|Year : 2019 | Volume
| Issue : 1 | Page : 33-38
A gene-based analysis of variants in the Brain-derived Neurotrophic Factor gene with psychological distress in a Taiwanese population
Eugene Lin Ph.D. 1, Po- Hsiu Kuo Ph.D. 2, Yu- Li Liu Ph.D. 3, Albert C Yang M.D., Ph.D. 4, Shih- Jen Tsai M.D. 5
1 Department of Biostatistics; Department of Electrical and Computer Engineering, University of Washington, Seattle, Washington, USA; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
2 Department of Public Health, Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
3 Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan
4 Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan; Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, USA; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
5 Division of Psychiatry, National Yang-Ming University; Institute of Brain Science, National Yang-Ming University; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
|Date of Submission||19-Dec-2018|
|Date of Decision||10-Jan-2019|
|Date of Acceptance||11-Jan-2019|
|Date of Web Publication||28-Mar-2019|
Shih- Jen Tsai
No. 201, Shih-Pai Road, Section 2, Taipei 112
Source of Support: None, Conflict of Interest: None
Background: Brain-derived neurotrophic factor (BDNF), the most abundant and widely expressed neurotrophin in the brain, is believed to play an important role in depression and anxiety. In this study, we hypothesized that single-nucleotide polymorphisms (SNPs) within the BDNF gene should be linked with depression and anxiety through complex interactions in the general population. Methods: We analyzed 7,098 Taiwanese participants from the Taiwan Biobank. Measures of anxiety and depression were evaluated using the Patient Health Questionnaire-4 (PHQ-4). We used 43 BDNF polymorphisms in the genetic analysis. Results: We found a nominal association between nine BDNF genetic variants and depression state, after having adjusted for the factors of age and gender. Furthermore, three BDNF SNPs showed evidence of nominal association with PHQ-4 scores. In addition, an interaction significantly existed between the BDNF rs73430670 and BDNF rs4923461 in influencing depression state (p < 0.05). Finally, we found that influence of interaction significantly existed between BDNF rs12418745 and physical activity (p < 0.05) in depression state. Conclusion: Those results suggest that the BDNF genetic variants may contribute to psychological distress independently as well as through SNP-SNP and gene-physical activity interactions in the general population.
Keywords: Anxiety, depression, Patient Health Questionnaire-4, polymorphism
|How to cite this article:|
Lin E, Kuo PH, Liu YL, Yang AC, Tsai SJ. A gene-based analysis of variants in the Brain-derived Neurotrophic Factor gene with psychological distress in a Taiwanese population. Taiwan J Psychiatry 2019;33:33-8
|How to cite this URL:|
Lin E, Kuo PH, Liu YL, Yang AC, Tsai SJ. A gene-based analysis of variants in the Brain-derived Neurotrophic Factor gene with psychological distress in a Taiwanese population. Taiwan J Psychiatry [serial online] 2019 [cited 2021 May 17];33:33-8. Available from: http://www.e-tjp.org/text.asp?2019/33/1/33/255145
| Introduction|| |
Brain-derived neurotrophic factor (BDNF), a homodimeric neurotrophic factor, is the most abundant and widely expressed neurotrophin in the brain. Actions of BDNF are mediated through binding to two receptors – a specific and high-affinity receptor and a tyrosine kinase B receptor, as well as a nonspecific low-affinity receptor, p75. BDNF plays an important rôle in neuronal differentiation and survival during embryonic development, as well as in the maintenance of neuron viability in adulthood, in both the central and peripheral nervous systems,. Furthermore, BDNF can modulate synaptic plasticity and its molecular mediators across multiple neurotransmitter systems. In the brain, BDNF is most active in the hippocampus and prefrontal cortex – areas vital to learning, memory, and mood.
Accumulating evidence from animal and clinical studies support the importance of BDNF in depression and antidepressant drug action. Lowered hippocampal BDNF has been hypothesized to contribute to developing depression and elevation in hippocampal BDNF in improving antidepressant therapeutic effect. Previous animal studies indicated that immobilization stress can decrease BDNF mRNA levels in the hippocampus and other brain regions. Chronic antidepressant treatments in animals upregulate the expression of brain BDNF, and an infusion of BDNF into the midbrain gives an antidepressant-like effect in animal depression models. In support of those findings, we have shown that cysteamine, an enhancer of brain BDNF secretion, has an antidepressant-like effect in the animal depression model. For a clinical study, Karege et al. found that depression severity shows a negative association and that compared to controls, serum BDNF levels are lower in depressed patients. A postmortem study indicated that expression of BDNF mRNA is decreased in both the prefrontal cortex and hippocampus in participants who have committed suicide. In addition, BDNF is also involved in anxiety-like behaviors in animal models, and many various types of stressors can cause lowered expression of BDNF,. Both Bdnf mutants with conditional deletion of Bdnf and knock-in hBDNF Met mice show increased depression/anxiety-related behaviors,.
The tissue and brain region-specific human BDNF gene which is composed of 11 exons and 9 functional promoters, has been mapped to chromosome 11p13. A nonconservative amino acid alteration (valine to methionine) at exon position 66 (Val66Met, rs6265) is caused by a common single-nucleotide polymorphism (SNP) consisting of a missense change (G196A). Substitution of Val66 with Met66 disrupts cellular processing, trafficking, and activity-dependent secretion of BDNF. Previous studies found that this polymorphism is associated with various neuropsychiatric diseases or their therapeutic responses including major depression, schizophrenia, Alzheimer's disease (AD), violent behaviors, suicide behaviors, personality traits, and substance abuse,,,,,,,,,,,, although not all studies have similar findings. Some information from other BDNF SNPs is overlooked because that investigating a single BDNF polymorphism (i.e., the Val66Met polymorphism) might only reveal some of the BDNF genetic variability. Genetic studies of other BDNF polymorphisms have been done in BDNF SNP, C270T polymorphism (rs56164415) in the BDNF 5' noncoding region, which has been identified to be associated with AD. Licinio et al. showed that six BDNF SNPs (rs12273539, rs11030103, rs6265, rs28722151, rs41282918, and rs11030101) are associated with major depression through sequencing the BDNF gene and the 5-kb flanking region.
BDNF plays an important role in the development of depression and anxiety. To our knowledge, the BDNF genetic effect in depression and anxiety is sparse in the general population. In this study, we hypothesized that BDNF genetic polymorphisms would be linked with depression and anxiety. With a Taiwanese general population, we intended to assess the potential SNP-SNP and gene-physical activity effects of these associations on the mood states.
| Methods|| |
The study participants were partially original to the Taiwan Biobank. The study cohort consisted of 7,098 participants. The study protocols including recruitment and sample collection procedures were approved by the Internal Review Board of the Taiwan Biobank before conducting the study with the requirement of a signed informed consent form from each participating individual.
Depression and anxiety assessment
We assessed psychological distress with the self-report Patient Health Questionnaire-4 (PHQ-4), which is an ultra-brief screening tool to detect emotional disorders in primary care. PHQ-4 has 4 items (0–3 for each item; total score ranges from 0 to 12) to measure anxiety and depressive symptoms in the past 2 weeks and has been demonstrated to be a general marker of psychological distress.
We isolated DNA from blood samples with a QIAamp DNA blood kit following the manufacturer's instructions (Qiagen, Valencia, California, USA). The quality of the isolated genomic DNA was evaluated using agarose gel electrophoresis, and the quantity was determined using spectrophotometry. We carried out SNP genotyping with the custom Taiwan Biobank chips and run on the Axiom Genome-Wide Array Plate System (Affymetrix, Santa Clara, California, USA). To efficiently obtain maximal genetic information from Taiwanese Han Chinese samples, we designed the custom Taiwan Biobank chips with SNPs on the Axiom Genome-Wide CHB 1 Array (Affymetrix, Inc., Santa Clara, California, USA) with minor allele frequencies (MAFs) being greater than or equal to 5%, using SNPs in exons with MAFs being greater than 10% on the Human Exome BeadChip (Illumina, Inc., San Diego, California, USA). In this study, quality criteria for BDNF SNP exclusion from further analyses were the following: due to the failure to achieve the Hardy–Weinberg equilibrium, a genotyping call rate being smaller than 90% or to MAF being smaller than 1%. After the quality control procedure, we used 43 BDNF SNPs for further analysis.
To estimate the association of the investigated SNP with depression state, we did a logistic regression analysis to evaluate the odds ratios and their 95% confidence intervals, adjusting for covariates including the factors of age and gender. Furthermore, we estimated the associations of the investigated BDNF SNPs with PHQ-4 scores with a general linear model using age and gender as covariates.
To investigate SNP-SNP and gene-physical activity interactions, we leveraged the generalized multifactor dimensionality reduction (GMDR) method. We tested two-way interactions with 10-fold cross-validation. The GMDR software provided some output parameters, including testing accuracy and empirical p- values, to assess each selected interaction. Moreover, we provided age and gender as covariates for gene-gene and gene-physical activity interaction models in our interaction analyses. Permutation testing obtained empirical p-values of prediction accuracy as a benchmark based on 1,000 shuffles.
Multiple testing was adjusted using the Bonferroni correction. The criterion for significance was set at p < 0.05 for all tests. Data are presented as the mean ± standard deviation.
All study data were computed using the Statistical Package for the Social Sciences version 22 for Windows (SPSS Inc., Chicago, Illinois, USA). The difference between groups were considered significant if p < 0.05.
| Results|| |
This study included 7,098 participants (male: 3,213, female: 3,885, age range: 30 - 70 years, 49.9 ± 11.0 [mean ± standard deviation] years). The median PHQ-4 score was 0 and the interquartile range was 0 - 2.
A score of 3 in the 4th item of the PHQ-4 (feeling down, depressed, or hopeless) has been suggested as “current major depression and/or dysthymia.” Among the studied participants, 52 had core of 3 in this item [Table 1] and were grouped as depression group, while the others were as normal group. As shown in [Table 2], we identified that nine BDNF SNPs (including rs7127239, rs1038660, rs12418745, rs7481311, rs12577586, rs10767649, rs73430670, rs56405868, and rs4923460) were associated with depression state although significance did not survive correction for multiple testings.
|Table 2: Odds ratio analysis with odds ratios after adjustment for covariates between the Patient Health Questionnaire-4 (normal: Patient Health Questionnaire-4=0, 1, and 2; depression: Patient Health Questionnaire-4=3) and 43 single-nucleotide polymorphisms in the BDNF gene|
Click here to view
Then, we investigated the association between total PHQ-4 scores and BDNF SNPs. Among the tested 43 BDNF SNPs in this study, three SNPs were found in the BDNF gene having significant association (p < 0.05) with PHQ-4 scores [Table 3]. The association with PHQ-4 scores did not persist with significance after applying Bonferroni correction.
|Table 3: Linear regression models of associations between the Patient Health Questionnaire-4 (as a continuous outcome) and 43 single-nucleotide polymorphisms in the BDNF gene|
Click here to view
The GMDR analysis with adjustment for age and gender was used to assess the impacts of combinations between two key SNPs in depression state. A significant two-way model existed involving BDNF rs73430670 and BDNF rs4923461 (p < 0.05), indicating a potential SNP-SNP interaction between these two polymorphisms in influencing depression state.
Physical activity and gene interaction models were evaluated by the GMDR method with adjustment for age and gender. A significant two-way model [Table 2] existed involving BDNF rs12418745 and physical activity (p < 0.05), indicating potential physical activity and gene interaction in influencing depression state.
| Discussion|| |
Psychological distress, including depression and anxiety, can increase the risk of developing physical illnesses and the use of general medical services. In this study, we tested whether psychological distress was affected by BDNF genetic variants in a general population. Among the 43 BDNF SNPs tested [Table 2] and [Table 3], nine SNPs showed significant association with depression state (p < 0.05 or p < 0.01). Our study is the first to date to track down whether the BDNF SNPs are associated with psychological distress independently and/or through SNP-SNP and gene-physical activity interactions among Taiwanese individuals. Here, we found that the BDNF gene may play a key role in modulating depression and/or anxiety in the general population. Our findings are in line with animal studies that Bdnf mutants with conditional deletion of Bdnf or knock-in hBDNF Met mice show increased anxiety-related behaviors,. Regarding BDNF genetic studies in human depression and anxiety, the study findings are not consistent. In 2003, we first reported that the association study exists between the BDNF Val66Met polymorphism and major depressed outpatients as well as inpatients,. Regarding negative findings in those two studies, we suggested that the BDNF Val66Met polymorphism is not a major contributing factor to depression susceptibility. The negative findings are supported by the following studies in Korean population, Japanese population, Belgian population, Spanish population (that used eight BDNF polymorphisms), British population, and Chinese population,. However, haplotype analysis with three BDNF polymorphisms in a German population has produced nominally association for major depression. The above studies were done using adult depressed patients. In 2006, we tested the association between the BDNF Val66Met polymorphism and geriatric depression and found that the Met66 allele is a risk allele for geriatric depression. The following study in Caucasian participants replicated our findings. Thus, to test BDNF genetic effect in depression, we suggest that age can be an important confounding factor.
Intriguingly, another finding was that we further inferred the BDNF SNP-SNP interaction effect in influencing psychological stress using the GMDR approach. One of the problems with most genetic studies is that they are mostly focused on SNP associations with phenotype. Such approach disregards the joint effect of multiple loci and also the complex interaction network in between, and is thus most likely to underestimate the roles of genetics in human diseases. This may explain why the expectations of genetic studies in human health have not met so far. To our knowledge, no other study has been conducted to evaluate the SNP-SNP interaction in depression. Besides the statistical significance, the potential biological mechanism under the interaction models was our concern. The functional relevance of the interactive effects of BDNF in depression remains to be elucidated.
The current major causes of burden in mental disorders, although known to have strong genetic determinants, are considered multifactorial consequences of rather complex interactions among environmental and genetic factors. Remarkably, the GMDR analysis of gene-environment interactions in this study reflected the interplay among BDNF and the physical activity in influencing depression state. Exercise interventions [Table 2] showed significantly improved depression in depressed patients (p < 0.05). One potential mechanism by which exercise improves depression is through a positive impact on the release of brain BDNF and therefore neuron plasticity.
This study presents three limitations which require considerations in interpreting our findings or overinterpreting the results:
- Our data showed nominal associations of depression and/or anxiety with several BDNF SNPs. However, none of these SNPs persisted significantly after performing Bonferroni correction. This could be due to small sample size in the depression group. Further studies with large sample size are warranted
- PHQ-4 is a self-report questionnaire that consists of a 4-item inventory. Reliability of the self-report questionnaires used by researchers depends on the honesty of their participants. The lack in introspective ability of the participant to provide accurate response to a question remains an issue. On the other hand, factor analysis confirmed two discrete factors (depression and anxiety) that explained 84% of the total variance. Increasing PHQ-4 scores are strongly associated with functional impairment, disability days, and health-care use
- The sample was recruited from a population of Taiwanese population. Several meta-analyses of BDNF genetic studies have demonstrated that the positive association findings of the BDNF polymorphisms are dependent on ethnicity; therefore, our findings in this study require further confirmation in other ethnic groups.
We have comprehensively analyzed the genetic association of the BDNF with psychological distress in Taiwanese general population samples. On the basis of the present study findings, we found that the BDNF genetic variants may contribute to psychological distress independently as well as through SNP-SNP and gene-physical activity interactions. Independent replication studies with larger sample sizes will likely demonstrate further insights into the rôle of the BDNF gene found in this study.
| Acknowledgment|| |
The author thanks Emily Ting for English editing.
| Financial Support and Sponsorship|| |
This work was financially supported by the Taiwan Ministry of Science and Technology with grant no. MOST 107-2634-F-075-002 and the Taipei Veterans General Hospital with grant no. V105D17-002-MY2-2.
| Conflicts of Interest|| |
There are no conflicts of interest.
| References|| |
Reichardt LF: Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci
2006; 361: 1545-64.
Hong CJ, Liou YJ, Tsai SJ: Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull
2011; 86: 287-97.
Tsai SJ: Critical issues in BDNF Val66Met genetic studies of neuropsychiatric disorders. Front Mol Neurosci
2018; 11: 156.
Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry
1997; 54: 597-606.
Smith MA, Makino S, Kvetnanský R, et al.
: Effects of stress on neurotrophic factor expression in the rat brain. Ann N Y Acad Sci
1995; 771: 234-9.
Nibuya M, Morinobu S, Duman RS: Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci
1995; 15: 7539-47.
Siuciak JA, Lewis DR, Wiegand SJ, et al.
: Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav
1997; 56: 131-7.
Shieh CH, Hong CJ, Huang YH, et al.
: Potential antidepressant properties of cysteamine on hippocampal BDNF levels and behavioral despair in mice. Prog Neuropsychopharmacol Biol Psychiatry
2008; 32: 1590-4.
Karege F, Perret G, Bondolfi G, et al.
: Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res
2002; 109: 143-8.
Dwivedi Y, Rizavi HS, Conley RR, et al.
: Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry
2003; 60: 804-15.
Suliman S, Hemmings SM, Seedat S: Brain-derived neurotrophic factor (BDNF) protein levels in anxiety disorders: systematic review and meta-regression analysis. Front Integr Neurosci
2013; 7: 55.
Chen MH, Tsai SJ: Treatment-resistant panic disorder: clinical significance, concept and management. Prog Neuropsychopharmacol Biol Psychiatry
2016; 70: 219-26.
Lindholm JS, Castrén E: Mice with altered BDNF signaling as models for mood disorders and antidepressant effects. Front Behav Neurosci
2014; 8: 143.
Pruunsild P, Kazantseva A, Aid T, et al.
: Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics
2007; 90: 397-406.
Egan MF, Kojima M, Callicott JH, et al.
: The BDNF Val66Met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell
2003; 112: 257-69.
Chen SP, Fuh JL, Wang SJ, et al.
: Brain-derived neurotrophic factor gene Val66Met polymorphism modulates reversible cerebral vasoconstriction syndromes. PLoS One
2011; 6: e18024.
Hong CJ, Huo SJ, Yen FC, et al.
: Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology
2003; 48: 186-9.
Hwang JP, Tsai SJ, Hong CJ, et al.
: The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging
2006; 27: 1834-7.
Kao CF, Liu YL, Yu YW, et al.
: Gene-based analysis of genes related to neurotrophic pathway suggests association of BDNF and VEGFA with antidepressant treatment-response in depressed patients. Sci Rep
2018; 8: 6983.
Lin E, Hong CJ, Hwang JP, et al.
: Gene-gene interactions of the brain-derived neurotrophic-factor and neurotrophic tyrosine kinase receptor 2 genes in geriatric depression. Rejuvenation Res
2009; 12: 387-93.
Tsai SJ, Cheng CY, Yu YW, et al.
: Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet
2003; 123B: 19-22.
Tsai SJ, Gau YT, Liu ME, et al.
: Association study of brain-derived neurotrophic factor and apolipoprotein E polymorphisms and cognitive function in aged males without dementia. Neurosci Lett
2008; 433: 158-62.
Tsai SJ, Hong CJ, Liou YJ: Recent molecular genetic studies and methodological issues in suicide research. Prog Neuropsychopharmacol Biol Psychiatry
2011; 35: 809-17.
Tsai SJ, Hong CJ, Liu HC, et al.
: The brain-derived neurotrophic factor gene as a possible susceptibility candidate for Alzheimer's disease in a Chinese population. Dement Geriatr Cogn Disord
2006; 21: 139-43.
Tsai SJ, Hong CJ, Yu YW, et al.
: Association study of a brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and personality trait and intelligence in healthy young females. Neuropsychobiology
2004; 49: 13-6.
Tsai SJ, Liao DL, Yu YW, et al.
: A study of the association of (Val66Met) polymorphism in the brain-derived neurotrophic factor gene with alcohol dependence and extreme violence in Chinese males. Neurosci Lett
2005; 381: 340-3.
Kunugi H, Ueki A, Otsuka M, et al.
: A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol Psychiatry
2001; 6: 83-6.
Licinio J, Dong C, Wong ML: Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry
2009; 66: 488-97.
Lin E, Yang AC, Tsai SJ: Association between metabolic syndrome and cognitive function in old adults in a Taiwanese population. Taiwan J Psychiatry (Taipei)
2017; 31: 232-40.
Kroenke K, Spitzer RL, Williams JB, et al.
: An ultra-brief screening scale for anxiety and depression: The PHQ-4. Psychosomatics
2009; 50: 613-21.
Lou XY, Chen GB, Yan L, et al.
: A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. Am J Hum Genet
2007; 80: 1125-37.
Osório FL, Lima MP, Chagas MH: Screening tools for psychiatry disorders in cancer setting: caution when using. Psychiatry Res
2015; 229: 739-42.
Goodwin GM: Depression and associated physical diseases and symptoms. Dialogues Clin Neurosci
2006; 8: 259-65.
Schumacher J, Jamra RA, Becker T, et al.
: Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry
2005; 58: 307-14.
Taylor WD, Züchner S, McQuoid DR, et al.
: Allelic differences in the brain-derived neurotrophic factor Val66Met polymorphism in late-life depression. Am J Geriatr Psychiatry
2007; 15: 850-7.
Yang CH, Chuang LY, Lin YD: Multiobjective multifactor dimensionality reduction to detect SNP-SNP interactions. Bioinformatics
2018; 34: 2228-36.
Dinoff A, Herrmann N, Swardfager W, et al.
: The effect of exercise on resting concentrations of peripheral brain-derived neurotrophic factor (BDNF) in major depressive disorder: a meta-analysis. J Psychiatr Res
2018; 105: 123-31.
[Table 1], [Table 2], [Table 3]