S100A10 identified in a genome-wide gene × cannabis dependence interaction analysis of risky sexual behaviours

S100A10 identified in a genome-wide gene × cannabis dependence interaction analysis of risky sexual behaviours

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J Psychiatry Neurosci 2017;42(4):252-261

Renato Polimanti, PhD; Shashwath A. Meda, MSc; Godfrey D. Pearlson, MA, MBBS; Hongyu Zhao, PhD; Richard Sherva, PhD; Lindsay A. Farrer, PhD; Henry R. Kranzler, MD; Joel Gelernter, MD


Background: We conducted a genome-wide gene × environment interaction analysis to identify genetic variants that interact with cannabis dependence (CaD) in influencing risky sexual behaviours (RSB).

Methods: Our sample included cannabis-exposed and sexually experienced African-American and European-American participants. A DSM-IV CaD diagnosis and RSB were evaluated using the SemiStructured Assessment for Drug Dependence and Alcoholism. We analyzed RSBs as a score that takes into account experiences of unprotected sex and multiple sexual partners.

Results: A total of 3350 people participated in our study; 43% had a CaD diagnosis, 56% were African-American and 33% were women. We identified a genome-wide significant locus in African-American participants (S100A10 rs72993629, p = 2.73 × 10–8) and a potential transpopulation signal in women (CLTC rs12944716, p = 5.27 × 10–8). A resting-state fMRI follow-up analysis of S100A10 rs72993629 conducted in an independent cohort showed 2 significant associations: reduced power of the left paracentral lobule in amplitude of low frequency fluctuations (ALFF) analysis (p = 7.8 × 10–3) and reduced power of the right pallidum in fractional ALFF analysis (p = 4.6 × 10–3). The activity of these brain regions is known to be involved in sexual functions and behaviours. The S100A10 result functionally recapitulated our S100B finding observed in our previous genome-wide association study of CaD. The probability of identifying 2 S100 genes in 2 independent genome-wide investigations by chance is approximately 1 in 1.1 million.

Limitations: We were not able to identify any African-American cohort with appropriate sample size, and phenotypic assessment is available to replicate our findings.

Conclusion: The S100A10 and S100B genes, which are located on different chromosomes, encode specialized calcium-binding proteins. These data support a role for calcium homeostasis in individuals with CaD and its induced behaviours.

Submitted Sept. 22, 2016; Revised Dec. 21, 2016; Accepted Feb. 5, 2017; Early-released Apr. 18, 2017

Acknowledgements: This study was supported by National Institutes of Health grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, P50 AA012870, R01 AA016599, RC1 AA019036, the Connecticut and Crescenz Philadelphia VA MIRECCs, and a NARSAD Young Investigator Award (to R. Polimanti) from the Brain & Behavior Research Foundation. The authors appreciate the work in recruitment and assessment provided at Yale University School of Medicine and the APT Foundation, McLean Hospital, the Medical University of South Carolina and the University of Pennsylvania. Genotyping services for a part of our GWAS were provided by the Center for Inherited Disease Research (CIDR) and Yale University Center for Genome Analysis. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). The authors are grateful to Ann Marie Lacobelle and Christa Robinson for their excellent technical assistance, and to the SSADDA interviewers, led by Yari Nunez, who devoted substantial time and effort to phenotype the study sample.

Affiliations: From the Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, Conn., USA (Polimanti, Pearlson, Gelernter); Olin Research Center, Institute of Living/Hartford Hospital, Hartford, Conn., USA (Meda, Pearlson); the Department of Neuroscience, Yale University School of Medicine, New Haven, Conn., USA (Pearlson, Gelernter); the Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Mass., USA (Sherva, Farrer); the Department of Biostatistics, Yale University School of Public Health, New Haven, Conn., USA (Zhao); the Department of Genetics, Yale University School of Medicine, New Haven, Conn., USA (Zhao, Gelernter); the Departments of Neurology, Ophthalmology, Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Mass., USA (Farrer); and the Department of Psychiatry, University of Pennsylvania School of Medicine and VISN 4 MIRECC, Crescenz VAMC, Philadelphia, Pa., USA (Kranzler).

Competing interests: H. Kranzler has been an advisory board member, consultant, or CME speaker for Indivior, Lundbeck, and Otsuka. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Pfizer, and XenoPort. None declared by any other authors.

Contributors: R. Polimanti and J. Gelernter designed the study. S. Meda, G. Pearlson, L. Farrer, H. Kranzler and J. Gelernter acquired the data, which all authors analyzed. R. Polimanti wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.160189

Correspondence to: J. Gelernter, Yale University School of Medicine, Department of Psychiatry, 950 Campbell Ave., West Haven, CT 06516; joel.gelernter@yale.edu