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Long tracks of homozygosity predict the severity of alcohol use disorders in an American Indian population

Molecular Psychiatry volume 26, pages 2200–2211 (2021)Cite this article

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Abstract

Runs of homozygosity (ROH) arise when an individual inherits two copies of the same haplotype segment. While ROH are ubiquitous across human populations, Native populations—with shared parental ancestry arising from isolation and endogamy—can carry a substantial enrichment for ROH. We have been investigating genetic and environmental risk factors for alcohol use disorders (AUD) in a group of American Indians (AI) who have higher rates of AUD than the general U. S. population. Here we explore whether ROH might be associated with incidence and severity of AUD in this admixed AI population (n = 742) that live on geographically contiguous reservations, using low-coverage whole genome sequences. We have found that the genomic regions in the ROH that were identified in this population had significantly elevated American Indian heritage compared with the rest of the genome. Increased ROH abundance and ROH burden are likely risk factors for AUD severity in this AI population, especially in those diagnosed with severe and moderate AUD. The association between ROH and AUD was mostly driven by ROH of moderate lengths between 1 and 2 Mb. An ROH island on chromosome 1p32.3 and a rare ROH pool on chromosome 3p12.3 were found to be significantly associated with AUD severity. They contain genes involved in lipid metabolism, oxidative stress and inflammatory responses; and OSBPL9 was found to reside on the consensus part of the ROH island. These data demonstrate that ROH are associated with risk for AUD severity in this AI population.

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Fig. 1: ROH distribution on chromosome 1 in the American Indian population.
Fig. 2: Relationships between ROH and American Indian ancestry.
Fig. 3: Two subgroups were identified by the unsupervised clustering analysis with respect to the relationships between AUD severity and FROH.
Fig. 4: Associations between ROH pools and AUD severity.

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Data and code availability

In accordance with the wishes of the tribes no sharing of the AI data are possible. All analysis codes were written in R and are available upon requests.

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Acknowledgements

We would like to acknowledge and thank all of our American Indian participants, and the following people for their roles in (1) the genotyping effort: Kirk Wilhelmsen, Scott Chasse, Piotr Mieczkowski, Ewa Patrycja Malc, Joshua Sailsbery, Phil Owens, and Chris Bizon; and (2) recruiting participants, and collection and preparation of the clinical data: David Gilder, Corinne Kim, Evie Phillips, Phillip Lau, and Derek Wills. This work was supported by the National Institutes of Health (NIH): National Institute on Alcohol Abuse and Alcoholism (NIAAA) K25 AA025095 to QP; NIAAA R01 AA027316 to CLE; National Institute on Drug Abuse (NIDA) R01 DA030976 to CLE. NIAAA and NIDA had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

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  1. Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Qian Peng & Cindy L. Ehlers

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Peng, Q., Ehlers, C.L. Long tracks of homozygosity predict the severity of alcohol use disorders in an American Indian population. Mol Psychiatry 26, 2200–2211 (2021). https://doi.org/10.1038/s41380-020-00989-9

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