Date Published: January 24, 2019
Publisher: Public Library of Science
Author(s): Asraa Faris Aldoghachi, Yin Sim Tor, Siti Zubaidah Redzun, Khairul Aiman Bin Lokman, Nurul Asyikin Abdul Razaq, Aishah Farhana Shahbudin, Ibrahim Mohamed Badamasi, Pike-See Cheah, Johnson Stanslas, Abhi Veerakumarasivam, Rozita Rosli, Normala Ibrahim, Munn Sann Lye, King-Hwa Ling, Kenji Hashimoto.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin found in abundance in brain regions such as the hippocampus, cortex, cerebellum and basal forebrain. It has been associated with the risk of susceptibility to major depressive disorder (MDD). This study aimed to determine the association of three BDNF variants (rs6265, rs1048218 and rs1048220) with Malaysian MDD patients.
The correlation of these variants to the plasma BDNF level among Malaysian MDD patients was assessed. A total of 300 cases and 300 matched controls recruited from four public hospitals within the Klang Valley of Selangor State, Malaysia and matched for age, sex and ethnicity were screened for BDNF rs6265, rs1048218 and rs1048220 using high resolution melting (HRM).
BDNF rs1048218 and BDNF rs1048220 were monomorphic and were excluded from further analysis. The distribution of the alleles and genotypes for BDNF rs6265 was in Hardy-Weinberg equilibrium for the controls (p = 0.13) but was in Hardy Weinberg disequilibrium for the cases (p = 0.011). Findings from this study indicated that having BDNF rs6265 in the Malaysian population increase the odds of developing MDD by 2.05 folds (95% CI = 1.48–3.65). Plasma from 206 cases and 206 controls were randomly selected to measure the BDNF level using enzyme-linked immunosorbent assay (ELISA). A significant decrease in the plasma BDNF level of the cases as compared to controls (p<0.0001) was observed. However, there was no evidence of the effect of the rs6265 genotypes on the BDNF level indicating a possible role of other factors in modulating the BDNF level that warrants further investigation. The study indicated that having the BDNF rs6265 allele (A) increase the risk of developing MDD in the Malaysian population suggesting a possible role of BDNF in the etiology of the disorder.
Major depressive disorder (MDD) is one of the most common mental illnesses worldwide affecting an individual’s feelings, thoughts and behaviour. It results from an interaction of both genetic and environmental factors. The symptoms of major depressive disorder usually last for two or more constitutive weeks. The symptoms are characterised by having a persistent form of sadness and loss of interest in once pleasurable activities and several other physical and cognitive symptoms such as inability to concentrate, changes in sleep and eating habits, physical inactivity, suicidal thoughts and suicidality . Currently, MDD is a major cause to the global burden of disease affecting more than 300 million individuals globally . It is the third most disabling disorder worldwide and is expected to be the first by the year 2030 . In Malaysia, it is one of the most common reported mental illnesses with about 29% of the Malaysians suffering from depression in the year 2015 .
Out of the 800 subjects approached for this study, only 300 cases and 300 matched controls met the criteria to join the study. The remaining subjects were rejected as they were diagnosed with anxiety or other neuropsychiatric disorders, refused to consent for blood withdrawal and/or were uncontactable after initial agreement to participate in the study. The socio-demographic information for all the participants included in the study are listed in Table 2.
The brain derived neurotrophic factor is one of the most abundant neurotrophins in the mammalian brain and is involved in the function, development and survival of neurons . The role of a single nucleotide polymorphism in the coding region of BDNF gene, BDNF rs6265 has been investigated in several neuropsychiatric disorders including major depressive disorder [16,31–34]. To date, there has been no study associating the BDNF rs6265 to MDD in the Malaysian population. In this study, we found that having the mutant variant increases the risk of MDD by approximately 2.05 (95%CI 1.48–3.65; p = 0.015) as compared to the wild type allele. Findings from our study agrees with the study by Ribeiro et al., (2007)  on the Caucasian population whereby they found a significant difference of the alleles between cases and controls (p = 0.005). The same study demonstrated that subjects with the mutant genotype had an odds ratio of 1.7 (95% CI 1.17–2.47) of developing MDD as compared to subjects of other genotypes. Similarly, Schumacher et al., (2005) studied two SNPs (rs988748 and rs6265) and a dinucleotide repeat (GT)n of BDNF and found no association between the individual SNPs and depression . However, an association was obtained at the haplotype level of both the SNPs and the dinucleotide repeat (p = 0.0057).
The current study is the first to screen for BDNF rs6265 in the Malaysian population and associate it to the risk of development of MDD. Findings from this study indicate that having BDNF rs6265 increase the odds of developing MDD in the Malaysian population approximately by 2.05-fold. Hence, these findings strengthen the role of BDNF in the development of major depressive disorder in the Malaysian population and therefore serve a potential biomarker for early MDD screening in the future. Furthermore, a significant decrease in plasma BDNF levels was seen in the cases as compared to controls but not among the three genotypes. This implies a need for future studies to look at other single nucleotide polymorphisms in the BDNF gene and study their role and susceptibility to MDD both at the individual and at the haplotype level. In addition, further investigation of the cause and effect of reduction in the BDNF level is of equal importance.