Symposium fredag d. 18. november 2011; Auditorium 61A, RH

Tekst og foto: Anders Gade

Avshalom Caspi, Lars Kessing, & Terrie Moffitt

Avshalom Caspi
Gene x environment in depression: evidence and perspectives

Avshalom Caspi og Terrie Moffitts 2003 Science-artikel om sammenhængen mellem 5-HTTLPR-polymorfien og stress (og opvækstvilkår) for udvikling af depression har været enormt betydningsfuld og omdiskuteret. Den grundlæggende figur er vist til højre, og Caspi startede også sit foredrag med et sådant billede.

Figur. Stress, genetik og depression. Sammenhæng mellem stressende livsbegivenheder og depression som funktion af 5-HTT polymorfien. Foroven er vist sandsynligheden for en depressionsperiode inden for det sidste år; forneden sandsynligheden for selvmordsforsøg eller tanker om selvmord. S/s: to kopier af s-allelen; l/l: to kopier af l-allelen; s/l: én af hver.

Efter data fra Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H. et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386-389.

Terrie Moffitt
The effects of stressful life events and a traumatic childhood in genetically vulnerable individuals

Vibe Frøkjær
What can we learn about vulnerability from PET-studies?

After a coffee break: Panel discussion with two local 'opponents': Jens Bukh & Maj Vinberg

Jens Bukh

Bukh, J. D., Bock, C., Vinberg, M., Werge, T., Gether, U., & Vedel, K. L. (2009). Interaction between genetic polymorphisms and stressful life events in first episode depression. Journal of Affective Disorders, 119, 107-115.

BACKGROUND: A polymorphism in the serotonin transporter (5-HTT) gene seems to moderate the influence of stressful life events on depression. However, the results from previous studies of gene-environment interactions in depression are inconsistent and might be confounded by the history of depression among participants. METHOD: We applied a case-only design, including 290 ethnically homogeneous patients suffering exclusively from first episode depression. Psychiatric mo-morbidity, personality traits and disorders and stressful life events in a six months period preceding onset of depression were evaluated by means of interviews and questionnaires. Additionally, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophane hydroxylase, and the serotonin receptors 1A, 2A, and 2C. RESULTS: The low activity variants of the 5-HTT-linked polymorphic region in the serotonin transporter gene and the Met-allele of a single nucleotide polymorphism (Val66Met) in the gene encoding brain derived neurotrophic factor were independently associated with the presence of stressful life events prior to onset of depression, also when corrected for the effect of age, gender, marital status, personality disorder, neuroticism, and severity of depressive symptoms at the time of interview. CONCLUSION: Polymorphisms in the genes encoding the serotonin transporter and the brain derived neurotrophic factor interact with recent stressful life events on depression among patients with no history of previous depressive episodes Department of Psychiatry, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark. jens.bukh@rh.regionh.dk

Maj Vinberg

Maj and Jens raised a number of questions for discussion:
1) The 'lemming effect': By now more than 50 studies in adults and 20 in children have been conducted trying to replicate the 2003 landmark study by Caspi et al.
2) The heterogeneity of depression as a phenotype which may mean that future studies should look at continua or spectrum disorders
3) The question of whether the presence of recurrent episodes of depression may be relevant for the interaction of stress / childhood adversity and genes in predicting depression
This last question has in fact been addressed by the research group:

Uher, R., Caspi, A., Houts, R., Sugden, K., Williams, B., Poulton, R. et al. (2011). Serotonin transporter gene moderates childhood maltreatment's effects on persistent but not single-episode depression: Replications and implications for resolving inconsistent results. Journal of Affective Disorders.

Terrie Moffitt

Abstract: BACKGROUND: Genetic and environmental factors shape life-long vulnerability to depression, but most gene-environment interaction (GxE) research has focused on cross-sectional assessments rather than life-course phenotypes. This study tests the hypothesis that the GxE involving the length polymorphism in the serotonin-transporter-gene-linked-promoter-region (5-HTTLPR) and childhood maltreatment is specific to depression that runs a persistent course in adulthood. METHODS: The hypothesis is tested in two cohorts. Men and women in the Dunedin Study (N=847), New Zealand, followed to age 32years with 96% retention and women in the E-Risk Study (N=930), England, followed to age 40years with 96% retention. Diagnoses of past-year major depressive episode were established at four separate assessments. Depression diagnosed on two or more occasions was considered persistent. RESULTS: In both cohorts, statistical tests of gene-environment interactions showed positive results for persistent depression but not single-episode depression. Individuals with two short 5-HTTLPR alleles and childhood maltreatment had elevated risk of persistent but not single-episode depression. LIMITATIONS: Some cases of recurrent depression may have been misclassified as single-episode due to non-contiguous assessment windows, but this would have a conservative effect on the findings. Chronic and recurrent depression could not be reliably distinguished due to non-contiguous periods of assessment. Therefore, the term persistent depression is used to describe either chronic or recurrent course. CONCLUSIONS: The specific effect on persistent depression increases the significance of this GxE for public health. Research that does not distinguish persistent course may underestimate GxE effects and account for some replication failures in GxE research.

One of the things discussed and also stressed by Avshalom Caspi in his presentation was the extension of the gene-environment research into neurobiological mechanisms of depression and vulnerability.

Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E. (2010). Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. American Journal of Psychiatry, 167, 509-527.

He pointed, for an overview of this, to his 201o review paper in the American Journal of Psychiatry.

Avshalom Caspi

Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science.

Department of Psychology, and Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA. ac115@duke.edu

Avshalom Caspi og Terrie Moffitt har i usædvanlig grad haft evne og mulighed for at belyse væsentlige psykologiske problemstillinger med data fra store prospektive kohorte-undersøgelser. Mødet i København i november 2011 handlede om depression, men de har ydet banebrydende bidrag på mange andre områder. Her er nogle få af dem. De er udvalgt efter mine subjektive kriterier og er dem, som jeg har omtalt i undervisning og artikler.

Caspi, A., McClay, J., Moffitt, T. E., Mill, J., Martin, J., Craig, I. W. et al. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851-854.

Kuntsi, J., Eley, T. C., Taylor, A., Hughes, C., Asherson, P., Caspi, A. et al. (2004). Co-occurrence of ADHD and low IQ has genetic origins. American Journal of Medical Genetics, 124B, 41-47.

Caspi, A., Moffitt, T. E., Cannon, M., McClay, J., Murray, R., Harrington, H. et al. (2005). Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biological Psychiatry, 57, 1117-1127.

Moffitt, T. E., Caspi, A., Harrington, H., Milne, B. J., Melchior, M., Goldberg, D. et al. (2007). Generalized anxiety disorder and depression: childhood risk factors in a birth cohort followed to age 32. Psychological Medicine, 37, 441-452.

Moffitt, T. E., Harrington, H., Caspi, A., Kim-Cohen, J., Goldberg, D., Gregory, A. M. et al. (2007). Depression and generalized anxiety disorder: cumulative and sequential comorbidity in a birth cohort followed prospectively to age 32 years. Archives of General Psychiatry, 64, 651-660.

Koenen, K. C., Moffitt, T. E., Caspi, A., Gregory, A., Harrington, H., & Poulton, R. (2008). The developmental mental-disorder histories of adults with posttraumatic stress disorder: a prospective longitudinal birth cohort study. Journal of Abnormal Psychology, 117, 460-466.

Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E. (2010). Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. American Journal of Psychiatry, 167, 509-527.

Reichenberg, A., Caspi, A., Harrington, H., Houts, R., Keefe, R. S., Murray, R. M. et al. (2010). Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study. American Journal of Psychiatry, 167, 160-169.

Moffitt, T. E., Arseneault, L., Belsky, D., Dickson, N., Hancox, R. J., Harrington, H. et al. (2011). A gradient of childhood self-control predicts health, wealth, and public safety. Proceedings of the National Academy of Sciences of the United States of America, 108, 2693-2698.