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Letter to the Editor

Association of the rs2242446 Polymorphism in the Norepinephrine Transporter Gene SLC6A2 and Anxious Arousal Symptoms of Posttraumatic Stress Disorder

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To the Editor: Recently, we found that greater norepinephrine transporter (NET) availability in the locus ceruleus of trauma survivors with posttraumatic stress disorder (PTSD) was associated with increased severity of anxious arousal (ie, hypervigilance and exaggerated startle) symptoms, but not any of the other empirically derived symptom clusters that characterize this disorder.1 This finding suggests that greater NET availability in the locus ceruleus may serve a compensatory function of clearing elevated synaptic norepinephrine and maintaining anxious arousal symptoms in persons with PTSD.

A single-nucleotide polymorphism (SNP) found in the promoter region of the NET gene SLC6A2 (solute carrier family 6 [neurotransmitter transporter], member 2) (rs2242446) has been associated with panic disorder.2,3 Given similarities in the clinical presentation of panic disorder and anxious arousal symptoms of PTSD,4 and data linking NET availability in the locus ceruleus to anxious arousal,1 it is reasonable to hypothesize that this SNP might be linked to anxious arousal in trauma survivors. We evaluated this possibility using data from the Detroit Neighborhood Health Study (DNHS), an epidemiologic study of trauma-related psychopathology in a representative sample of predominantly African-American adults from urban Detroit.5

Method. Data were analyzed from 580 participants who completed measures of trauma exposure and PTSD symptoms and had valid data for rs2242446 from blood or saliva samples.5 Although some additional SNPs have been significantly associated with panic disorder in prior studies,2,3 only rs2242446 was genotyped in the DNHS; thus, we focused on this SNP. The DNHS was approved by the University of Michigan Institutional Review Board, and all participants provided written informed consent.

PTSD symptom dimension scores from the PTSD Checklist6 (PCL) were computed by (1) summing item responses to create scale scores for each symptom cluster and (2) counting the number of symptoms endorsed at a moderate or greater level for each symptom cluster. Linear regressions predicting scores on the 5 PTSD symptom dimensions were conducted using PLINK version 1.07,7 with age, sex, and number of traumatic event types entered as covariates; the first 2 principal components from a multidimensional scaling analysis of genome-wide data were additionally included as covariates to adjust for population stratification. The alpha level was set to .01 to reduce the likelihood of type I error when testing associations between number of minor (G) alleles and the different symptom dimensions.

Results. Table 1 shows sample characteristics and results of regression analyses, which revealed that rs2242446 genotype, coded additively as the number of minor (G) alleles, significantly predicted both scale scores and count of anxious arousal symptoms but none of the other symptom clusters or severity or probable diagnosis of PTSD. Participants with 2 G alleles reported the highest level of anxious arousal symptoms (meanscale score = 5.27; meancount = 1.00), followed by those with 1 G allele (meanscale score = 4.74; meancount = 0.81), and those with zero G alleles (meanscale score = 4.58; meancount = 0.73). No significant interactions between rs2242446 genotype and the number of traumatic event types emerged for either anxious arousal outcome, all β values < 0.17, all P values > .01.

Table 1

Click figure to enlarge

Discussion. These results build on our prior finding that greater NET availability in the locus ceruleus is linked to increased anxious arousal1 and previous studies linking SNPs in SLC6A2 to panic disorder2,3 to suggest an independent association between a polymorphism in the promoter region of SLC6A2 (rs2242446) and anxious arousal symptoms of PTSD. The magnitude of this association ranged from small-to-moderate based on the number of risk alleles.8 Given that the SLC6A2 gene encodes for the NET, this polymorphism may affect synthesis of the NET, which in turn modulates anxious arousal symptoms in trauma survivors. This association was especially pronounced for exaggerated startle response, which suggests a role for this SNP in modulating panic-based hyperreactivity4 in trauma survivors. Importantly, that this association was not significant for any other symptom cluster or for total severity or probable diagnosis of PTSD underscores the importance of evaluating how candidate genetic markers for PTSD are linked to symptom clusters that comprise this phenotype.

This study demonstrates the utility of a translational epidemiologic approach to characterizing genetic correlates of psychiatric phenotypes, as it uses the best available, empirically derived information regarding the phenotypic expression of PTSD4 and attempts to link candidate genetic polymorphisms to component aspects of this complex phenotype. Further research will be useful in replicating these results, assessing how other genetic markers may be linked to the phenotypic expression of PTSD, and evaluating the utility of genotyping for risk genes associated with PTSD in personalizing treatment approaches for symptomatic trauma survivors.

References

1. Pietrzak RH, Gallezot JD, Ding YS, et al. Association of posttraumatic stress disorder with reduced in vivo norepinephrine transporter availability in the locus coeruleus. JAMA Psychiatry. 2013;70(11):1199-1205. PubMed doi:10.1001/jamapsychiatry.2013.399

2. Buttenschøn HN, Kristensen AS, Buch HN, et al. The norepinephrine transporter gene is a candidate gene for panic disorder. J Neural Transm. 2011;118(6):969-976. PubMed doi:10.1007/s00702-011-0624-7

3. Lee YJ, Hohoff C, Domschke K, et al. Norepinephrine transporter (NET) promoter and 5– UTR polymorphisms: association analysis in panic disorder. Neurosci Lett. 2005;377(1):40-43. PubMed doi:10.1016/j.neulet.2004.11.063

4. Armour C, Carragher N, Elhai JD. Assessing the fit of the dysphoric arousal model across two nationally representative epidemiological surveys: the Australian NSMHWB and the United States NESARC. J Anxiety Disord. 2013;27(1):109-115. PubMed doi:10.1016/j.janxdis.2012.10.006

5. Uddin M, Aiello AE, Wildman DE, et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc Natl Acad Sci U S A. 2010;107(20):9470-9475. PubMed doi:10.1073/pnas.0910794107

6. Weathers FW, Litz BT, Herman DS, et al. The PTSD Checklist (PCL): reliability, validity, and diagnostic utility. Paper presented at the 9th Annual Conference of the ISTSS; 1993; San Antonio, TX.

7. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-575. PubMed doi:10.1086/519795

8. Chen H, Cohen P, Chen S. How big is a big odds ratio? interpreting the magnitudes of odds ratios in epidemiological studies. Comm Statist Simulation Comput. 2010;39(4):860-864. doi:10.1080/03610911003650383

Robert H. Pietrzak, PhD, MPH

robert.pietrzak@yale.edu

Jennifer A. Sumner, PhD

Allison E. Aiello, PhD

Monica Uddin, PhD

Alexander Neumeister, MD

Guia Guffanti, PhD

Karestan C. Koenen, PhD

Author affiliations: United States Department of Veterans Affairs, National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, and Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut (Dr Pietrzak); Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York (Drs Summer, Guffanti, and Koenen); Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill (Dr Aiello); Center for Molecular Medicine and Genetics, and Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan (Dr Uddin); and Departments of Psychiatry and Radiology, New York University School of Medicine, New York (Dr Neumeister).

Potential conflicts of interest: None reported.

Funding/support: This research was funded by National Institutes of Health grants (R01DA022720, R01DA022720-S1 [PhenX], R01DA022720-S1 [Supplement], and RC1MH088283). Preparation of this report was supported in part by the US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder and a private donation.

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