Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Sep;23(5):1145-1159.
doi: 10.1111/adb.12569. Epub 2017 Oct 30.

Problematic alcohol use associates with sodium channel and clathrin linker 1 (SCLT1) in trauma-exposed populations

Lynn M Almli  1 , Adriana Lori  1 , Jacquelyn L Meyers  2 , Jaemin Shin  3 , Negar Fani  1 , Adam X Maihofer  4   5 , Caroline M Nievergelt  4   5 , Alicia K Smith  1   6 , Kristina B Mercer  7 , Kimberly Kerley  1 , Jennifer M Leveille  1 , Hao Feng  7 , Duna Abu-Amara  8 , Janine D Flory  8   9 , Rachel Yehuda  8   9 , Charles R Marmar  8 , Dewleen G Baker  4   5   10 , Bekh Bradley  1   11 , Karestan C Koenen  12 , Karen N Conneely  7 , Kerry J Ressler  1   13
Affiliations

Problematic alcohol use associates with sodium channel and clathrin linker 1 (SCLT1) in trauma-exposed populations

Lynn M Almli et al. Addict Biol. 2018 Sep.

Abstract

Excessive alcohol use is extremely prevalent in the United States, particularly among trauma-exposed individuals. While several studies have examined genetic influences on alcohol use and related problems, this has not been studied in the context of trauma-exposed populations. We report results from a genome-wide association study of alcohol consumption and associated problems as measured by the alcohol use disorders identification test (AUDIT) in a trauma-exposed cohort. Results indicate a genome-wide significant association between total AUDIT score and rs1433375 [N = 1036, P = 2.61 × 10-8 (dominant model), P = 7.76 × 10-8 (additive model)], an intergenic single-nucleotide polymorphism located 323 kb upstream of the sodium channel and clathrin linker 1 (SCLT1) at 4q28. rs1433375 was also significant in a meta-analysis of two similar, but independent, cohorts (N = 1394, P = 0.0004), the Marine Resiliency Study and Systems Biology PTSD Biomarkers Consortium. Functional analysis indicated that rs1433375 was associated with SCLT1 gene expression and cortical-cerebellar functional connectivity measured via resting state functional magnetic resonance imaging. Together, findings suggest a role for sodium channel regulation and cerebellar functioning in alcohol use behavior. Identifying mechanisms underlying risk for problematic alcohol use in trauma-exposed populations is critical for future treatment and prevention efforts.

Keywords: AUDIT; alcohol consumption; alcohol use disorder; expression QTL; fMRI; genome-wide association study.

PubMed Disclaimer

Conflict of interest statement

FINANCIAL DISCLOSURE

The authors declare no conflict of interest, financial or otherwise.

Figures

Figure 1
Figure 1
Genome-wide association study (GWAS) for problematic alcohol use and behavior in the GTP discovery sample. (a) Manhattan plot of the GWAS for total alcohol use disorders identification test score (N = 1036, rsl433375 P = 7.76 × 10–8, black line is Bonferroni-adjusted threshold for genome-wide significance). (b) Regional plot of single-nucleotide polymorphism (SNP) associations within 500 kb of rsl433375 (purple triangle) on chromosome 4. Several SNPs are ir linkage disequilibrium with the top SNP
Figure 2
Figure 2
Meta-analysis of two independent cohorts extends the findings of association between single-nucleotide polymorphism (SNP) rsl433375 and problematic alcohol use and behavior. Forest plot showing the meta-analysis of SNP rs1433375 with total AUDIT score ir the additional samples (N = 1394, P = 0.0004). Abbreviations: EA, European Americans; AA, African Americans; HNA, Hispanic/Native Americans; SBPBC, Systems Biology PTSD Biomarkers Consortium
Figure 3
Figure 3
Functional analyses of rsl433375 in Grady Trauma Project discovery sample. (a) rsl433375 associates with gene SCLTI as shown by significant differences in SCLTI messenger RNA expression levels ir blood (probe signal intensities, mean + standard error of the mean) between genotypes (N = 330, P = 0.026). (b) Allen Brain Atlas image shows high SCLT1 expression (red dots) in the cerebellum. (c) Effect of genotype on resting state functional connectivity in executive control network using the right seed: the risk group (A-allele carriers, N =15) showed decreased fronto-cerebellar connectivity relative to the resilient group (GG genotype, N = 52), between the left cerebellum crus region and a cluster in the left ventrolateral prefrontal cortex (Brodmann area 44, BA 44)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Agrawal A, Grant JD, Littlefield A, Waldron M, Pergadia ML, Lynskey MT, Madden PA, Todorov A, Trull T, Bucholz KK, Todd RD, Sher K, Heath AC (2009) Developing a quantitative measure of alcohol consumption for genomic studies on prospective cohorts. J Stud Alcohol Drugs 70:157–168. - PMC - PubMed
    1. Agrawal A, Wetherill L, Bucholz KK, Kramer J, Kuperman S, Lynskey MT, Nürnberger JI Jr, Schuckit M, Tischfield JA, Edenberg HJ, Foroud T, Bierut LJ (2013) Genetic influences on craving for alcohol. Addict Behav 38:1501–1508. - PMC - PubMed
    1. Allen JP, Crawford EF, Kudler H (2016) Nature and treatment of comorbid alcohol problems and post traumatic stress disorder among American military personnel and veterans. Alcohol Res 38:133–140. - PMC - PubMed
    1. Almli LM, Mercer KB, Kerley K, Feng H, Bradley B, Conneely KN, Ressler KJ (2013) ADCYAP1R1 genotype associates with posttraumatic stress symptoms in highly traumatized African-American females. Am J Med Genet B Neuropsychiatr Genet 162B:262–272. - PMC - PubMed
    1. Andersen BB (2004) Reduction of Purkinje cell volume in cerebellum of alcoholics. Brain Res 1007:10–18. - PubMed

Publication types

MeSH terms