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Published in final edited form as:
Emotion. 2009 August ; 9(4): 579–584. doi:10.1037/a0016189.
The BDNF Val66Met polymorphism is associated with rumination
in healthy adults
Christopher G. Beevers,
University of Texas at Austin
Tony T. Wells, and
University of Texas at Austin
John E. McGeary
Providence Veterans Affairs Medical Center and Center for Alcohol and Addiction Studies, Brown
University
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Abstract
This study examined associations between the tendency to ruminate and two polymorphisms: the
Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and 5-HTTLPR
polymorphism in the serotonin transporter gene (SLC6A4). Participants were a homogenous group
of healthy, unmedicated, never depressed individuals with few current symptoms of depression (N
= 71). Results indicated that met heterozygotes of the BDNF allele were significantly more likely to
ruminate than individuals homozygous for the val BDNF allele. There was no association between
rumination and the 5-HTTLPR polymorphism. Further, the interaction between the 5-HTTLPR and
BDNF polymorphisms did not predict rumination. Results suggest that variation in the BDNF gene
may contribute to the tendency to ruminate. Since this association exists in healthy adults, it may
represent a susceptibility factor for affective disorders.
Keywords
genetic association; rumination; depression; BDNF; 5-HTTLPR
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The tendency to ruminate—a repetitive focus on one’s negative thoughts and feelings—has
been posited to play an important role in the maintenance and etiology of depression (NolenHoeksema, 2000). Indeed, several studies have now documented that rumination is associated
with a more severe episode of depression, precedes the onset of depressive episodes, and
contributes to more persistent depressive episodes (e.g., Beevers, Rohde, Stice, & NolenHoeksema, 2007; Nolen-Hoeksema, 2000; Spasojevic & Alloy, 2001). Despite its welldocumented role in depression, the etiology of rumination has received relatively little
attention. The goal of this article is to examine the genetic etiology of rumination.
A single nucleotide polymorphism in the brain-derived neurotropic factor (BDNF) gene has
been implicated in depression vulnerability (Nestler et al., 2002). BDNF is a protein involved
Correspondence concerning this article should be addressed to Christopher G. Beevers, Department of Psychology, University of Texas
at Austin, 1 University Station, A8000, Austin, TX 78712. beevers@psy.utexas.edu.
Publisher's Disclaimer: The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting,
fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American
Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript
version, any version derived from this manuscript by NIH, or other third parties. The published version is available at
www.apa.org/pubs/journals/emo.
Beevers et al.
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in the growth and differentiation of new and existing neurons and synapses. Lower levels of
BDNF have been associated with depressive states in animals and central administration of
BDNF can reverse these states (Shirayama, Chen, Nakagawa, Russell, & Duman, 2002).
An amino acid substitution (valine to methionine) at codon 66 (Val66Met) of the BDNF gene
results in two alleles: val and met. Slightly more than one third of Caucasians inherit at least
one copy of the met allele, producing allele frequencies of .67 for val/val, .28 for val/met, and .
05 for met/met (Egan et al., 2003). Importantly, the met allele is associated with decreased
synaptic activity and plasticity in the hippocampus, abnormal hippocampal activation, lower
BDNF secretion, and poorer episodic memory (Egan et al., 2003). Met allele carriers have been
shown to have smaller hippocampal volumes (Frodl et al., 2007), reduced grey-matter volume
in prefrontal cortex (Nemoto et al., 2006), and poorer executive functioning (Rybakowski et
al., 2006) than val allele homozygotes. The BDNF genotype may therefore confer vulnerability
to depression via its effect on cognitive functioning.
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Consistent with this possibility, recent research has found an association between the BDNF
gene Val66Met polymorphism and rumination (Hilt, Sander, Nolen-Hoeksema, & Simen,
2007). Among mothers who had experienced adult-onset depression, the val/met BDNF
genotype was associated with greater rumination and depression than the val/val genotype.
Further, analyses suggested that rumination mediated the relationship between the BDNF
polymorphism and depressive symptoms. Rumination may therefore be an important
intermediate phenotype that contributes to the expression of depression.
The serotonin transporter (SLC6A4) is a second gene that has been posited to be associated
with rumination (Canli et al., 2006). The serotonin transporter (5-HTT) gene regulates the
reuptake of serotonin to the presynaptic neuron for recycling or degradation after serotonin has
been released. Importantly, the efficiency with which the transporter returns serotonin to the
presynaptic neuron appears to be influenced by a polymorphism in the serotonin transporter
gene-linked polymorphic region (5-HTTLPR).
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A common polymorphism in the promoter region of the 5-HTT gene results in 2 variants: a
short allele and a long allele. The presence of one or two short alleles, rather than two copies
of the long allele, is associated with reduced transcriptional efficiency that putatively results
in significant decreases (approximately 50%) in serotonin reuptake (Lesch et al., 1996). Short
5-HTTLPR allele carriers thus have increased levels of extracellular serotonin compared to
long allele homozygotes. Further, it has recently been determined that the long 5-HTTLPR
allele has two variants (i.e., LA and LG). In the first of two extra 20 to 23 bp repeats in the L
allele, a common single nucleotide polymorphism occurs at the sixth nucleotide (adenine to
guanine; A to G) (Wendland, Martin, Kruse, Lesch, & Murphy, 2006). The LG variant and the
S allele appear to be very similar in terms of transcriptional activity; therefore, only the LA
variant is high expressing with regard to transcriptional activity (Hu et al., 2005).
A number of studies have reported that the 5-HTTLPR is associated with cognitive
vulnerability to depression. For instance, carriers of the low expressing 5-HTTLPR allele report
a more negative attributional style (Sheikh et al., 2008), endorse more negative thoughts
following a mood induction (Beevers, Scott, McGeary, & McGeary, in press), display biased
attention for emotional stimuli (Beevers, Gibb, McGeary, & Miller, 2007), and recall more
negative self-referent words (Hayden et al., 2008) than long allele homozygotes. More relevant
to the current study, Canli et al. (2006) found that low expressing 5-HTTLPR allele carriers
who had recently experienced life stress reported higher levels of rumination than long allele
homozygotes. No other studies have examined the association between the 5-HTTLPR and
rumination.
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The studies by Hilt and colleagues (2007) and Canli et al. (2006) provide important initial
evidence regarding genetic associations with rumination. However, additional study of these
associations is warranted for a number of reasons. First, initial behavioral genetics findings are
often not replicated in subsequent studies (Ioannidis, Ntzani, Trikalinos, & ContopoulosIoannidis, 2001), so replication is critical to determine whether the initial findings are reliable.
Second, no studies have examined the association between the BDNF Val66Met polymorphism
and rumination in non-depressed samples. Depressive symptoms and rumination are typically
strongly correlated; therefore, in samples that include depressed individuals, it is difficult to
determine whether the candidate gene is associated with rumination per se or if depression
severity accounts for the association between the candidate gene and rumination. This can be
disentangled to a degree by examining the relationship between genetic variants and rumination
among individuals with low levels of depression. Finally, no study has examined associations
between rumination and more than one gene within the same sample. Studying multiple
candidate genes within the same sample facilitates comparisons across genetic groups and also
allows for the study of gene-by-gene interactions.
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The current study builds upon this relatively small body of research and examines whether
polymorphisms of the BDNF and 5-HTTLPR, both alone and in combination, are associated
with self-reported rumination in a healthy, unmedicated, never depressed sample of college
aged adults. Based on previous work, we expected met heterozygotes of the BDNF allele to
report more rumination than val allele homozygotes. The 5-HTTLPR has been associated with
rumination in the context of life stress in one small study (N = 21); however, the direct effect
of the polymorphism on rumination was relatively small (Canli et al., 2006). Nevertheless,
given the associations between 5-HTTLPR and other forms of cognitive vulnerability, we
thought it was plausible that the 5-HTTLPR might also be associated with rumination.
Method
Participants
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Participants were seventy-one undergraduate students recruited from introductory classes from
a large, southwestern university (see Table 1 for demographic information). Participants
received credit towards satisfying requirements of their introductory psychology class. The
average laboratory session was approximately one hour. Participants completed self-report
inventories that measured rumination, current depressive symptoms, the presence of past
episodes of depression, current medication use, demographic information, and other
assessments not included in this report. They also provided buccal cells used to extract DNA
for genotyping. Inclusion criteria included minimal current depressive symptoms (BDI-II < 9)
at the time of the testing, no history of major depressive disorder, and not currently taking any
psychiatric medication.
Assessments
Beck Depression Inventory – II (BDI-II; Beck, Brown, & Steer, 1996)—The BDI-II
is a widely used self-report questionnaire to assess depression severity. The BDI-II consists of
21 items and measures the presence and severity of cognitive, motivational, affective, and
somatic symptoms of depression. Past reports indicate test-retest reliability is adequate and the
BDI-II has been found to be valid among college student samples (Beck et al., 1996). Internal
consistency reliability in the current study was good (α = .81). Participants were required to
have BDI-II scores of less than 9 at the time of testing to be included in this study.
The Inventory for Diagnosing Depression-Lifetime Version (IDD-L; Zimmerman
& Coryell, 1987)—The IDD-L is a 24-item self-report questionnaire used to diagnose lifetime
presence of major depressive disorder. It has been shown to have similar sensitivity and
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specificity as the Diagnostic Interview Schedule, and good construct validity and test-retest
reliability (Zimmerman & Coryell, 1987). People who endorsed the presence of five of nine
symptoms for a two week period or greater were classified as having a history of depression.
Participants were required not to have a past history of depression to be included in this study.
Ruminative Responses Scale (RRS; Treynor, Gonzalez, & Nolen Hoeksema,
2003)—The RRS is a 10-item self-report scale that measures rumination, typically defined as
a repetitive and passive focus on one’s negative emotional state. Each question on the RRS has
a four-item response option ranging from 1 (almost never) to 4 (almost always). The RRS
provides an assessment of rumination that is not confounded with depressive symptoms. This
scale has shown good internal reliability and predictive validity (Treynor et al., 2003). The
RRS also contains two related subscales, reflection and brooding. These subscales were
moderately correlated in the present study (r = .50). Total score and subscale scores were used
in this study.
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Genotyping—Genomic DNA were isolated from buccal cells using a modification of
published methods (e.g., Freeman et al., 1997). The cheeks and gums are rubbed for 20 s with
three sterile, cotton-tipped wooden swabs. The swabs are placed in a 50-ml capped
polypropylene tube containing lysis buffer (500 μl of 1 M Tris-HCl; 200 mM disodium ethylene
diaminetetracetic acid (EDTA), pH 8.0; 500 μl of 10% sodium docecyl sulfate; and 100 μl of
5 M sodium chloride). The subjects then rinse out the mouth vigorously with 10 ml of distilled
water for 20 sec and this was added to the 50-ml tube. The tubes were stored at 4°C until the
DNA was extracted.
Brain derived neurotropic factor (BDNF)—The Val66Met polymorphism (rs6265) was
genotyped using Taqman assay C___11592758_10 (Applied Biosystems) using an ABI 7300
Real time PCR system. The frequency of the BDNF genotypes (val/val, n = 49; val/met, n =
22; met/met, n = 4) did not differ from the Hardy-Weinberg equilibrium (χ2 = 0.08, p = 0.77).
Because the rare met/met allele group only contained 4 participants, these individuals were not
included in this study due to low statistical power.
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Serotonin transporter promoter region polymorphism (5-HTTLPR)—The 5HTTLPR gene, which maps to 17q11.1–17q12, contains a 44 bp insertion/deletion in the 5′
regulatory region of the gene (Heils et al., 1996). This polymorphism in the promoter appears
to be associated with variations in transcriptional activity: the long variant (528 bp) has
approximately three times the basal activity of the shorter promoter (484 bp) with the deletion
(Lesch et al., 1996). The assay is a modification of the method of Lesch and colleagues (Lesch
et al., 1996). The primer sequences are: forward, 5′-GGCGTTGCCGCTCTGAATGC-3′
(fluorescently labeled), and reverse, 5′-GAGGGACTGAGCTGGACAACCAC-3′. These
primer sequences yield products of 484 or 528 bp. Allele sizes are scored by two investigators
independently and inconsistencies were reviewed and rerun when necessary.
To distinguish between the S, LA, and LG fragments, the PCR fragment was digested with
MspI according to the methods found in Wigg et al. (2006). The resulting polymorphic
fragments were separated using an ABI 377 DNA sequencer (S: 297, 127, 62 bp, LA: 340, 127,
and 62 bp, LG: 174, 166, 127, and 62 bp). Using this approach, allele frequencies were S: n =
63 (44.4%), LA: n = 75 (52.8%), LG: n = 4 (2.8%). Consistent with previous research, the low
expressing S and LG alleles were designated S′ and the higher expressing LA allele was
designated L′. We therefore formed three groups: (a) S′S′ (i.e., SS: n = 15 (21.1%), SLG: n =
0 (0.0%), LGLG: n = 0 (0%)), (b) S′L′ (i.e., SLA: n = 33 (46.5%), LGLA: n = 4 (5.6%)), and (c)
L′L′ (i.e., LALA: n = 19 (26.8%)). Distributions for the triallelic genotypes were in HardyWeinberg equilibrium using the exact test for multiple alleles (p = 0.25).
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Procedure
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Participants were initially recruited based on their scores on the short form of the Beck
Depression Inventory completing during mass pre-testing sessions at the beginning of the
academic semester. Individuals with low scores (< 4) were contacted and invited to participate
in the current study. Upon arrival to the laboratory, participants were oriented to the laboratory,
provided informed consent, completed the self-report questionnaires (including a second
assessment of depression severity), and provided buccal cells via a cheek swab for genotyping.
Upon completion of study procedures, participants were debriefed and were assigned course
credit for their participation. The internal review board approved all study procedures.
Results
Sample Characteristics
Descriptive statistics for the sample are presented in Table 1 stratified by BDNF and 5HTTLPR allele groups. There were no significant differences for any of the participant
variables as a function of allele grouping for the BDNF and 5-HTTLPR (see Table 1).
BDNF
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A one-way analysis of variance (ANOVA) with BDNF group (allele: val/val, val/met) as a
between subjects factor with total score on the RRS was conducted. Results indicated a
significant main effect for BDNF allele group, F(1, 69) = 6.93, p < .05, η2 = .09; the val/met
group reported significantly more rumination than the val/val group (d = 0.66; see Figure 1).
Identical analyses were conducted for the reflection and brooding subscales of the RRS. The
val/met group reported significantly more reflective rumination, F(1, 69) = 7.00, p < .05, η2
= .09, than the val/met group (M = 6.50, SD = 3.58 and M = 4.28, SD = 3.11, respectively; d
= .66). The val/met group also tended to endorse more brooding rumination, F(1, 69) = 3.22,
p < .10, η2 = .05, than the val/val group (M = 4.37, SD = 2.73 and M = 5.63, SD = 2.80,
respectively; d = .45), although this effect fell short of statistical significance.
5-HTTLPR
A one-way analysis of variance (ANOVA) with 5-HTTLPR group (allele: S′S, S′L′, L′L′) as
a between subjects factor with total score on the RRS was conducted. Results indicated a nonsignificant main effect for 5-HTTLPR allele group, F(2, 68) = 0.18, ns, η2 = .00; there were
no group differences among 5-HTTLPR allele groups (see Figure 1). Not surprisingly, there
were no 5-HTTLPR allele effects for either the reflection, F(2, 68) = 0.43, ns, η2 = .01, or
brooding, F(2, 68) = 0.11, ns, η2 = .00, subscales of the RRS.
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BDNF-by-5-HTTLLPR interaction
The final analysis served two purposes: (a) to examine whether the BDNF Val66Met
polymorphism continued to predict rumination after the 5-HTTLPR polymorphism was
entered simultaneously into an ANOVA, and (b) whether the 5-HTTLPR moderated the effect
of the Val66Met BDNF polymorphism on total score rumination. Consistent with the previous
analyses, there was a main effect for the BDNF polymorphism, F(1, 65) = 6.93, p < .05, η2 = .
10, but not the 5-HTTLPR polymorphism, F(2, 65) = 0.32, ns, η2 = .01. Further, the interaction
between the 5-HTTLPR and the BDNF did not approach statistical significance, F(2, 65) =
0.46, ns, η2 = .01.
Discussion
The overall aim of the current study was to examine whether individual differences in the
BDNF and 5-HTTLPR genes were associated with the tendency to ruminate in a healthy, non-
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medicated, non-depressed sample. Results suggest that val/met BDNF heterozygotes are
significantly more likely to ruminate than individuals homozygous for the val allele. In contrast,
there was no association between the 5-HTTLPR and rumination. Indeed, it was notable that
the rumination scores were nearly identical across the 5-HTTLPR allele groups.
These findings provide additional support that individual differences in the BDNF gene
contribute to the tendency to ruminate. This association has now been observed in adult women
who varied in current and past depression (Hilt et al., 2007) and healthy adults with no current
or history of depression. The fact that similar results were observed in studies that used different
methodologies and samples suggests that this finding may be reliable. Nevertheless, additional
replication in studies with large samples is still needed.
Additional work is also needed to determine why the met allele of the BDNF gene is associated
with rumination. BDNF plays a critical role in cortical functioning by influencing the
development and maintenance of cortical neurons and cortical synapses (Weickert et al.,
2003). Genetically mediated alterations in the regulation of BDNF could therefore contribute
to poorer executive functioning. Interestingly, depression is often characterized by poor
prefrontal control, such as difficulty inhibiting negative thoughts or stimuli. For instance,
Joormann (2004) reported that current dysphoria and lifetime depression were both associated
with poor inhibitory control when processing negative word stimuli.
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Inhibitory processes are thought to be responsible for updating working memory and for
preventing irrelevant information from entering working memory. It follows that poor
inhibitory control could lead to repeated processing of irrelevant information—a defining
feature of rumination. Consistent with this possibility, Joormann (2006) has demonstrated that
rumination is associated with poor inhibitory control, even after controlling for current
depressive symptoms. More specifically, individuals high in rumination experienced more
difficulty inhibiting irrelevant information than individuals low in rumination regardless of
depressive symptoms. Similarly, Davis and Nolen-Hoeksema (2000) found that ruminators
had a more inflexible cognitive style, as measured by the Wisconsin Card Sorting Task.
This raises the possibility that the BDNF Val66Met polymorphism contributes to rumination
via its influence on inhibitory control. Met BDNF carriers may have poorer inhibitory control
over irrelevant stimuli due to altered BDNF regulation in brain regions that are critical for
inhibitory control, such as the prefrontal cortex. This poor inhibitory control, in turn, may
contribute to the tendency to ruminate. Additional work is needed to test this possibility. Indeed,
additional interdisciplinary work that comprehensively examines the etiology of rumination
across levels of analysis (e.g., neural, cognitive, genetic) within the same sample may be critical
for developing a better understanding of the origins of rumination.
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In contrast to the BDNF allele, there was virtually no association between the 5-HTTLPR
polymorphism and rumination. Indeed, rumination was nearly identical across the 5-HTTLPR
allele groups (see Figure 1). This is in contrast to other research, which has found that the 5HTTLPR is associated with other forms of cognitive vulnerability to depression (for a review,
see Beevers & Wells, in press). However, it should be noted that one study has found that the
5-HTTLPR combines with recent life stressors to predict higher levels of rumination (Canli et
al., 2006). This suggests that the 5-HTTLPR gene may influence the tendency to ruminate
following recent adversity. Thus, whereas the BDNF polymorphism may directly influence
rumination, the 5-HTTLPR polymorphism may contribute to rumination following the
occurrence of life stress.
Although previous work has found an interaction between BDNF and 5-HTTLPR for neural
structures involved in emotion processing (Pezawas et al., 2008), we found no evidence of
epistasis in the current study. Nevertheless, future work should continue exploring the
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contribution of gene-by-gene interactions to rumination. It is highly probable that multiple
genes contribute to the expression of a complex phenotype such as rumination. Indeed, given
that the BDNF gene putatively influences neural plasticity, it may be an excellent gene with
which to study gene-by-gene interactions. Consistent with this possibility, Nagel et al.
(2008), reported that BDNF met carriers performed significantly worse on executive
functioning tasks if they were also Catechol-O-Methyltransferase (COMT) Val allele carriers.
In other words, the BDNF gene moderated the effect of the COMT polymorphism on prefrontal
cognitive performance. Given these genetic associations with executive function, this finding
may have particular relevance for understanding rumination. It also suggests that additional
research should examine associations between polymorphisms of the COMT gene and
rumination.
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Several limitations of this study should be noted. Small sample size is an important limitation,
as effects observed in small samples are less likely to be replicated than effects initially
observed in large samples. Further, small sample size may have also limited our ability to detect
significant gene-by-gene interactions. Given the positive findings for the association between
the BDNF polymorphism and rumination, larger scale studies involving participants with
greater variability in depression and age seem warranted. Similar studies that also measure life
stress are needed to further establish a link between 5-HTTLPR and rumination. As with any
genetic association study, population stratification is a potential concern. This confound is
unlikely as the vast majority of participants were Caucasian and ethnicity was unrelated to
rumination or allele status. Third variable explanations, such as the possibility that the BDNF
and 5-HTTLPR polymorphisms are in linkage disequilibrium with another functional genetic
marker, should also be considered as alternative explanations for the observed effects.
Despite these limitations, we believe this study makes an important and interesting contribution
to understanding rumination. Individuals who inherit the met variant of the BDNF gene may
be more likely to ruminate. This proclivity to ruminate may contribute vulnerability to
depression and therefore represent one psychological pathway that connects individual
differences in the BDNF gene to the expression of depression. However, the expression of
depression is obviously more complex than a single pathway. Additional work that tests
complex etiological models of depression across levels of analyses (genetic, neural, cognitive,
environmental) may allow for the development more comprehensive models, and further our
understanding of this important and debilitating disorder.
Acknowledgments
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Christopher G. Beevers and Tony T. Wells, Department of Psychology, University of Texas at Austin; John E.
McGeary, Providence Veterans Affairs Medical Center and Center for Alcohol and Addiction Studies, Brown
University. The authors thank the research assistants of the Mood Disorders Laboratory at the University of Texas for
their help with data collection.
Preparation of this article was facilitated by a grant (R01MH076897) from the National Institute of Mental Health to
Christopher Beevers and a shared equipment grant from the National Center for Research Resources (S10RR023457)
to John McGeary.
References
Beevers CG, Gibb BE, McGeary JE, Miller IW. Serotonin Transporter Genetic Variation and Biased
Attention for Emotional Word Stimuli Among Psychiatric Inpatients. Journal of Abnormal Psychology
2007;116(1):208. [PubMed: 17324031]
Beevers CG, Rohde P, Stice E, Nolen-Hoeksema S. Recovery from major depressive disorder among
female adolescents: A prospective test of the scar hypothesis. Journal of Consulting and Clinical
Psychology 2007;75(6):888. [PubMed: 18085906]
Emotion. Author manuscript; available in PMC 2010 August 1.
Beevers et al.
Page 8
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Beevers CG, Scott WD, McGeary C, McGeary JE. Negative cognitive response to a sad mood induction:
Associations with polymorphisms of the serotonin transporter (5-HTTLPR) gene. Cognition &
Emotion. (in press).
Beevers, CG.; Wells, T. Genetic associations with cognitive vulnerablity to depression. In: Ingram, RE.,
editor. The International Encyclopedia of Depression. New York: Springer; (in press)
Canli T, Qiu M, Omura K, Congdon E, Haas BW, Amin Z, et al. Neural correlates of epigenesis. PNAS
2006;103(43):16033–16038. [PubMed: 17032778]
Davis RN, Nolen-Hoeksema S. Cognitive inflexibility among ruminators and nonruminators. Cognitive
Therapy and Research 2000;24(6):699–711.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met
Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal
Function. Cell 2003;112(2):257–269. [PubMed: 12553913]
Freeman B, Powell J, Ball D, Hill L, Graig I, Plomin R. DNA by mail: An inexpensive and noninvasive
method for collecting DNA samples from widely dispersed populations. Behavioral Genetics
1997;27:251–257.
Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P, et al. Association of the Brain-Derived
Neurotrophic Factor Val66Met Polymorphism With Reduced Hippocampal Volumes in Major
Depression. Arch Gen Psychiatry 2007;64(4):410–416. [PubMed: 17404118]
Hayden EP, Dougherty LR, Maloney B, Olino TM, Sheikh H, Durbin CE, et al. Early-emerging cognitive
vulnerability to depression and the serotonin transporter promoter region polymorphism. Journal of
Affective Disorders 2008;107(1–3):227–230. [PubMed: 17804080]
Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, et al. Allelic variation of the human serotonin
transporter gene expression. Journal of Neurochemistry 1996;66:2621–2624. [PubMed: 8632190]
Hilt LM, Sander LC, Nolen-Hoeksema S, Simen AA. The BDNF Val66Met polymorphism predicts
rumination and depression differently in young adolescent girls and their mothers. Neurosci Lett.
2007
Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA. An expanded evaluation of the relationship
of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res
2005;29(1):8–16. [PubMed: 15654286]
Joormann J. Attentional bias in dysphoria: The role of inhibitory processes. Cognition & Emotion 2004;18
(1):125–147.
Joormann J. Differential Effects of Rumination and Dysphoria on the Inhibition of Irrelevant Emotional
Material: Evidence from a Negative Priming Task. Cognitive Therapy and Research 2006;30(2):149.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related
traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274
(5292):1527–1531. [PubMed: 8929413]
Nagel IE, Chicherio C, Li S-C, von Oertzen T, Sander T, Villringer A, et al. Human aging magnifies
genetic effects on executive functioning and working memory. Frontiers in Human Neuroscience
2008;2
Nemoto K, Ohnishi T, Mori T, Moriguchi Y, Hashimoto R, Asada T, et al. The Val66Met polymorphism
of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neuroscience
Letters 2006;397(1–2):25–29. [PubMed: 16388901]
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of Depression.
Neuron 2002;34(1):13–25. [PubMed: 11931738]
Nolen-Hoeksema S. The role of rumination in depressive disorders and mixed anxiety/depressive
symptoms. Journal of Abnormal Psychology 2000;109(3):504–511. [PubMed: 11016119]
Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS, et al. Evidence
of biologic epistasis between BDNF and SLC6A4 and implications for depression. Molecular
Psychiatry 2008;13(7):709–716. [PubMed: 18347599]
Rybakowski JK, Borkowska A, Skibinska M, Szczepankiewicz A, Kapelski P, Leszczynska-Rodziewicz
A, et al. Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met
polymorphism of the brain-derived neurotrophic factor gene. Psychiatry and Clinical Neurosciences
2006;60(1):70–76. [PubMed: 16472361]
Emotion. Author manuscript; available in PMC 2010 August 1.
Beevers et al.
Page 9
NIH-PA Author Manuscript
Sheikh HI, Hayden EP, Singh SM, Dougherty LR, Olino TM, Durbin CE, et al. An examination of the
association between the 5-HTT promoter region polymorphism and depressogenic attributional styles
in childhood. Personality and Individual Differences 2008;45(5):425–428. [PubMed: 19122845]
Shirayama Y, Chen ACH, Nakagawa S, Russell DS, Duman RS. Brain-Derived Neurotrophic Factor
Produces Antidepressant Effects in Behavioral Models of Depression. J Neurosci 2002;22(8):3251–
3261. [PubMed: 11943826]
Spasojevic J, Alloy LB. Rumination as a common mechanism relating depressive risk factors to
depression. Emotion 2001;1(1):25–37. [PubMed: 12894809]
Treynor W, Gonzalez R, Nolen Hoeksema S. Rumination Reconsidered: A Psychometric Analysis.
Cognitive Therapy and Research 2003;27(3):247–259.
Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE. Reduced brain-derived
neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2003;8(6):
592–610. [PubMed: 12851636]
Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL. Simultaneous genotyping of four functional
loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry 2006;11(3):
224. [PubMed: 16402131]
Wigg KG, Takhar A, Ickowicz A, Tannock R, Kennedy JL, Pathare T, et al. Gene for the serotonin
transporter and ADHD: No association with two functional polymorphisms. American journal of
medical genetics Part B, Neuropsychiatric genetics 2006;141(6):566–570.
Zimmerman M, Coryell W. The inventory to diagnose depression, lifetime version. Acta Psychiatrica
Scandinavica 1987;75(5):495–499. [PubMed: 3604734]
NIH-PA Author Manuscript
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Figure 1.
Mean and standard errors for total rumination scores, measured with the Ruminative Responses
Scale, presented as a function of (a) BDNF and (b) 5-HTTLPR allele groups.
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Table 1
BDNF
Age (years)
5-HTTLPR
Val/Val (n = 49)
Val/Met (n = 22)
S′S (n = 15)
S′L′ (n = 37)
L′L′ (n = 19)
Emotion. Author manuscript; available in PMC 2010 August 1.
19.4 (1.65)
18.8 (1.05)
19.5 (2.07)
18.9 (1.05)
18.7 (0.96)
% Gender (F/M)
65/35
46/54
42/58
62/38
67/33
% Hispanic (Yes/No)
18/82
12/88
5/95
14/86
28/71
% Caucasian/Other
71/29
84/16
80/20
84/16
72/28
3.09 (2.91)
4.00 (3.37)
3.68 (2.31)
2.57 (2.54)
2.87 (2.77)
Depressive symptoms
Beevers et al.
Demographic data presented as a function of Val66Met and 5-HTTLPR allele status.
Note: within each genetic group, there were no statistically significant allele group differences on any of these variables.
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