The DOI matches its Crossref record; 68 of the 69 references it cites were found in a registry or an index.
Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis
Open accessAbstract
CONTEXT: Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression. OBJECTIVE: To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. DATA SOURCES: Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis. STUDY SELECTION: Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data. DATA EXTRACTION: Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression. RESULTS: In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data. CONCLUSION: This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“a recent meta-analysis by Risch et al. (2009) examined GxE between stressful life events and 5-HTTLPR on depression using 14 studies (N=14,250). Just under half of the included studies focused on the effects of ELS. The authors concluded that there was no support for an interaction effect”
From Gene–environment interactions: early life stress and risk for depressive and anxiety disorders (2011) · cites this paper as Risch et al. (2009)
In the citing paper
“This association did not replicate in an independent but similar study from the same geographic region, casting particular doubt on the reported association. 115”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [115]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120
The Future of Genetic Studies of Complex Human Diseases
Risch, N., & Merikangas, K. (1996) · Science · doi:10.1126/science.273.5281.1516 · Cited by 5,355 · cited 1×
“Strengths of the analysis reported herein include: (1) use of the same variable definitions (ie, the number of S alleles and an ordinal measure of life events) and analytic approach that was used in the original report in order to provide a valid test of replication; (2) inclusion of primary data from numerous studies…”
MethodSelf-citationRole of genotype in the cycle of violence in maltreated children
Caspi, A., McClay, J., Moffitt, T. E., Mill, J., Martin, J., Craig, I. W., Taylor, A., & Poulton, R. (2002) · Science · doi:10.1126/science.1072290 · Cited by 4,842 · cited 5×
“Surtees et al,25 2006 4175 (1950) 60 (41-80) 33 49 18 Crosssectional No List of Threatening Eventsb Major depression (DSM-IV) Failed to replicate”
BackgroundInfluentialDean, M. C., Carrington, M. N., Winkler, C. A., Huttley, G. A., Smith, M. W., Allikmets, R. L., Goedert, J. J., Buchbinder, S., Vittinghoff, E., Gomperts, E. D., et al. (1996) · Science · doi:10.1126/science.273.5283.1856 · Cited by 2,503 · cited 5×
“Surtees et al,25 2006 4175 (1950) 60 (41-80) 33 49 18 Crosssectional No List of Threatening Eventsb Major depression (DSM-IV) Failed to replicate”
BackgroundInfluentialLohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S., & Hirschhorn, J. N. (2003) · Nature Genetics · doi:10.1038/ng1071 · Cited by 1,900
Caspi, A., Moffitt, T. E., Cannon, M., McClay, J., Murray, R., Harrington, H., Taylor, A., Arseneault, L., Williams, B., Braithwaite, A., et al. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.01.026 · Cited by 1,409 · cited 5×
“Surtees et al,25 2006 4175 (1950) 60 (41-80) 33 49 18 Crosssectional No List of Threatening Eventsb Major depression (DSM-IV) Failed to replicate”
BackgroundInfluentialReplicating genotype–phenotype associations
NCI-NHGRI Working Group on Replication in Association Studies, Chanock, S. J., Manolio, T., Boehnke, M., Boerwinkle, E., Hunter, D. J., Thomas, G., Hirschhorn, J. N., Abecasis, G., Altshuler, D., et al. (2007) · Nature · doi:10.1038/447655a · Cited by 1,352
Self-citationGene–environment interactions in human diseases
Hunter, D. J. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1578 · Cited by 1,132 · cited 2×
“Strengths of the analysis reported herein include: (1) use of the same variable definitions (ie, the number of S alleles and an ordinal measure of life events) and analytic approach that was used in the original report in order to provide a valid test of replication; (2) inclusion of primary data from numerous studies…”
MethodBrugha, T. S., Bebbington, P., Tennant, C., & Hurry, J. (1985) · Psychological Medicine · doi:10.1017/s003329170002105x · Cited by 1,108 · cited 5×
“Surtees et al,25 2006 4175 (1950) 60 (41-80) 33 49 18 Crosssectional No List of Threatening Eventsb Major depression (DSM-IV) Failed to replicate”
BackgroundInfluentialAllen, N. C., Bagade, S., McQueen, M. B., Ioannidis, J. P. A., Kavvoura, F. K., Khoury, M. J., Tanzi, R. E., & Bertram, L. (2008) · Nature Genetics · doi:10.1038/ng.171 · Cited by 1,054
Research works printed but not linked: 2
- [14]Gene X environment interactions and developmental psychopathology National Institute of Mental Health Workshop Research Challenges and Opportunities June 27 28 2006 Washington, DC
- [61]Breakthrough of the year: the runners-up Science 2003 302 5653 2039 2045 14700029
Cited by
Sorted by citations
Items 701–800 of 1,006
Nielsen, D. A., Harding, M. J., Hamon, S., Huang, W., & Kosten, T. R. (2012) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2012.00839.x · Cited by 29
“The functional polymorphism that we studied in the promoter of the serotonin transporter gene has been associated with a number of psychiatric disorders and behaviors, although some of these findings have lacked replication (Risch et al. 2009).”
ResultTaylor, Z., Sulik, M. J., Eisenberg, N., Spinrad, T. L., Silva, K. M., Lemery‐Chalfant, K., Stover, D. A., & Verrelli, B. C. (2013) · Social Development · doi:10.1111/sode.12041 · Cited by 35
“Also important, because associations between genes and developmental adjustment have a history of being inconsistent, the association between serotonin haplotypes and ego-resiliency should be replicated with other samples (Risch et al., 2009).”
BackgroundConway, C., Slavich, G. M., & Hammen, C. L. (2014) · Cognitive Therapy and Research · doi:10.1007/s10608-014-9657-1 · Cited by 36
“Although this work has received criticism (e.g., Risch et al. 2009), several metaanalytic reviews have demonstrated that when a priori hypotheses and good measurement techniques are employed (especially for assessing stress), some key hypothesized gene–environment interactions tend to replicate and…”
Rawson, K. S., Dixon, D. J., Nowotny, P., Ricci, W. M., Binder, E. F., Rodebaugh, T. L., Wendleton, L., Doré, P., & Lenze, E. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120685 · Cited by 32
“Studies, like Caspi’s [42], investigating 5HTTLPR and depression, have been particularly arguable in the context of gene-environment effects [67,68].”
BackgroundEffects of environmental manipulations in genetically targeted animal models of affective disorders
Renoir, T., Pang, T. Y., & Hannan, A. J. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.04.003 · Cited by 32
van Roekel, E., Engels, R. C. M. E., Verhagen, M., Goossens, L., & Scholte, R. H. J. (2010) · Journal of Youth and Adolescence · doi:10.1007/s10964-010-9560-3 · Cited by 35
Feurer, C., McGeary, J. E., Knopik, V. S., Brick, L. A. D., Palmer, R. H. C., & Gibb, B. E. (2017) · Journal of Abnormal Psychology · doi:10.1037/abn0000316 · Cited by 30
“…transporter gene (5-HTTLPR) moderated the impact of stressful life events on depression risk, though subsequent research on the role of 5-HTTLPR in depression risk has been more mixed (for reviews, see Culverhouse et al., in press; Karg, Burmeister, Shedden, & Sen, 2011; Risch et al., 2009).”
de Vries, Y. A., Roest, A. M., Franzen, M., Munafò, M. R., & Bastiaansen, J. A. (2016) · Psychological Medicine · doi:10.1017/s0033291716000805 · Cited by 28
“However, when we examined early citations (prior to 2010) and late citations separately, there was little evidence that citation bias toward positive studies has changed since the publication of critical meta-analyses in 2009 (Munafò et al. 2009; Risch et al. 2009), although there did seem to be a decrease in citation…”
BackgroundInfluentialTrucco, E. M., Villafuerte, S., Heitzeg, M. M., Burmeister, M., & Zucker, R. A. (2016) · Development and Psychopathology · doi:10.1017/s0954579415000255 · Cited by 29
“Social sciences research has tended to focus on the identification of novel G E relationships across various candidate genes, social environments, and outcomes, rather than on which associations withstand the test of replication (Risch et al., 2009).”
BackgroundGenetic epidemiology of depression in the molecular era
Merikangas, A. K., & Merikangas, K. R. (2020) · doi:10.1093/med/9780198713005.003.0075 · Cited by 29
Self-citationNeurological entanglements: The case of paediatric depressions, SSRIs and suicidal ideation
Wilson, E. (2011) · Subjectivity · doi:10.1057/sub.2011.12 · Cited by 29
Rotating disk electrode voltammetric measurements of serotonin transporter kinetics in synaptosomes
Hagan, C. E., Neumaier, J. F., & Schenk, J. O. (2010) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2010.08.009 · Cited by 29
McDonald, S. (2019) · Eating and Weight Disorders - Studies on Anorexia Bulimia and Obesity · doi:10.1007/s40519-019-00688-7 · Cited by 29
Correlation of a set of gene variants, life events and personality features on adult ADHD severity
Müller, D. J., Chiesa, A., Mandelli, L., Luca, V. D., Ronchi, D. D., Jain, U., Serretti, A., & Kennedy, J. L. (2009) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2009.11.011 · Cited by 29
El‐Sayed, A. M., Haloossim, M., Galea, S., & Koenen, K. C. (2012) · Biology of Mood & Anxiety Disorders · doi:10.1186/2045-5380-2-10 · Cited by 29
Leighton, C., Botto, A., Silva, J. R., Jiménez, J. P., & Luyten, P. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00106 · Cited by 33
Wabnitz, P., Gast, U., & Catani, C. (2013) · European Journal of Psychotraumatology · doi:10.3402/ejpt.v4i0.21452 · Cited by 28
“Given the impact of various childhood traumata on the pathogenesis of psychopathology (i.e., Egeland, 2009; Risch et al., 2009) and the relationship among childhood trauma, PTSD, (i.e., Breslau, 2002) and Citation: European Journal of Psychotraumatology 2013, 4: 21452 -…”
BackgroundWiggins, J. L., Bedoyan, J. K., Carrasco, M., Swartz, J. R., Martin, D. M., & Monk, C. S. (2012) · Human Brain Mapping · doi:10.1002/hbm.22208 · Cited by 29
5‐ HTTLPR and anxiety modulate brain‐heart covariation
Mueller, E. M., Stemmler, G., Hennig, J., & Wacker, J. (2013) · Psychophysiology · doi:10.1111/psyp.12016 · Cited by 29
“Hence the direct association between the s-allele and increased vulnerability for affective disturbance is weak at best (Risch et al., 2009).”
Beaver, K. M., Vaughn, M. G., WRIGHT, J. P., & DeLisi, M. (2012) · American Journal of Orthopsychiatry · doi:10.1111/j.1939-0025.2012.01148.x · Cited by 28
“…four reviews and metaanalyses were conducted that examined the literature testing for an interaction between 5HTTLPR and stressful life events in relation to depression (Clarke, Flint, Attwood, & Munafò, 2010; Munafò, Durrant, Lewis, & Flint, 2009; Risch et al., 2009; Uher & McGuffin, 2010).”
BackgroundMethodInfluentialZhang, M., Zhang, Y., Sun, H., Ni, H., Sun, J., Yang, X., Chen, W., Zhao, W., Zhong, X., He, C., et al. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.627056 · Cited by 30
Cisler, J. M., Amstadter, A. B., Begle, A. M., Resnick, H. S., Danielson, C. K., Saunders, B. E., & Kilpatrick, D. G. (2011) · Addictive Behaviors · doi:10.1016/j.addbeh.2011.05.014 · Cited by 28
Lindell, S. G., Yuan, Q., Zhou, Z., Goldman, D. A., Thompson, R. C., López, J. F., Suomi, S. J., Higley, J. D., & Barr, C. S. (2012) · Development and Psychopathology · doi:10.1017/s0954579412000788 · Cited by 28
“…was performed in 2009 that called into question the validity of many of the 5-HTTLPR Stress findings that had been reported in the literature regarding humans (Risch et al., 2009), although other meta-analyses have since been conducted that demonstrate modest 5-HTTLPR E effects (Karg et al., 2011).”
MethodMing, Q., Zhang, Y., Chai, Q., Chen, H.-Y., Hou, C.-J., Wang, M., Wang, Y.-P., Cai, L., Zhu, X., Yi, J., et al. (2013) · BMC Psychiatry · doi:10.1186/1471-244x-13-142 · Cited by 28
“[44] confirmed this effect in a study of the association between 5-HTTLPR and hypothalamicpituitary-adrenal axis regulation.”
BackgroundThe Long-Run Effect of Maternity Leave Benefits on Mental Health: Evidence from European CountriesPreprint
Avendaño, M., Berkman, L. F., Brugiavini, A., & Pasini, G. (2014) · SSRN Electronic Journal · doi:10.2139/ssrn.2435850 · Cited by 28
Rocha, T. B.-M., Hutz, M. H., Salatino‐Oliveira, A., Genro, J. P., Polanczyk, G. V., Sato, J. R., Wehrmeister, F. C., Barros, F. C., Menezes, A. M. B., Rohde, L. A., et al. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.14070896 · Cited by 27
Cutuli, J. J., Raby, K. L., Cicchetti, D., Englund, M. M., & Egeland, B. R. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.08.011 · Cited by 30
“For example, in a widely cited meta-analysis Risch et al. (2009) failed to support a G E effect for 5-HTTLPR variation and life stress.”
BackgroundResultTimothy, A., Benegal, V., Shankarappa, B. M., Saxena, S., Jain, S., & Purushottam, M. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109649 · Cited by 27
Short alleles, bigger smiles? The effect of 5-HTTLPR on positive emotional expressions.
Haase, C. M., Beermann, U., Saslow, L. R., Shiota, M. N., Saturn, S. R., Lwi, S. J., Casey, J., Nguyen, N. K., Whalen, P. K., Keltner, D. J., et al. (2015) · Emotion · doi:10.1037/emo0000074 · Cited by 26
“The Effect of 5-HTTLPR on Positive Emotional Expressions Claudia M. Haase Northwestern University Ursula Beermann University of Geneva Laura R. Saslow University of California, San Francisco Michelle N. Shiota Arizona State University Sarina R. Saturn Oregon State University Sandy J. Lwi, James J.…”
InfluentialDepression and suicide are natural kinds: Implications for physician-assisted suicide
Tsou, J. Y. (2013) · International Journal of Law and Psychiatry · doi:10.1016/j.ijlp.2013.06.013 · Cited by 27
“Studies on specific genetic regions have identified polymorphisms in the serotonin transporter gene (5-HTTLPR), which is theorized to interact with environmental factors to increase the risk of depression (Ogilvie et al., 1996; Risch et al., 2009).”
BackgroundSilventoinen, K., Volanen, S., Vuoksimaa, E., Rose, R. J., Suominen, S., & Kaprio, J. A. (2014) · Social Psychiatry and Psychiatric Epidemiology · doi:10.1007/s00127-014-0851-y · Cited by 27
Grabe, H.-J., Schwahn, C., Appel, K., Mahler, J., Schulz, A., Spitzer, C., Barnow, S., John, U., Freyberger, H. J., Rosskopf, D., et al. (2010) · Molecular Psychiatry · doi:10.1038/mp.2010.45 · Cited by 27
Epidemiological Methods: About Time
KRAEMER, H. C. (2009) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph7010029 · Cited by 27
Conway, C., Hammen, C. L., Espejo, E. P., Wray, N. R., Najman, J. M., & Brennan, P. A. (2011) · Cognitive Therapy and Research · doi:10.1007/s10608-011-9368-9 · Cited by 29
Arguable Assumptions, Debatable Conclusions
Kaufman, J., Gelernter, J. E., Kaffman, A., Caspi, A., & Moffitt, T. E. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.07.041 · Cited by 27
State, M. W., & Thapar, A. (2015) · Wiley eBooks · doi:10.1002/9781118381953.ch24 · Cited by 27
Young, A. H. (2014) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000020 · Cited by 25
“Among nongenetic factors, stressful life events have been shown to provoke mood episodes, and early-life adversity has been shown to alter adult responses to stress.(4,5) Our research group has shown that the hypothalamic-pituitary-adrenal axis is dysfunctional in BD patients who have recovered from acute illness.”
BackgroundThe Individual and Societal Burden of Treatment-Resistant Depression
Baig-Ward, K. M., Jha, M. K., & Trivedi, M. H. (2023) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2023.02.001 · Cited by 35
Is there a personalized medicine for mood disorders?
Bartova, L., Berger, A., & Pezawas, L. (2010) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-010-0152-8 · Cited by 26
Brain activity related to the ability to inhibit previous task sets: an fMRI study
Whitmer, A. J., & Banich, M. T. (2012) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-012-0118-6 · Cited by 26
Impact of serotonin transporter gene on rTMS augmentation of SSRIs for obsessive compulsive disorder
Zhang, K., Fan, X., Yuan, J., Yin, J., Su, H., Hashimoto, K., & Wang, G. (2019) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s209319 · Cited by 26
Park, S., & Kim, Y. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-981-33-6044-0_7 · Cited by 27
Fang, Z., Zhu, S., Gillihan, S. J., Korczykowski, M., Detre, J. A., & Rao, H. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00704 · Cited by 26
“…the S allele exhibited more depressive symptoms, diagnosable depression, and suicidality in response to stressful life events than L allele homozygotes, which was also replicated by other studies (Kaufman et al., 2004; Kendler et al., 2005; but see Risch et al., 2009; Klumpers et al., 2012).”
The winner and loser effect, serotonin transporter genotype, and the display of offensive aggression
Kloke, V., Jansen, F., Heiming, R. S., Palme, R., Lesch, K., & Sachser, N. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.04.021 · Cited by 29
Botto, A., Julia Acuña, R., & Jiménez, J. P. (2014) · Revista médica de Chile · doi:10.4067/s0034-98872014001000010 · Cited by 26
Serotonin transporter genotype x construction stress interaction in rats
Schipper, P., Nonkes, L. J. P., Karel, P., Kiliaan, A. J., & Homberg, J. R. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.04.037 · Cited by 26
Yang, Y., Zhao, M., Zhang, Y., Shen, X., & Yuan, Y. (2016) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2016.2581 · Cited by 27
“However, a meta-analysis of 14 independent studies (14) did not support this conclusion.”
InfluentialUsing rodents to model abnormal sensitivity to feedback in depression
Ryguła, R., Noworyta, K., Drozd, R., & Kozub, A. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.10.008 · Cited by 25
“…which suggested gene-environment interaction between the short/short allele of the 5-HTTLPR and life stress as predictor for major depression there were mixed results in replication, and several recent meta-analyses were negative (Culverhouse et al., 2018; Munafo et al., 2009; Risch et al., 2009).”
The study of gene environment interactions in psychiatry: Limited gains at a substantial cost?
Zammit, S., Wiles, N., & Lewis, G. (2010) · Psychological Medicine · doi:10.1017/s0033291709991280 · Cited by 25
Stressful life events and the serotonin transporter gene ( 5-HTT ) in recurrent clinical depression
Fisher, H. L., Cohen‐Woods, S., Hosang, G. M., Uher, R., Powell‐Smith, G., Keers, R., Tropeano, M., Korszun, A., Jones, L. A., Jones, I. R., et al. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.09.016 · Cited by 25
“The lack of interaction between SLEs and 5-HTTLPR is contrary to many previous studies but consistent with two meta-analyses that found no replicable evidence of interaction (Munafò et al., 2009; Risch et al., 2009).”
BackgroundResultMurray, A. V., Carson, M. J., Morris, C. A., & Beckwith, J. (2010) · Trends in Genetics · doi:10.1016/j.tig.2010.08.001 · Cited by 26
Ways of knowing in precision health
Corwin, E. J., Redeker, N. S., Richmond, T. S., Docherty, S. L., & Pickler, R. H. (2019) · Nursing Outlook · doi:10.1016/j.outlook.2019.05.011 · Cited by 25
Serotonin and Depression: Scrutiny of New Targets for Future Anti- Depressant Drug Development
Pannu, A. S., & Goyal, R. K. (2023) · Current Drug Targets · doi:10.2174/1389450124666230425233727 · Cited by 25
Wu, G.-S., Luo, H., Dong, C., Mastronardi, C. A., Licinio, J., & Wong, M. (2010) · Psychiatric Genetics · doi:10.1097/ypg.0b013e32834133d2 · Cited by 25
Common Polymorphisms in the Age of Research Domain Criteria (RDoC): Integration and Translation
Glatt, C. E., & Lee, F. S. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.12.020 · Cited by 27
“An initial meta-analysis that subjected data from a number of studies to a single analytic framework found no interaction effect (57) but a subsequent meta-analysis that included many more studies but also relied on each study’s independent analysis by combining studies at the level of their significance tests identif…”
Shinozaki, G., Romanowicz, M., Passov, V., Rundell, J. R., Mrazek, D. A., & Kung, S. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.11.043 · Cited by 25
Nature, nurture and socioeconomic policy—What can we learn from molecular genetics?
Lundborg, P., & Stenberg, A. (2010) · Economics & Human Biology · doi:10.1016/j.ehb.2010.08.002 · Cited by 29
Line, S. J., Barkus, C., Rawlings, N. B., Jennings, K. A., McHugh, S. B., Sharp, T., & Bannerman, D. M. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12744 · Cited by 26
“…susceptibility to psychiatric illness and response to psychotropic drugs (Lesch et al., 1996; Caspi et al., 2003; Lee et al., 2004; Hariri et al., 2005; Homberg & Lesch, 2011; Murphy & Moya, 2011), although these findings are not without controversy (Risch et al., 2009; Uher & McGuffin, 2010).”
BackgroundChild and adolescent psychiatric genetics
Hebebrand, J., Scherag, A., SCHIMMELMANN, B. G., & Hinney, A. (2010) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-010-0091-y · Cited by 25
Carlström, E. L., Saetre, P., Rosengren, A., Thygesen, J. H., Djurovic, S., Melle, I. S., Andreassen, O. A., Werge, T. M., Agartz, I., Hall, H., et al. (2012) · Behavioral and Brain Functions · doi:10.1186/1744-9081-8-24 · Cited by 24
“Meta-analyses have reported association between 5-HTTLPR S-variant - and sometimes also the 17-bp VNTR in intron 2 polymorphism and bipolar disorder [52-55], co-morbid bipolar disorder and tobacco use disorder [56], alcohol dependence [57,58], major depression [59,60], antidepressant-induced mania [61,62], a modulatio…”
BackgroundReappraisal as a mediator in the link between 5-HTTLPR and social anxiety symptoms.
Miu, A. C., Vulturar, R., Chiş, A., Ungureanu, L., & Gross, J. J. (2013) · Emotion · doi:10.1037/a0033383 · Cited by 29
Dressler, W. W., Balieiro, M. C., de Araújo, L. F., Silva, W. A., & dos Santos, J. E. (2016) · Social Science & Medicine · doi:10.1016/j.socscimed.2016.05.033 · Cited by 25
Examining the stress-burnout relationship: the mediating role of negative thoughts
Chang, K.-H., Lu, F. J., Chyi, T., Hsu, Y.-W., Chan, S., & Wang, E. T. W. (2017) · PeerJ · doi:10.7717/peerj.4181 · Cited by 27
“Literature has suggested that chronic stress leads to depression (Risch et al., 2009), increasing hopelessness and suicidal ideation (Glick et al., 2012).”
Dada, R., Tolahunase, M., & Sagar, R. (2018) · Indian Journal of Psychiatry · doi:10.4103/psychiatry.indianjpsychiatry_398_17 · Cited by 26
“[27] This widely studied polymorphism is linked to both psychiatric and somatic disorders, including depression.[28-31] In particular, S allele is associated with increased risk[32] and LL genotype is associated with protection against MDD,[33] although some studies report contradictory findings.”
ResultSecretory Carrier Membrane Protein (SCAMP) deficiency influences behavior of adult flies
Zheng, J., Tham, C. T., Keatings, K., Fan, S. H. Y., Liou, A. Y.-C., Numata, Y., Allan, D. W., & Numata, M. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2014.00064 · Cited by 24
“In light of the significant role of cell-surface SLC6 in emotion and social behavior (Chen et al., 2004; Risch et al., 2009; Kristensen et al., 2011), potential impact of SCAMPs-mediated targeting of these transporters is substantial.”
BackgroundReiner, I., & Spangler, G. (2010) · Attachment & Human Development · doi:10.1080/14616731003759674 · Cited by 24
Bodden, C., Richter, S. H., Schreiber, R. S., Kloke, V., Gerß, J., Palme, R., Lesch, K., Lewejohann, L., Kaiser, S., & Sachser, N. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00047 · Cited by 25
“…1997; Caldji et al., 1998; Meaney, 2001), complexity of environmental enrichment (Marashi et al., 2003, 2004; Gross et al., 2011), social defeat (Rodgers and Cole, 1993; Jansen et al., 2010; Kloke et al., 2011), and mating experience (Rodríguez-Manzo et al., 1999; Edinger and Frye, 2007) can…”
An alternative approach to future diagnostic standards for major depressive disorder
Kim, Y., & Park, S. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110133 · Cited by 24
“depression risk, which implicate the genes related to serotonergic or hypothalamic-pituitary-adrenal axis function, have been presented (Heim and Binder, 2012; Karg et al. 2011; Risch et al. 2009).”
BackgroundImaging–Genetics Applications in Child Psychiatry
Pine, D. S., Ernst, M., & Leibenluft, E. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2009.12.022 · Cited by 24
Cicchetti, D., Toth, S. L., & Handley, E. D. (2015) · Development and Psychopathology · doi:10.1017/s0954579414001278 · Cited by 26
“Although there is some disagreement in the literature (compare Risch et al., 2009; to Caspi et al., 2010; and Karg, Burmeister, Shedden, & Sen, 2011), variation in the promoter region of the 5-HTT gene has been linked to stress sensitivity in humans.”
ResultQiao, L., Wei, D., Li, W. F., Chen, Q., Che, X., Li, B., Li, Y., Qiu, J., Zhang, Q. L., & Liu, Y. J. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.09.053 · Cited by 24
“Numerous studies have suggested that genetic factors, such as the serotonin transporter (5-HTT) gene (Caspi et al., 2003), may determine one’s reaction to stressful life events (Kendler et al., 1995, 1999, 2001; Straub et al., 1995; Kendler and KarkowskiShuman, 1997; Risch et al., 2009).”
BackgroundGene × cognition interaction on stress-induced eating: Effect of rumination
Schepers, R., & Markus, C. R. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.01.013 · Cited by 25
Animal models of major depressive disorder and the implications for drug discovery and development
Demin, K. A., Sysoev, M., Chernysh, M. V., Savva, A. K., Koshiba, M., Wappler-Guzzetta, E. A., Song, C., de Abreu, M. S., Leonard, B. E., Parker, M. O., et al. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1575360 · Cited by 24
Resilience: concepts, findings, and clinical implications
Rutter, M. L. (2015) · Wiley eBooks · doi:10.1002/9781118381953.ch27 · Cited by 25
Behavioral Biomarkers: What Are They Good For?
Baum, M. L., & Savulescu, J. (2013) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780199844180.003.0002 · Cited by 23
Shokr, M. M., Eladawy, R. M., Azar, Y. O., & Raish, S. M. A. (2025) · Foods · doi:10.3390/foods14172926 · Cited by 25
“Large-scale genetic studies consistently confirm SLC6A4 as a significant risk factor for major depression [122,123].”
Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder
Lee, K. Y., Jeong, S. H., Kim, S. H., Ahn, Y. M., Kim, Y. S., Jung, H. Y., Bang, Y. W., & Joo, E.-J. (2014) · Psychiatry Investigation · doi:10.4306/pi.2014.11.2.192 · Cited by 24
Gene-environment Interactions in Late Life: Linking Psychosocial Stress with Brain Aging
Zannas, A. S. (2018) · Current Neuropharmacology · doi:10.2174/1570159x15666171109121452 · Cited by 23
“While some of these findings have been accompanied with controversy [44-46], GxE have generally yielded more consistent associations –as compared to genome-wide association studies– with stress-related psychiatric disorders.”
ResultBasu, A., Chadda, R. K., Sood, M., Kaur, H., & Kukreti, R. (2019) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2019.05.028 · Cited by 23
Yan, S., Shan, Y., Zhong, S., Miao, H., Luo, Y., Ran, H., & Jia, Y. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.700458 · Cited by 26
Mitterauer, B. (2010) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00178.x · Cited by 24
Muehlhan, M., Kirschbaum, C., Wïttchen, H., & Alexander, N. (2015) · Human Brain Mapping · doi:10.1002/hbm.22923 · Cited by 25
“, 2014], however overall results have been mixed [Munafo et al., 2009; Risch et al., 2009].”
ResultInfluentialMouse Models of the 5-HTTLPR × Stress Risk Factor for Depression
Carola, V., & Gross, C. T. (2011) · Current topics in behavioral neurosciences · doi:10.1007/7854_2011_190 · Cited by 23
Children at risk for depression: Memory biases, self-schemas, and genotypic variation
Asarnow, L. D., Thompson, R. J., Joormann, J., & Gotlib, I. H. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.02.020 · Cited by 28
“Most recently a meta-analysis concluded that no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression (Risch et al., 2009).”
The Emergence of Socio-Genomics
Conley, D., Fletcher, J. M., & Dawes, C. T. (2014) · Contemporary Sociology A Journal of Reviews · doi:10.1177/0094306114539640 · Cited by 24
“…experience incredible reductions in life outcomes, while abused children with alternate gene variants are worse off, but not multiplicatively so (Caspi, Sugden, and Moffitt 2003; Risch, Herrell, and Lehner 2009; Conley and Rauscher 2013; Karg and Burmeister 2011; Conley, Rauscher, and Siegal 2013).”
BackgroundConley, D., Rauscher, E. A., & Siegal, M. L. (2013) · Biodemography and Social Biology · doi:10.1080/19485565.2013.774620 · Cited by 23
“Previous research has suggested that individuals with a short allele in the promoter region of 5-HTT have stronger depressive reactions to stressful life experiences than those who do not possess this short allele (Caspi et al. 2003; however, c.f. Risch et al. 2009).”
Hettema, J. M., Chen, X., Sun, C., & Brown, T. A. (2015) · Psychological Medicine · doi:10.1017/s0033291715000021 · Cited by 23
“…the 5-HTTLPR(s) polymorphism is the moderate coupling (r2 = 0.72)ofourchosen tagging2-markerhaplotypewith this polymorphism (Wray et al. 2009); however, many prior association studies present a picture of either weak or inconsistent association overall (Willis-Owen et al. 2005; Risch et al. 2009).”
InfluentialWei, X., & Zhang, J. (2016) · Genetics · doi:10.1534/genetics.116.195487 · Cited by 22
“In humans, G3E has been implicated in cancer (Thorgeirsson et al. 2008), inflammatory disorder (Chamaillard et al. 2003), immune system diseases (Padyukov et al. 2004), and mental disorders (Risch et al. 2009; Byrd and Manuck 2014; Luck et al. 2014).”
BackgroundHooten, W. M., Townsend, C. O., & Sletten, C. D. (2017) · Journal of Pain Research · doi:10.2147/jpr.s134231 · Cited by 23
“6 Primary pain diagnosis Low back pain, n (%) 62 (22) 9 (15) 32 (21) 21 (31) Fibromyalgia 60 (23) 13 (21) 32 (21) 15 (22) Abdominal 21 (8) 9 (15) 8 (5) 4 (6) Generalized 37 (13) 7 (11) 23 (15) 7 (10) Chronic headache 28 (10) 4 (7) 18 (12) 6 (9) Pelvic 10 (4) 2 (3) 7 (5) 1 (2) Lower extremity 15 (5) 4 (6) 7 (5) 4 (6) F…”
Wilson, S. J., Padin, A. C., Birmingham, D. J., Malarkey, W. B., & Kiecolt‐Glaser, J. K. (2018) · The Gerontologist · doi:10.1093/geront/gny150 · Cited by 23
Heininga, V., Oldehinkel, A., Veenstra, R., & Nederhof, E. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125383 · Cited by 24
“Similar to other genotypes in psychiatric genetics research, however, the original findings of Caspi and colleagues [11] often appeared non-replicable, and even meta-analytical efforts have failed to detect converging lines of evidence [4,12–14].”
ResultBeck, A., Heinz, A. J., & Heinz, A. (2013) · Current topics in behavioral neurosciences · doi:10.1007/7854_2013_258 · Cited by 23
Pavot, W., & Diener, E. (2011) · Wiley eBooks · doi:10.1002/9781444343120.ch27 · Cited by 23
Epigenetics and the developmental origins of vulnerability for mental disorders
Meaney, M. J., & O’Donnell, K. J. (2015) · Wiley eBooks · doi:10.1002/9781118381953.ch25 · Cited by 23
Differential Sensitivity to Context: Implications for Developmental Psychopathology
Bush, N. R., & Boyce, W. T. (2016) · Wiley eBooks · doi:10.1002/9781119125556.devpsy203 · Cited by 23
Cicchetti, D., & Toth, S. L. (2015) · Wiley eBooks · doi:10.1002/9781118963418.childpsy313 · Cited by 25
- Genetics of Suicidal Behavior in Children and Adolescents
Dwivedi, Y. (2012) · CRC Press eBooks · doi:10.1201/b12215-20 · Cited by 21
Wankerl, M., Zyriax, B., Bondy, B., Hinkelmann, K., Windler, E. E. T., & Otte, C. (2010) · Biological Psychology · doi:10.1016/j.biopsycho.2010.07.007 · Cited by 24
Hinshaw, S. P. (2015) · Journal of Abnormal Psychology · doi:10.1037/abn0000110 · Cited by 25
Cha, J., Guffanti, G., Gingrich, J. A., Talati, A., WICKRAMARATNE, P. J., Weissman, M. M., & Posner, J. E. (2017) · Cerebral Cortex · doi:10.1093/cercor/bhx097 · Cited by 21
Metadata
- Authors
- Risch, N., Herrell, R., Lehner, T., Liang, K.-Y., Eaves, L., Hoh, J., Griem, A., Kovacs, M., Ott, J., & Merikangas, K. R.
- Affiliations
- University of California, San Francisco (US)
- National Institutes of Health (US)
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2009-06-17
- Volume
- 301
- Issue
- 23
- Pages
- 2462
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC2938776
- OpenAlex
- W2042170262
- Cited by
- 1,655
- References
- 69
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 12 · 2023: 33 · 2022: 21 · 2021: 49 · 2020: 68 · 2019: 64 · 2018: 70 · 2017: 89 · 2016: 114 · 2015: 138 · 2014: 130 · 2013: 147 · 2012: 176
- FWCI
- 94.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000005)
- National Institute of Mental Health (Z01MH002804)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- 5-HTTLPR, serotonin transporter gene, life events, major depressive disorder, gene-environment interaction, short allele, depression risk, sex differences, genetic susceptibility, microdata
- MeSH terms
- Depressive Disorder, Major, Major Depressive Disorder, Female, Genotype, Humans, Life Change Events, Male, Risk Factors, Stress, Psychological, Serotonin Plasma Membrane Transport Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
