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Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings

Abstract

Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. Understanding the genetic architecture of this comorbidity could be improved by focusing on intermediate traits that show positive genetic correlation with the disorders. Thus, we aimed to characterize the shared vs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD) –beyond genetic correlation, and boost discovery for jointly-associated loci. Summary statistics for MOOD (a binary measure of the tendency to report frequent mood swings), AC (number of standard drinks over a typical consumption week) and AUD GWASs (Ns > 200,000) were analyzed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD. To do so, we used a newly established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly associated genomic loci, which were mapped to genes and biological functions. MOOD was highly polygenic (10.4k single nucleotide polymorphisms, SNPs, SD = 2k) compared to AC (4.9k SNPs, SD = 0.6k) and AUD (4.3k SNPs, SD = 2k). The polygenic overlap of MOOD and AC was twice that of MOOD and AUD (98% vs. 49%), with opposite genetic correlation (−0.2 vs. 0.23), as confirmed in independent samples. MOOD&AUD associated SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 jointly associated loci, fifteen were novel for MOOD, AC and AUD. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated partly shared biological underpinnings, yet, clearly distinct functional patterns between MOOD&AC and MOOD&AUD, suggesting new mechanisms for the comorbidity of AUD with mood disorders.

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Fig. 1: Venn diagrams from MiXer analysis.
Fig. 2: Manhattan plot for the conjFDR analysis.

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Acknowledgements

The authors would like to thank all the support personnel from the Norwegian center of excellence for mental disorders (NORMENT) and all the researchers that provided valuable input for the current study. The authors would also like the INTPART program for supporting a post-doc exchange for RI.

Funding

We were funded by the Research Council of Norway (276082, 213837, 223273, 204966/F20, 229129, 249795/F20, 225989, 248778, 249795), the South-Eastern Norway Regional Health Authority (2013-123, 2014-097, 2015-073, 2016-064, 2017-004), Stiftelsen Kristian Gerhard Jebsen (SKGJ-Med-008), The European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC Starting Grant, Grant Agreement No. 802998) and National Institutes of Health (R01MH100351, R01GM104400, NIDA/NCI: U24DA041123). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) (tsd-drift@usit.uio.no). Computations were also performed on resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway. This work used the Extreme Science and Engineering Discovery Environment (XSEDE) including COMET and OASYS resources at the UCSD through allocation TG-IBN200001. The funding source had no role in the conception, the recruitment or the statistical analyses included in the current study. OAA has received speaker’s honorarium from Lundbeck and is a consultant for Healthlytix.

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(CRediT roles) RI, GH, AS, OF and OAA, Conceptualization; AS, Formal analysis; KOC, SD, AMD, TVL, OS and OAA, Funding acquisition; Methodology, AL, OF, SB, WC, CF, AMD, OS, OAA; NK, Project administration; MCH, SD, TVL, Resources; RI, Writing - original draft; AS, BH, GH, OF, OS, OAA, Writing - review & editing. All authors have critically reviewed and approved the manuscript.

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Correspondence to Romain Icick.

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AMD is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board. He is also a member of the Scientific Advisory Board of Healthlytix and receives research funding from General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. The remaining authors declare no competing interests.

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Icick, R., Shadrin, A., Holen, B. et al. Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings. Neuropsychopharmacol. 47, 1883–1891 (2022). https://doi.org/10.1038/s41386-022-01401-6

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