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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.
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“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)
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“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]
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Cites
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
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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
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“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…”
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“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”
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Sorted by citations
Items 501–600 of 1,006
Gene–environment interdependence
Rutter, M. L. (2012) · European Journal of Developmental Psychology · doi:10.1080/17405629.2012.661174 · Cited by 49
“Risch et al. (2009) argued that it is improper to test for interactions if there is no statistical main effect.”
Background5-HTTLPR X Stress in Adolescent Depression: Moderation by MAOA and Gender
Priess, H. A., & Hyde, J. S. (2012) · Research on Child and Adolescent Psychopathology · doi:10.1007/s10802-012-9672-1 · Cited by 56
“The finding of a four-way interaction of 5-HTTLPR, MAOA-uVNTR, negative life events, and gender on depressive symptoms in adolescents may provide an important explanation for the sometimes inconsistent results of studies of the interaction of 5-HTTLPR and stress (Karg et al. 2011; Risch et al. 2009).”
BackgroundResultLundin, A., Falkstedt, D., Lundberg, I., & Hemmingsson, T. (2014) · Occupational and Environmental Medicine · doi:10.1136/oemed-2013-101721 · Cited by 49
Impact of institutional care on attachment disorganization and insecurity of Ukrainian preschoolers
Bakermans‐Kranenburg, M. J., Dobrova‐Krol, N. A., & van IJzendoorn, M. H. (2011) · International Journal of Behavioral Development · doi:10.1177/0165025411406858 · Cited by 49
“…cast some doubt on the replicability of effects resulting from the interplay between the 5HTT genotype and stressful life events (Munafo, Durrant, Lewis, & Flint, 2009; Risch et al., 2009), these studies unintentionally underscored the importance of adequately measuring the environment.”
BackgroundHappiness in Behaviour Genetics: An Update on Heritability and Changeability
Nes, R. B., & Røysamb, E. (2016) · Journal of Happiness Studies · doi:10.1007/s10902-016-9781-6 · Cited by 59
“A number of GxE studies, including several meta-analyses (Karg et al. 2011; Kim-Cohen et al. 2006; Risch 2009), indicate that indi-”
BackgroundBoffetta, P., Winn, D. M., Ioannidis, J. P., Thomas, D. C., Little, J., Smith, G. D., Cogliano, V. J., Hecht, S. S., Seminara, D., Vineis, P., et al. (2012) · International Journal of Epidemiology · doi:10.1093/ije/dys010 · Cited by 48
Chiou, S.-S., Hsu, Y., Chiu, Y., Chou, C., Gill, D. L., & Lu, F. J.-H. (2020) · Frontiers in Psychology · doi:10.3389/fpsyg.2019.03007 · Cited by 48
Verschoor, E., & Markus, C. R. (2011) · Biological Psychology · doi:10.1016/j.biopsycho.2011.06.001 · Cited by 52
Amone‐P’Olak, K., Burger, H., Huisman, M. A., Oldehinkel, A. J., & Ormel, J. (2009) · Journal of Epidemiology & Community Health · doi:10.1136/jech.2009.092569 · Cited by 50
Lemogne, C., Gorwood, P. A. P. M., Boni, C., Pessiglione, M., Lehéricy, S., & Fossati, P. (2011) · Human Brain Mapping · doi:10.1002/hbm.21150 · Cited by 48
“…the association of the S allele with vulnerability for depression has been challenged by two recent negative metaanalyses [Munafò et al., 2009a; Risch et al., 2009], another meta-analysis confirmed its association with a greater amygdala reactivity in healthy subjects [Munafò et al., 2008].”
Resultvan der Doelen, R. H. A., Deschamps, W., D'Annibale, C., Peeters, D. G. A., Wevers, R. A., Zelena, D., Homberg, J. R., & Kozicz, T. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.57 · Cited by 46
The Genetics of Eating Disorders
Helder, S. G., & Collier, D. A. (2010) · Current topics in behavioral neurosciences · doi:10.1007/7854_2010_79 · Cited by 49
Post, R. M., Altshuler, L. L., Kupka, R., McElroy, S. L., Frye, M. A., Rowe, M., Grunze, H., Suppes, T. M., Keck, P. E., Leverich, G. S., et al. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.06.008 · Cited by 50
Molecular Mechanisms of Stress-Induced Increases in Fear Memory Consolidation within the Amygdala
Aubry, A., Serrano, P. A., & Burghardt, N. S. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00191 · Cited by 52
Lamiani, G., Dordoni, P., & Argentero, P. (2017) · Stress and Health · doi:10.1002/smi.2769 · Cited by 52
Nilsson, K. W., Åslund, C., Comasco, E., & Oreland, L. (2018) · Journal of Neural Transmission · doi:10.1007/s00702-018-1892-2 · Cited by 55
“For example, there is seldom a high explained variance in cG×E studies of depression that have investigated 5-HTT promoter polymorphism (Munafo et al. 2009; Risch et al. 2009; Sharpley et al. 2014; Bleys et al. 2018; Culverhouse et al. 2017).”
BackgroundEnvironmental stress alters genetic regulation of novelty seeking in vervet monkeys
Fairbanks, L. A., Bailey, J. N., Breidenthal, S. E., Laudenslager, M. L., Kaplan, J. R., & Jorgensen, M. J. (2011) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2011.00707.x · Cited by 47
Polygenic Risk and Social Support in Predicting Depression Under Stress
Cleary, J. L., Fang, Y., Zahodne, L. B., Bohnert, A. M., Burmeister, M., & Sen, S. (2023) · American Journal of Psychiatry · doi:10.1176/appi.ajp.21111100 · Cited by 48
Applying an evolutionary mismatch framework to understand disease susceptibility
Lea, A. J., Clark, A. G., Dahl, A., Devinsky, O., García, A. R., Golden, C. D. W., Kamau, J., Kraft, T. S., Lim, Y. A. L., Martins, D. J., et al. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002311 · Cited by 66
“…similar successes in elucidating GxE mismatches at other well-known risk loci that replicate across postindustrial contexts (e.g., FTO , ADCY3 , BRCA1/2 ), though we caution that candidate gene studies should always be undertaken with care due to potential bias and replication issues [83,84].”
Markus, C. R., & Raedt, R. D. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.221 · Cited by 50
Hankin, B. L., Barrocas, A. L., Young, J. F., Haberstick, B. C., & Smolen, A. (2014) · Psychiatry Research · doi:10.1016/j.psychres.2014.11.037 · Cited by 55
Carskadon, M. A., Sharkey, K. M., Knopik, V. S., & McGeary, J. E. (2012) · SLEEP · doi:10.5665/sleep.1876 · Cited by 47
Bogdan, R., Arpana Agrawal, A., Gaffrey, M. S., Tillman, R., & Luby, J. L. (2013) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12142 · Cited by 51
“Recent meta-analyses have weighed heavily against evidence for the 5-HTTLPR 9 SLEs interaction (Duncan & Keller, 2011; Munafo, Durrant, Lewis & Flint, 2009; Risch et al., 2009), although opinions continue Conflict of interest statement: No conflicts declared.”
BackgroundMcGuffin, P., Alsabban, S., & Uher, R. (2011) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.110.085225 · Cited by 48
Ngoupaye, G. T., Yassi, F. B., Bahane, D. A. N., & Bum, E. N. (2017) · Metabolic Brain Disease · doi:10.1007/s11011-017-0148-4 · Cited by 47
“Since the hippocampus is one of the essential structures of the brain involved in cognitive function (Rubin et al. 2014), it has been speculated that the reduced hippocampal size can be a leading cause of memory deficit seen in people with MDD (Murrough et al. 2011; Gray et al. 2013).”
BackgroundTelomeres in neurological disorders
Anitha, A., Thanseem, I., Vasu, M. M., Viswambharan, V., & Poovathinal, S. A. (2019) · Advances in clinical chemistry · doi:10.1016/bs.acc.2019.01.003 · Cited by 49
Developmental Risk I: Depression and the Developing Brain
Weir, J. M., Zakama, A. K., & Rao, U. (2012) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2012.01.004 · Cited by 54
Cimino, S., Cerniglia, L., Ballarotto, G., Marzilli, E., Pascale, E., D’Addario, C., Adriani, W., Maremmani, A. G. I., & Tambelli, R. (2019) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph16142567 · Cited by 47
“On the basis of these studies, recent literature has emphasized the mutual interaction between genetic and environmental factors in the development and maintenance of children’s psychological outcomes [8,9], underlining the role of di↵erential susceptibility [10,11] in response to exposure to certain environments, in…”
BackgroundSerotonin transporter gene polymorphism and psychiatric disorders: Is there a link?
Margoob, M., & Mushtaq, D. (2011) · Indian Journal of Psychiatry · doi:10.4103/0019-5545.91901 · Cited by 52
“Contrary to the results of the smaller two earlier meta-analyses by Risch et al. [56] and Munafò et al .”
Hankin, B. L., Jenness, J. L., Abela, J. R. Z., & Smolen, A. (2011) · Journal of Clinical Child & Adolescent Psychology · doi:10.1080/15374416.2011.581613 · Cited by 49
Gene × Environment Interaction in Developmental Disorders: Where Do We Stand and What’s Next?
Esposito, G., Azhari, A., & Borelli, J. L. (2018) · Frontiers in Psychology · doi:10.3389/fpsyg.2018.02036 · Cited by 48
Chronic Clomipramine Treatment Reverses Core Symptom of Depression in Subordinate Tree Shrews
Wang, J., Chai, A., Zhou, Q., Lv, L., Wang, L., Yang, Y., & Xu, L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080980 · Cited by 46
“Stressful life events are a major cause of depression [13–15].”
BackgroundWaters, P., & McCormick, C. M. (2011) · Biology of Mood & Anxiety Disorders · doi:10.1186/2045-5380-1-4 · Cited by 48
Early Institutionalization: Neurobiological Consequences and Genetic Modifiers
Sheridan, M. A., Drury, S. S., McLaughlin, K. A., & Almas, A. N. (2010) · Neuropsychology Review · doi:10.1007/s11065-010-9152-8 · Cited by 50
The stress-coping (mis)match hypothesis for nature×nurture interactions
Homberg, J. R. (2011) · Brain Research · doi:10.1016/j.brainres.2011.11.037 · Cited by 47
Haase, C. M., Saslow, L. R., Bloch, L., Saturn, S. R., Casey, J. J., Seider, B. H., Lane, J. R., Coppola, G., & LEVENSON, R. W. (2013) · Emotion · doi:10.1037/a0033761 · Cited by 45
“Given earlier concerns about the replicability of these kinds of single-gene effects (e.g., Risch et al., 2009), we designed our analyses to be maximally conservative by: (a) controlling for variance in marital satisfaction shared by positive and negative emotional behavior; (b) considering…”
Hyde, L. W. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000188 · Cited by 48
“These relationships are supported by meta-analysis (Karg, Burmeister, Shedden, & Sen, 2011; though see Risch et al., 2009) and animal models (Caspi et al., 2010), and a wealth of other G E studies have demonstrated similar relationships across other genes, environments, and phenotypes (e.g., Byrd &…”
ResultHofmann, A., Hilgers, A., Lehnung, M., Liebermann, P., Ostacoli, L., Schneider, W., & Hase, M. (2014) · Journal of EMDR Practice and Research · doi:10.1891/1933-3196.8.3.103 · Cited by 47
“The presence of a serotonin transporter gene polymorphism alone, even in combination with stressful life events, was not significantly correlated with the occurrence of depressive episodes in the same meta-analysis (Risch et al., 2009).”
BackgroundRozenblat, V., Ong, D., Fuller‐Tyszkiewicz, M., Akkermann, K., Collier, D. A., Engels, R. C. M. E., Fernández‐Aranda, F., Harro, J., Homberg, J. R., Karwautz, A. F. K., et al. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.09.023 · Cited by 46
“Despite substantial research investigating GxE interactions with 5-HTTLPR and other polymorphisms, many studies are limited by small sample size, and replicability remains a major issue (see Duncan et al., 2014 for a review; Risch et al., 2009).”
BackgroundKeers, R., & Pluess, M. (2017) · Development and Psychopathology · doi:10.1017/s0954579417001493 · Cited by 51
“Nevertheless, G E findings have often failed to replicate, even in high-quality studies with very similar methodologies (e.g., Fergusson, Horwood, Miller, & Kennedy, 2011) resulting in negative meta-analyses (Munafo, Durrant, Lewis, & Flint, 2009; Risch et al., 2009).”
Mann, J. J., & Currier, D. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-252-6_33 · Cited by 45
Pryce, C. R., & Seifritz, E. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.05.003 · Cited by 47
Warren, C. S., Holland, S. A., Billings, H., & Parker, A. (2012) · Body Image · doi:10.1016/j.bodyim.2012.03.008 · Cited by 50
“…is associated with impairments in physical and mental health (Bogdan & Pizzagalli, 2006; McGrath, 1976; Michaud, Mathenson, Kelly, & Anisman, 2008; Risch et al., 2009; Walburn, Vedhara, Hankins, Rixon, & Weinman, 2009) and a large body of research suggests a positive relationship between stress…”
BackgroundRosenberg, J., Pennington, B. F., Willcutt, E. G., & Olson, R. K. (2011) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2011.02452.x · Cited by 45
Developmental Risk of Depression: Experience Matters
Beardslee, W. R., Gladstone, T. R. G., & O’Connor, E. (2012) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2011.12.001 · Cited by 46
Translational Epidemiology in Psychiatry
Weissman, M. M., Brown, A. S., & Talati, A. (2011) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.47 · Cited by 43
Agnafors, S., Svedin, C. G., Oreland, L., Bladh, M. K., Comasco, E., & Sydsjö, G. (2016) · Child Psychiatry & Human Development · doi:10.1007/s10578-016-0684-x · Cited by 48
Starr, L. R., & Huang, M. (2018) · Development and Psychopathology · doi:10.1017/s0954579418000779 · Cited by 49
Antidepressant pharmacogenetics
Singh, A., Bousman, C., Ng, C. H., & Berk, M. (2013) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000023 · Cited by 44
“Given approximately 50% of whites [34] and 25% of Asian individuals [35] are l carriers, this polymorphism is common enough for potential clinical relevance.”
BackgroundDevelopmental Changes in Genetic Influences on Alcohol Use and Dependence
Dick, D. M. (2011) · Child Development Perspectives · doi:10.1111/j.1750-8606.2011.00207.x · Cited by 45
Fisher, H. L., Cohen‐Woods, S., Hosang, G. M., Korszun, A., Owen, M., Craddock, N. J., Craig, I., FARMER, A. E., McGuffin, P., & Uher, R. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.05.032 · Cited by 44
“The potential aetiological role of an interaction between stressful experiences and a functional insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTTLR) in depression has sparked a great deal of debate and an array of inconsistent findings (Caspi et al., 2010; Munafò et al.,…”
Result5-HTTLPR and Early Childhood Adversities Moderate Cognitive and Emotional Processing in Adolescence
Owens, M., Goodyer, I. M., Wilkinson, P. O., Bhardwaj, A., Abbott, R., Croudace, T. J., Dunn, V. J., Jones, P. B., Walsh, N., Ban, M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048482 · Cited by 45
Ishii, T., Wakabayashi, R., Kurosaki, H., Gemma, A., & Kida, K. (2010) · Journal of Human Genetics · doi:10.1038/jhg.2010.133 · Cited by 43
Vrieze, S. I., Iacono, W. G., & McGue, M. K. (2012) · Development and Psychopathology · doi:10.1017/s0954579412000648 · Cited by 46
“…specific genetic variants and behavior have been notoriously difficult to replicate, and the validity of research investigating the interaction between specific functional genetic variants and the environment has recently been called into question (Duncan & Keller, 2011; Risch et al., 2009).”
BackgroundResultInfluentialGenetic Research in Psychiatry and Psychology
Joseph, J. (2010) · Wiley eBooks · doi:10.1002/9781444327632.ch18 · Cited by 43
Nikolova, Y. S., Bogdan, R., & Pizzagalli, D. A. (2011) · Neuropsychobiology · doi:10.1159/000329105 · Cited by 41
Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression
Culverhouse, R., Bowes, L., Breslau, N., Nürnberger, J. I., Burmeister, M., Fergusson, D. M., Munafo, M. R., Saccone, N. L., & Bierut, L. J. (2013) · BMC Psychiatry · doi:10.1186/1471-244x-13-304 · Cited by 42
“Meta-analyses, also, have come to quite different conclusions [16,19-22] and various reasons for these differences have been proposed [21,23-25].”
BackgroundImpact of family history and depression on amygdala volume
Saleh, K., Carballedo, A., Lisiecka, D., Fagan, A. J., Connolly, G., Boyle, G., & Frodl, T. (2012) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2011.10.004 · Cited by 42
“Additionally, a meta-analysis based on 14,250 participants clearly demonstrated that stressful life events have a potent association with the risk of developing depression (Risch et al., 2009).”
Pharmacological management of unipolar depression
Malhi, G. S., Hitching, R., Berk, M., Boyce, P. M., Porter, R., & Fritz, K. (2013) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12122 · Cited by 41
5‐HTTLPR S‐allele: a genetic plasticity factor regarding the effects of life events on personality?
Kuepper, Y., Wielpuetz, C., Alexander, N., Mueller, E., Grant, P. S., & Hennig, J. (2012) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2012.00783.x · Cited by 49
“These results might also, at least partially, explain why several studies were not able to replicate the 5-HTTLPR × stressful LEs interaction on measures such as neuroticism or incidences of affective disorders in which positive LEs were not assessed (Middeldorp et al. 2010; Risch et al. 2009).”
BackgroundResultZhang, Z.-Y., Mao, Y., Feng, X., Zheng, N., Lü, L., Ma, Y., Qin, D., & Hu, X. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.03.040 · Cited by 44
Salo, J., Jokela, M. M., Lehtimäki, T. J., & Keltikangas‐Järvinen, L. (2011) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2011.00708.x · Cited by 42
The Sociological Study of Mental Illness: A Critique and Synthesis of Four Perspectives
Horwitz, A. V. (2012) · Handbooks of sociology and social research · doi:10.1007/978-94-007-4276-5_6 · Cited by 45
Conway, C., Keenan‐Miller, D., Hammen, C. L., Lind, P. A., Najman, J. M., & Brennan, P. A. (2012) · Journal of Clinical Child & Adolescent Psychology · doi:10.1080/15374416.2012.632351 · Cited by 44
“A sizeable body of research has since supported the role of 5-HTTLPR in depressive responses to stress (Karg, Burmeister, Shedden, & Sen, 2011; but see also Risch et al., 2009).”
BackgroundSocial, Behavioral, and Genetic Linkages from Adolescence Into Adulthood
Harris, K. M., Halpern, C. T., Hussey, J. M., Whitsel, E. A., Killeya‐Jones, L. A., Tabor, J. W., Elder, G. H., Hewitt, J. K., Shanahan, M. J., Williams, R. B., et al. (2013) · American Journal of Public Health · doi:10.2105/ajph.2012.301181 · Cited by 41
Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks
Muller, J. M., Morelli, E., Ansorge, M. S., & Gingrich, J. A. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00652.x · Cited by 43
Molecular-genetic correlates of infant attachment: A cautionary tale
Roisman, G. I., Booth‐LaForce, C., Belsky, J., Burt, K. B., & Groh, A. M. (2013) · Attachment & Human Development · doi:10.1080/14616734.2013.768790 · Cited by 41
Population Disparities in Mental Health: Insights From Cultural Neuroscience
Chiao, J. Y., & Blizinsky, K. D. (2013) · American Journal of Public Health · doi:10.2105/ajph.2013.301440 · Cited by 44
Post‐GWAS in Psychiatric Genetics: A Developmental Perspective on the “Other” Next Steps
Dick, D. M., Barr, P. B., Cho, S. B., Cooke, M. E., Kuo, S. I., Lewis, T. J., Neale, Z. E., Salvatore, J. E., Savage, J. E., & Su, J. (2017) · Genes Brain & Behavior · doi:10.1111/gbb.12447 · Cited by 43
Manczak, E. M., Skerrett, K. A., Gabriel, L. B., Ryan, K. A., & Langenecker, S. A. (2018) · Journal of Family Psychology · doi:10.1037/fam0000451 · Cited by 42
“The stress associated with such events as romantic breakups, academic or professional failures, or experiences with crime have been robustly associated with higher rates of depression across the life span (Bouma, Ormel, Verhulst, & Oldehinkel, 2008; Monroe & Harkness, 2005; Risch et al., 2009).”
BackgroundCole, S. W., Arevalo, J. M. G., Manu, K. H., Telzer, E. H., Kiang, L., Bower, J. E., Irwin, M. R., & Fuligni, A. J. (2011) · Developmental Psychology · doi:10.1037/a0023871 · Cited by 41
A two-year follow-up study of salivary cortisol concentration and the risk of depression
Grynderup, M. B., Kolstad, H. A., Mikkelsen, S., Andersen, J. H., Bonde, J. P., Buttenschøn, H. N., Kærgaard, A., Kærlev, L., Rugulies, R., Thomsen, J. F., et al. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.03.013 · Cited by 44
Molecular Genetic Aspects of Personality
Strobel, A., & Brocke, B. (2011) · Wiley eBooks · doi:10.1002/9781444343120.ch11 · Cited by 41
“…activation by aversive stimuli (Canli et al., 2006)—could be replicated in several, (though not all) subsequent studies (for a recent meta-analysis see Risch et al., 2009); the mode of assessing or defining a stressful life event is one likely reason for inconsistencies between studies: Uher &…”
ResultVariants of SLC6A4 in depression risk following severe TBI
Failla, M. D., Burkhardt, J. N., Miller, M. A., Scanlon, J. M., Conley, Y. P., Ferrell, R. E., & Wagner, A. K. (2013) · Brain Injury · doi:10.3109/02699052.2013.775481 · Cited by 40
“One meta-analysis showed variation at 5-HTTLPR is implicated in major depression risk [11], but conflicting meta-analyses exist [12], potentially due to specific methodological differences.”
BackgroundResultGender differences in the genetic and environmental determinants of adolescent depression
Uddin, M., Koenen, K. C., Santos, R. D. L., Ware, E. B., Aiello, A. E., & Galea, S. (2010) · Depression and Anxiety · doi:10.1002/da.20692 · Cited by 40
Dalton, E. D., Hammen, C. L., Najman, J. M., & Brennan, P. A. (2014) · Journal of Family Psychology · doi:10.1037/fam0000032 · Cited by 47
Predictive and Diagnostic Genetic Testing in Psychiatry
Mitchell, P. B., Meiser, B., Wilde, A., Fullerton, J. M., Donald, J. A., Wilhelm, K. A., & Schofield, P. R. (2010) · Clinics in Laboratory Medicine · doi:10.1016/j.cll.2010.07.001 · Cited by 41
van der Doelen, R. H. A., Calabrese, F., Guidotti, G., Geenen, B., Riva, M. A., Kozicz, T., & Homberg, J. R. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00355 · Cited by 42
“Specifically, the short (S) allele of 5-HTTLPR has been associated with a significantly increased risk to develop depression in interaction with adverse events such as childhood abuse (Karg et al., 2011, but also see Risch et al., 2009).”
BackgroundNyman, E. S., Sulkava, S., Soronen, P., Miettunen, J., Loukola, A., Leppä, V., Joukamaa, M. I., Mäki, P. H., Järvelin, M., Freimer, N. B., et al. (2011) · BMJ Open · doi:10.1136/bmjopen-2011-000087 · Cited by 40
Bresin, K., Finy, M. S., & Verona, E. (2013) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.01.050 · Cited by 40
Altered timing of amygdala activation during sad mood elaboration as a function of 5-HTTLPR
Furman, D. J., Hamilton, J. P., Joormann, J., & Gotlib, I. H. (2010) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsq029 · Cited by 41
Genetic Factors and Suicidal Behavior
Dwivedi, Y. (2012) · CRC Press eBooks · doi:10.1201/b12215-17 · Cited by 41
Lolak, S., Suwannarat, P., & Lipsky, R. H. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-800977-2.00005-x · Cited by 43
A Whole-Brain and Cross-Diagnostic Perspective on Functional Brain Network Dysfunction
Spronk, M., Keane, B. P., Ito, T., Kulkarni, K. R., Ji, J. L., Anticevic, A., & Cole, M. W. (2020) · Cerebral Cortex · doi:10.1093/cercor/bhaa242 · Cited by 43
Zannas, A. S., McQuoid, D. R., Steffens, D. C., Chrousos, G. P., & Taylor, W. D. (2012) · Stress · doi:10.3109/10253890.2011.634263 · Cited by 42
“The risk of developing a new MDD episode increases with both greater severity and greater number of SLEs (Kendler et al. 1998; Hammen 2005; Risch et al. 2009), with risk being greatest shortly after the occurrence of the event and diminishing thereafter (Kendler et al. 1998; Tennant 2002).”
BackgroundSchlomer, G. L., Cleveland, H. H., Vandenbergh, D. J., Feinberg, M. E., Neiderhiser, J. M., Greenberg, M. T., Spoth, R. L., & Redmond, C. R. (2014) · Journal of Youth and Adolescence · doi:10.1007/s10964-014-0198-4 · Cited by 40
“Despite these promising results, it should be noted that cGxE studies have been the subject of criticism due, in part, to replication problems of primarily two studies (Caspi et al. 2002, 2003; see Munafò et al. 2009; Risch et al. 2009).”
BackgroundResultBeckner, V., Howard, I., Vella, L., & Mohr, D. C. (2009) · Journal of Behavioral Medicine · doi:10.1007/s10865-009-9235-2 · Cited by 45
Nielsen, J. D., Mennies, R. J., & Olino, T. M. (2020) · Clinical Psychology Review · doi:10.1016/j.cpr.2020.101922 · Cited by 42
“…different SNPs across 5763 adults with MDD and 6901 healthy controls (Wray et al., 2012), individual studies have identified associations between MDD and SNPs related to serotonin (Risch et al., 2009), BDNF (Verhagen et al., 2010), and immune responding (e.g., FKBP5 gene; Rao et al., 2016).”
BackgroundAnnual Research Review: Threats to the validity of child psychiatry and psychology
Rutter, M. L., & Pickles, A. R. (2015) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12461 · Cited by 41
Sher, K. J., Dick, D. M., Crabbe, J. C., Hutchison, K. E., O’Malley, S. S., & Heath, A. C. (2010) · Addiction Biology · doi:10.1111/j.1369-1600.2009.00189.x · Cited by 41
Condit, C. M., & Shen, L. (2010) · Public Health Genomics · doi:10.1159/000314915 · Cited by 39
Liu, Z., Liu, W., Yao, L., Yang, C., Xiao, L., Wan, Q., Gao, K., Wang, H., Zhu, F., Wang, G., et al. (2013) · Scientific Reports · doi:10.1038/srep01548 · Cited by 39
Stoltenberg, S. F., Anderson, C. M., Nag, P., & Anagnopoulos, C. (2012) · International Journal of Eating Disorders · doi:10.1002/eat.20976 · Cited by 41
Intermediate or brainless phenotypes for psychiatric research?
Meyer‐Lindenberg, A. (2009) · Psychological Medicine · doi:10.1017/s0033291709991929 · Cited by 39
Olfson, E., Edenberg, H. J., Nürnberger, J. I., Arpana Agrawal, A., Bucholz, K. K., Almasy, L. A., Chorlian, D. B., Dick, D. M., HESSELBROCK, V. M., Kramer, J., et al. (2014) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.12524 · Cited by 39
“First, the analysis focused on a genetic variant with strong statistical and biological evidence for alcoholrelated measures, which addresses common criticisms of G 9 E studies (Duncan and Keller, 2011; Joober et al., 2007; Risch et al., 2009).”
BackgroundFischmann, T., Russ, M. O., & Leuzinger‐Bohleber, M. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00877 · Cited by 39
“When looking at depression from the angle of brainphysiology, some interesting findings have been put forth: for instance that depression is related to a neurotransmitter disorder, or a frontal lobe dysfunction (cf. Caspi et al., 2003; Belmaker and Agam, 2008; Risch et al., 2009).”
BackgroundGene-Environment Interaction in the Etiology of Mathematical Ability Using SNP Sets
Docherty, S. J., Kovas, Y. V., & Plomin, R. J. (2010) · Behavior Genetics · doi:10.1007/s10519-010-9405-6 · Cited by 40
Hase, M., Plagge, J., Hase, A., Braas, R., Ostacoli, L., Hofmann, A., & Huchzermeier, C. (2018) · Frontiers in Psychology · doi:10.3389/fpsyg.2018.01384 · Cited by 41
Markus, C. R., & Firk, C. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.92 · Cited by 39
Trauma-focused treatments for depression. A systematic review and meta-analysis
Dominguez, S. K., Matthijssen, S. J. M. A., & Lee, C. W. (2021) · PLoS ONE · doi:10.1371/journal.pone.0254778 · Cited by 40
“One predisposing factor for depression repeatedly identified in the literature is the experience of aversive life events in childhood [7, 8].”
Background
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
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