Gene-by-Environment (Serotonin Transporter and Childhood Maltreatment) Interaction for Anxiety Sensitivity, an Intermediate Phenotype for Anxiety Disorders
Stein MB, Schork NJ, Gelernter J;
Commented by , 31 May 2007
Aim of the study
Life stress is associated with anxiety and depression, and the impact of this environmental experience is moderated by genotype. Personality constructs such as Anxiety Sensitivity (AS) are also associated with anxiety and depression and may serve as intermediate phenotypes for these clinical disorders.
This study addressed the question of whether a history of maltreatment in childhood (life stress) is moderated by serotonin transporter gene promoter polymorphism (5-HTTLPR) genotype to predict the personality construct AS in adulthood.
Method
College psychology undergraduates (total: n=247; American-Caucasian: n=150) provided a blood sample for genotyping, and completed the Anxiety Sensitivity Index (ASI), Childhood Trauma Questionnaire (CTQ) and the NEO Personality Inventory Revised (NEO-FFI). Using polymerase chain reaction (PCR) amplification, the 5-HTTLPR variant was determined following the diallelic (L-S) and tetra-allelic (La/Lg-Sa/Sg) classifications.
Results
For the American-Caucasian group, CTQ (emotional abuse subscale) and genotype interacted in the prediction of ASI total score (p=0.045) and the ASI physical concerns subscale score (p=0.015), but not the ASI psychological or social concern subscales score.
This interaction indicated that higher (retrospectively recorded) CTQ emotional abuse subscale scores were associated with higher AS in people with the 5-HTTPLR S/S genotype. This relationship held when the CTQ (physical abuse subscale) score was substituted for emotional abuse and when the whole sample (ethnically heterogeneous) group was included in the analysis.
In addition, the results were similar when the tetra-allelic stratification of 5-HTTPLR genotype was used. This interaction seemed to be specific for AS, as neuroticism (measured by the NEO-FFI) was not predicted by the CTQ by genotype interaction.
Dr Hood's and Prof Nutt's comments
Despite the widespread use and clear utility of serotonergic antidepressants in anxiety disorders, surprisingly little is understood about their anxiolytic mechanism of action. Functional neuroimaging (ref. 1) and pharmacological challenge (ref. 2, ref. 3) are active research methodologies exploring this issue.
Over the past few years a functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene has been found to moderate the influence of stressful life events on depressive (ref. 4) and anxiety (ref. 5) symptoms. The serotonin transporter, involved in the uptake of 5-HT at brain synapses, is a logical candidate for examining SSRI-responsive conditions.
The promoter region of this serotonin transporter, known as the 5-HTT gene-Linked Polymorphic Region (5-HTTLPR), has a short ("S") variant that is less transcriptionally efficient than the long ("L") variant (ref. 6). Most recently, (ref. 7) a A/G single nucleotide polymorphism (SNP) within the 5-HTTLPR has been noted, with the G variant of the L allele behaving more like the (less expressing) S allele – thus an "La/Lg-Sa/Sg" (tetra-allelic) classification has also been proposed.
The distribution of 5HTTLPR allelic frequencies is known to differ across ethnicities and by gender (ref. 8, ref. 9).
The psychological construct Anxiety Sensitivity (AS) is predictive of development of panic disorder, anxiety and depression (ref. 10, ref. 11) and also loads upon related biological challenge procedures (ref. 12). The physical concerns component of the AS is known to be heritable (ref. 13). Exploring the link between 5-HTTLPR and AS is the aim of this study.
The results are substantial, viz that the fear of physical sensations component of the AS may be moderated by a 5-HTTLPR genotype x early emotional mistreatment interaction. The authors reasonably proceed to suggest that a serotonergic system (S/S 5-HTTLPR status) may play a significant role in buffering stress, which is in line with some pharmacological challenge data from our group (ref. 14).
Study limitations aside (including the need to generalise beyond psychology undergraduates, and consideration of anxiety disorder status of this group), these results give us another view onto the complex interaction between genes, environment and disorder.
References
1. Nash J, Sargent P, Rabiner E, Hood SD, Argyropoulos SV, Grasby P et al. Altered 5HT1A binding in panic disorder demonstrated by PET scanning. Journal of Psychopharmacoly 2003; 17 (3); A30
2. Bell C, Hood SD, Nutt DJ. Acute tryptophan depletion. Part II: Clinical Effects and Implications. Australian and New Zealand Journal of Psychiatry 2005, 39, 565-574
3. Hood SD, Bell C, Nutt DJ. Acute tryptophan depletion. Part I: Rationale and Methodology. Australian and New Zealand Journal of Psychiatry 2005, 39, 558-564
4.Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301 (5631); 386-389
5.Fox NA, Nichols KE, Henderson HA, Rubin K, Schmidt L, Hamer D, et al. Evidence for a gene-environment interaction in predicting behavioral inhibition in middle childhood. Psychological Science 2005; 16(12); 921-926
6.Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274 (5292); 1527-1531
7.Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL. Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Molecular Psychiatry 2006; 11 (3); 224-226
8.Ng CH, Easteal S, Tan S, Schweitzer I, Ho BK, Aziz S. Serotonin transporter polymorphisms and clinical response to sertraline across ethnicities. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2006;30 (5):953-957. [Epub 2006 Apr 3]
9.Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, et al. Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology 2003; 28 (3); 533-541. [Epub 2002 Aug 29]
10.Schmidt NB, Lerew DR, Jackson RJ. Prospective evaluation of anxiety sensitivity in the pathogenesis of panic: replication and extension. Journal of Abnormal Psychology 1999; 108 (3); 532-537
11.Schmidt NB, Zvolensky MJ, Maner JK. Anxiety sensitivity: prospective prediction of panic attacks and Axis I pathology. Journal of Psychiatric Research 2006; 40 (8); 691-699. [Epub 2006 Sep 7]
12.Schmidt NB, Mallott M. Evaluating anxiety sensitivity and other fundamental sensitivities predicting anxiety symptoms and fearful responding to a biological challenge. Behaviour Research and Therapy 2006; 44 (11); 1681-1688. [Epub 2006 Jan 19]
13.Stein MB, Jang KL, Livesley WJ. Heritability of anxiety sensitivity: a twin study. American Journal of Psychiatry 1999; 156 (2); 246-251
14.SDavies SJ, Hood SD, Argyropoulos SV, Morris K, Bell C, Witchel HJ, et al. Depleting serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders. Journal of Clinical Psychopharmacology 2006; 26 (4); 414-418