Study Reverses Thinking on Genetic Link to Depression and Stress

Summary: Researchers find no evidence that a serotonin related gene alters the impact stress has on depression.

Source: WUSTL.

Scientists re-examine data exploring connection between serotonin gene, depression and stress.

New research findings often garner great attention. But when other scientists follow up and fail to replicate the findings? Not so much.

In fact, a recent study published in PLOS One indicates that only about half of scientific discoveries will be replicated and stand the test of time. So perhaps it shouldn’t come as a surprise that new research led by Washington University School of Medicine in St. Louis shows that an influential 2003 study about the interaction of genes, environment and depression may have missed the mark.

Since its publication in Science, that original paper has been cited by other researchers more than 4,000 times, and some 100 other studies have been published about links between a serotonin-related gene, stressful life events and depression risk. It indicated that people with a particular variant of the serotonin transporter gene were not as well-equipped to deal with stressful life events and, when encountering significant stress, were more likely to develop depression.

Such conclusions were widely accepted, mainly because antidepressant drugs called selective serotonin reuptake inhibitors (SSRIs) help relieve depression for a significant percentage of clinically depressed individuals, so many researchers thought it logical that differences in a gene affecting serotonin might be linked to depression risk.

But in this new study, the Washington University researchers looked again at data from the many studies that delved into the issue since the original publication in 2003, analyzing information from more than 40,000 people, and found that the previously reported connection between the serotonin gene, depression and stress wasn’t evident. The new results are published April 4 in the journal Molecular Psychiatry.

“Our goal was to get everyone who had gathered data about this relationship to come together and take another look, with each research team using the same tools to analyze data the same way,” said the study’s first author, Robert C. Culverhouse, PhD, an assistant professor of medicine and of biostatistics. “We all ran exactly the same statistical analyses, and after combining all the results, we found no evidence that this gene alters the impact stress has on depression.”

Over the years, dozens of research groups had studied DNA and life experiences involving stress and depression in the more than 40,000 people revisited in this study. Some previous research indicated that those with the gene variant were more likely to develop depression when stressed, while others didn’t see a connection. So for almost two decades, scientists have debated the issue, and thousands of hours of research have been conducted. By getting all these groups to work together to reanalyze the data, this study should put the questions to rest, according to the researchers.

“The idea that differences in the serotonin gene could make people more prone to depression when stressed was a very reasonable hypothesis,” said senior investigator Laura Jean Bierut, MD, the Alumni Endowed Professor of Psychiatry at Washington University. “But when all of the groups came together and looked at the data the same way, we came to a consensus. We still know that stress is related to depression, and we know that genetics is related to depression, but we now know that this particular gene is not.”

Image shows a depressed looking man.
For years, scientists have been trying to determine what effect a gene linked to the brain chemical serotonin may have on depression in people exposed to stress. But now, analyzing information from more than 40,000 people who have been studied over more than a decade, researchers led by a team at Washington University School of Medicine in St. Louis have found no evidence that the gene alters the impact stress has on depression. NeuroscienceNews.com image is adapted from the WUSTL news release.

Culverhouse noted that finally, when it comes to this gene and its connection to stress and depression, the scientific method has done its job.

“Experts have been arguing about this for years,” he said. “But ultimately the question has to be not what the experts think but what the evidence tells us. We’re convinced the evidence finally has given us an answer: This serotonin gene does not have a substantial impact on depression, either directly or by modifying the relationship between stress and depression.”

With this serotonin gene variant removed from the field of potential risk factors for depression, Culverhouse and Bierut said researchers now can focus on other gene-environment interactions that could influence the onset of depression.

About this genetics research article

Culverhouse, RC, et al. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Molecular Psychiatry. April 4, 2017.

Funding: This work was supported by the National Institute on Drug Abuse and the National Institute of Mental Health of the National Institutes of Health (NIH), grant numbers R21 DA033827, MH089995 and R01 DA026911. Other funding provided by the Wellcome Trust and other funding agencies from countries around the world. For a complete list of funding agencies and grants, please refer to the paper.

Potential conflicts of interest involving researchers who are authors of the study also are listed at the end of the paper. Some have received consultancy/speaking fees from various pharmaceutical companies and other business interests. LJ Bierut is one of the listed inventors on US Patent 8 080 371, “Markers for Addiction,” covering the use of certain DNA SNPs in determining the diagnosis, prognosis and treatment of addiction.

Source: Jim Dryden – WUSTL
Image Source: NeuroscienceNews.com image is adapted from the WUSTL news release.
Original Research: Abstract for “Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression” by R C Culverhouse, N L Saccone, A C Horton, Y Ma, K J Anstey, T Banaschewski, M Burmeister, S Cohen-Woods, B Etain, H L Fisher, N Goldman, S Guillaume, J Horwood, G Juhasz, K J Lester, L Mandelli, C M Middeldorp, E Olié, S Villafuerte, T M Air, R Araya, L Bowes, R Burns, E M Byrne, C Coffey, W L Coventry, K A B Gawronski, D Glei, A Hatzimanolis, J-J Hottenga, I Jaussent, C Jawahar, C Jennen-Steinmetz, J R Kramer, M Lajnef, K Little, H M zu Schwabedissen, M Nauck, E Nederhof, P Petschner, W J Peyrot, C Schwahn, G Sinnamon, D Stacey, Y Tian, C Toben, S Van der Auwera, N Wainwright, J-C Wang, G Willemsen, I M Anderson, V Arolt, C Åslund, G Bagdy, B T Baune, F Bellivier, D I Boomsma, P Courtet, U Dannlowski, E J C de Geus, J F W Deakin, S Easteal, T Eley, D M Fergusson, A M Goate, X Gonda, H J Grabe, C Holzman, E O Johnson, M Kennedy, M Laucht, N G Martin, M R Munafò, K W Nilsson, A J Oldehinkel, C A Olsson, J Ormel, C Otte, G C Patton, B W J H Penninx, K Ritchie, M Sarchiapone, J M Scheid, A Serretti, J H Smit, N C Stefanis, P G Surtees, H Völzke, M Weinstein, M Whooley, J I Nurnberger Jr, N Breslau and L J Bierut in Molecular Psychiatry. Published online April 4 2017 doi:10.1038/mp.2017.44

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]WUSTL “Study Reverses Thinking on Genetic Link to Depression and Stress.” NeuroscienceNews. NeuroscienceNews, 4 April 2017.
<https://neurosciencenews.com/genetics-depression-stress-6341/>.[/cbtab][cbtab title=”APA”]WUSTL (2017, April 4). Study Reverses Thinking on Genetic Link to Depression and Stress. NeuroscienceNew. Retrieved April 4, 2017 from https://neurosciencenews.com/genetics-depression-stress-6341/[/cbtab][cbtab title=”Chicago”]WUSTL “Study Reverses Thinking on Genetic Link to Depression and Stress.” https://neurosciencenews.com/genetics-depression-stress-6341/ (accessed April 4, 2017).[/cbtab][/cbtabs]


Abstract

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

“Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression” by R C Culverhouse, N L Saccone, A C Horton, Y Ma, K J Anstey, T Banaschewski, M Burmeister, S Cohen-Woods, B Etain, H L Fisher, N Goldman, S Guillaume, J Horwood, G Juhasz, K J Lester, L Mandelli, C M Middeldorp, E Olié, S Villafuerte, T M Air, R Araya, L Bowes, R Burns, E M Byrne, C Coffey, W L Coventry, K A B Gawronski, D Glei, A Hatzimanolis, J-J Hottenga, I Jaussent, C Jawahar, C Jennen-Steinmetz, J R Kramer, M Lajnef, K Little, H M zu Schwabedissen, M Nauck, E Nederhof, P Petschner, W J Peyrot, C Schwahn, G Sinnamon, D Stacey, Y Tian, C Toben, S Van der Auwera, N Wainwright, J-C Wang, G Willemsen, I M Anderson, V Arolt, C Åslund, G Bagdy, B T Baune, F Bellivier, D I Boomsma, P Courtet, U Dannlowski, E J C de Geus, J F W Deakin, S Easteal, T Eley, D M Fergusson, A M Goate, X Gonda, H J Grabe, C Holzman, E O Johnson, M Kennedy, M Laucht, N G Martin, M R Munafò, K W Nilsson, A J Oldehinkel, C A Olsson, J Ormel, C Otte, G C Patton, B W J H Penninx, K Ritchie, M Sarchiapone, J M Scheid, A Serretti, J H Smit, N C Stefanis, P G Surtees, H Völzke, M Weinstein, M Whooley, J I Nurnberger Jr, N Breslau and L J Bierut in Molecular Psychiatry. Published online April 4 2017 doi:10.1038/mp.2017.44

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