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VISN 1 New England MIRECC Past Human Neurobiological Research

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Alcohol Dependence Genetics Investigations
Contact: Joel Gelernter, M.D. (Joel.Gelernter@va.gov)

Genetic factors account for more than half of the interindividual differences in risk for alcohol dependence. Previously, we used genetic linkage to identify chromosomal regions likely to contain genes that influence risk for nicotine dependence. Then, we used family-based association methodology to identify a specific risk region, a haplotype that spans two genes, that strongly influences risk for this trait.
Findings: We studied the same chromosomal region, which includes the genes NCAM1, TTC12, ANKK1, and DRD2, and demonstrated that the markers centered on TTC12 and ANKK1 modulate risk for alcohol dependence. These convergent findings for two substance dependence traits will be important for understating comorbidity. The work has been replicated by multiple independent research groups. This work should lead to new understanding of disease mechanism and new treatment strategies. The next step for this project is detailed sequencing analysis of this genetic region in case control samples of alcohol dependent subjects. Presently, we are studying genome-wide association of alcohol dependence in three different populations (two American and one Asian). We have also recently published large meta-analyses documenting effects of variants at alcohol metabolizing enzyme genes on alcohol dependence risk.
Publications: (1) Li, D., Zhao, H., & Gelernter, J. (2012). Further clarification of the contribution of the ADH1C gene to vulnerability of alcoholism and selected liver diseases. Human Genetics, 131(8), 1361-1374; and (2) Li, D., Zhao, H., & Gelernter, J. (2011). Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases. Biological Psychiatry, 70(6), 504-512.

Deep Sequencing of Candidate Gene Regions for Substance Dependence Traits
Contact: Joel Gelernter, M.D. (Joel.Gelernter@va.gov)

As part of an ongoing effort, we are sequencing exonic regions of genes that are either strong physiological candidates, or positional candidates, or that have mapped common variants that influence risk of trait, to identify rare variants that also influence trait. Findings: To date we have published a study showing that rare variants at the CHRNA4 locus (the gene that encodes the α4 nicotinic receptor)are protective with respect to nicotine dependence. This followed a study where we confirmed previous reports of association of common variants at that same locus to nicotine dependence. Additional sequencing studies are presently undergoing peer review.
Publications: (1) Han, S., Yang, B-Z., Kranzler, H.R., Oslin, D., Anton, R., & Gelernter, J. (2011). Association of CHRNA4 polymorphisms with smoking behavior in two populations. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 156B(4), 421-429; and (2) Xie, P., Kranzler, H.R., Krauthammer, M., Cosgrove, K.P., Oslin, D., Anton, R.F., Farrer, L.A., Picciotto, M.R., Krystal, J.H., Zhao, H., & Gelernter, J. (2011). Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence. Biological Psychiatry, 70(6), 528-536.

Gene-by-Environment Studies in Substance Dependence and Related Phenotypes
Contact: Joel Gelernter, M.D. (Joel.Gelernter@va.gov)

In a series of studies, we are using a large collection of well-assessed individuals with substance dependence problems to investigate gene-by-environment (GxE) interaction. We have recently focused on post-traumatic stress disorder (PTSD) as a behavioral outcome. We have studied GxE interaction in two genes with PTSD, SLC6A4 (the serotonin transporter protein) and FKBP5. We replicated the former interaction in a separate sample. We also reported an interaction of the CHRNA5 gene and nicotine dependence. 
Publications: (1) Xie, P., Kranzler, H.R., Poling, J., Stein, M.B., Anton, R.F., Brady, K., Weiss, R.D., Farrer, L., & Gelernter, J. (2009). Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on post-traumatic stress disorder diagnosis in 2 independent populations. Archives of General Psychiatry, 66(11), 1201-1209; (2) Xie, P., Kranzler, H.R., Poling, J., Stein, M.B, Anton, R.F., Farrer, L., & Gelernter, J. (2010). Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology, 35(8), 1684-1692; (3) Xie, P., Kranzler, H.R., Farrer, L., & Gelernter, J. (2012). Serotonin transporter 5-HTTLPR genotype moderates the effects of childhood adversity on post-traumatic stress disorder risk: A replication study. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics, 159B(6), 644-652; and (4) Xie, P., Kranzler, H.R., Zhang, H., Oslin, D., Anton, R.F., Farrer, L.A., & Gelernter, J. (2012). Childhood adversity increases risk for nicotine dependence and interacts with alpha-5 nicotinic acetylcholine receptor genotype specifically in males. Neuropsychopharmacology, 37, 669-676.

Nicotine Dependence Genetics Investigations
Contact: Joel Gelernter, M.D. (Joel.Gelernter@va.gov)

Genetic factors account for more than half of individual differences in risk for nicotine dependence. We used genetic linkage to identify chromosomal regions likely to contain genes that influence risk for nicotine dependence. Then, we used family-based association methodology to identify a specific risk region—a haplotype that spans two genes—that strongly influences risk for this trait.
Findings: We have identified several genes that influence risk for nicotine dependence including a novel and now replicated finding that ANKK1 influences ND risk. This work should lead to the identification of specific genes affecting nicotine dependence and eventually lead to new understanding of disease mechanism and new treatment strategies.

Sensitivity to Intravenous Nicotine: Gender Differences
Contact: Mehmet Sofuoglu, M.D., Ph.D. (Mehmet.Sofuoglu@va.gov)

Nicotine dependence is a serious public health concern. Optimal treatment of nicotine dependence will require greater understanding of the mechanisms that contribute to the maintenance of smoking behaviors. A growing literature indicates sex and menstrual phase differences in responses to nicotine. The aim of this study was to assess sex and menstrual phase influences on a broad range of measures of nicotine response including subjective drug effects, cognition, physiological responses, and symptoms of withdrawal, craving, and affect. Using a well-established intravenous nicotine paradigm and biochemical confirmation of overnight abstinence and menstrual cycle phase, analyses were performed to compare sex (age 18-50 years; 115 male and 45 female) and menstrual cycle phase (29 follicular and 16 luteal) effects.
Findings: Females had diminished subjective drug effects of, but greater physiological responses to, nicotine administration. Luteal-phase females showed diminished subjective drug effects and better cognition relative to follicular-phase women. These findings offer candidate mechanisms through which the luteal phase, wherein progesterone is dominant relative to estradiol, may be protective against vulnerability to smoking.
Publication: Devito, E.E., Herman, A.I., Waters, A.J., Valentine, G.W., & Sofuoglu, M. (2014). Subjective, physiological, and cognitive responses to intravenous nicotine: Effects of sex and menstrual cycle phase. Neuropsychopharmacology, 39(6), 1431-1440.

Sensitivity to Intravenous Nicotine: Genetic Moderators
Contact: Mehmet Sofuoglu, M.D., Ph.D. (Mehmet.Sofuoglu@va.gov)

The catechol-O-methyltransferase (COMT) Val158Met polymorphism may be a risk factor for nicotine addiction. This study examined the influence of the COMT Val158Met polymorphism on subjective, physiological and cognitive effects of intravenous (IV) nicotine use in African Americans (AAs; n=56) and European Americans (EAs; n=68) smokers. Overnight, abstinent smokers received saline followed by 0.5 and 1.0 mg per 70 kg doses of nicotine, administered 30 minutes apart.
Findings: Smokers with valine (Val)/Val genotype, compared with methionine (Met) carriers, had greater negative subjective effects from IV nicotine and had more severe withdrawal severity following overnight abstinence from smoking. Women with Val/Val genotype reported greater difficulty concentrating and irritability than men with Val/Val or Met carrier genotypes. The Val/Val genotype was associated with better performance on the math task and in AA smokers it was associated with greater systolic blood pressure. These results support the rationale of pharmacologically inhibiting COMT to aid with smoking cessation among Val/Val genotype smokers.
Publication: Herman, A.I., Jatlow, P.I., Gelernter, J., Listman, J.B., & Sofuoglu, M. (2013). COMT Val158MET modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers. Pharmacogenomics, 13(6), 490-497.

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Contact

Mehmet Sofuoglu, M.D., Ph.D.
Director
203-937-4809
Mehmet.Sofuoglu@va.gov

Patricia Sweeney, Psy.D., CPRP
Director for Education
781-687-3015
Patricia.Sweeney@va.gov

Richard Carson, LCSW
Administrative Officer
203-932-5711 Ext. 4338
Richard.Carson@va.gov

Ilan Harpaz-Rotem, Ph.D.
Co-Director for MIRECC Fellowship Program
203-932-5711 Ext. 2599
Ilan.Harpaz-Rotem@va.gov

Suzanne Decker, Ph.D.
Co-Director for MIRECC Fellowship Program
203-932-5711 Ext. 7425
Suzanne.Decker@va.gov