controls). All participants were of European ancestry.

Measurements: Genomic loci shared between alcohol traits, SCZ and BD at conjFDR <0.05.

Findings: Conditional Q-Q plots showed SNP enrichment for both alcohol traits across different levels of significance with SCZ and BD, and vice versa. Using conjFDR analysis we leveraged this genetic enrichment and identified several loci shared between SCZ and AUD (n=28) and AC (n=24), BD and AUD (n=2) and AC (n=8) at conjFDR <0.05. Among these loci, 24 are novel for AUD, 15 are novel for AC, three are novel for SCZ and one is novel for BD. There was a mixture of same and opposite effect directions among the shared loci.

Conclusions: Alcohol use disorder and alcohol consumption share genomic loci with the psychiatric disorders schizophrenia and bipolar disorder with a mixed pattern of effect directions, indicating a complex genetic relationship between the phenotypes.

Keywords: AUDIT-C; Alcohol consumption; Alcohol use disorder; Bipolar disorder; GWAS; Genetic overlap; Schizophrenia.