Keywords
Obsessive Compulsive Disorder; BDNF; Val66Met polymorphism; Susceptibility; Neurotrophin
Abstract
Brain-Derived Neurotrophic Factor (BDNF) is required for neuron growth and maintenance. Single nucleotide polymorphisms (SNP) are reported in BDNF gene, which reduces proteins activity, Val66Met polymorphism is very well studied and reported as a risk factor for psychiatric diseases. Numerous case-control studies have evaluated the role BDNF Val 66Met (dbSNP: rs6265;196G>A) polymorphism in OCD susceptibility and provided ambiguous findings, hence present meta-analysis was designed to get an exact association between BDNF Val66Met polymorphism and OCD risk. A total of 14 case - control articles were identified through PubMed, Google Scholar, Science Direct and Springer link databases search, up to July 11, 2024. Odds ratios (ORs) with 95% con¬fidence intervals (CIs) were used as association measure. All statistical analyses were done by MetaDiSc (version 1.4).
Fourteen case-control studies involving 2,765 OCD cases and 5,585 controls were included in present meta-analysis. The results showed that the BDNF Val66Met polymorphism was not associated with OCD risk (allele contrast odds ratio ORAvsG = 0.96, 95% CI= 0.82-1.12, p= 0.000; homozygote ORAAvsGG = = 0.79, 95%CI= 0.59-1.06, p= 0.0058; dominant model ORAA+GAvsGG = 0.96, 95%CI= 0.86-1. 06, p= 0.17). In conclusion, the BDNF Val66Met polymorphism was not related to increased OCD susceptibility.
INTRODUCTION
Obsessive compulsive disorder (OCD) is a mental health condition characterized by repetitive intrusive thoughts, images and impulses (obsessions) and repetitive behaviours (compulsions). It is a leading cause of mental disability worldwide [1], with a lifetime prevalence of 1.3 - 2.3% [2,3]. In addition to being associated with significant functional impairment in daily living and quality of life [4,5], OCD has been associated with neurocognitive deficits, as measured using neuropsychological assessment. The average age of onset is around 19 years old. It affects men and women equally, but the onset in males is earlier than in females.
Genome-wide and twin studies reported higher involvement of hereditary factors in OCD [1, 6]. Published studies have reported numerous OCD candidates genes including COMT, SERT, SLC1A1, DLGAP1, PTPRD, NRXN1, HTR2A, CTTNBP2, REEP3 and BDNF [1,6]. BDNF (Brain-Derived Neurotrophic Factor) is a crucial protein belonging to the neurotrophin family, which supports the survival, development, neural plasticity and function of neurons [7 -10]. BDNF helps in the generation of new neurons from neural stem cells in hippocampus. BDNF has been reported to affect the synthesis of neurotransmitters and expression of their receptors. It regulates moods and reduced /altered BDNF expression involved in the pathophysiology of various psychiatric and neurodegenerative disorders, including depression, anxiety, schizophrenia, and bipolar disorder. It is reported very well that antidepressants and other medications up regulate BDNF expression.
BDNF gene is located at chromosome 11p14.1, spans about 70 kb and has a complex structure, it consists of 11 exons (I–IX, plus Vh and VIIIh), the coding sequence resides only in exon 9, and all upstream exons encode promoters, regulating regional and cell-type-specific expression (Figure 1). The gene contains multiple promoters that allow for tissue-specific and activity-dependent expression of BDNF. BDNF expression is tuned in response to various intrinsic and extrinsic stimuli. Exon IX, encodes precursor-BDNF protein (pre-pro-BDNF; ~ 27 kDa) in endoplasmic reticulum [11].
Several single nucleotide polymorphism are reported in BDNF genes include rs6265, rs11030101, rs12291186, rs7934165, rs11030104, rs1519480, rs8192466, rs539177035, and rs551669106 [12-14]. Val66Met polymorphism is located in exon 9 in which G is substituted by A at 196 position (G196A), resulting in substitution of amino acid valine with methionine at 66th codon (Val66Met). Val66Met alteration affects the activity-dependent secretion of BDNF, which is important for neuronal development, synaptic plasticity, neurogenesis and cognitive function. Val/Val genotype is generally associated with normal BDNF function. Met carriers (Val/Met or Met/Met) is often exhibit reduced activity-dependent BDNF secretion. Imaging and autopsy studies have reported functional and structural alterations in met allele carriers especially in hippocampus and prefrontal cortex regions. BDNF levels are associated with cognitive functions, mood regulation, and overall brain health. Decreased BDNF levels have been linked to cognitive decline and mood disorders such as depression. After knowing clinical implications of Val66Met polymorphism, authors designed and performed metaanalysis of case control studies to shed light on exact association between Val66Met polymorphism and OCD susceptibility.
MATERIALS AND METHODS
Eligible studies were identified by searching Pubmed, Springer link, Science Direct and Google Scholar databases up to July 11, 2024. The following search terms were used: “Brain Derived Neurotrophic Factor” or “BDNF”, and “Val158Met” in combination with “Obsessive compulsive disorder”, or “OCD”. Inclusion criteria for selection of studies were: (i) study should be published, (ii) case control approach was used by authors, and (iii) allele number/ genotypes numbers were reported in the study to calculate OR with 95%CI. Studies were excluded from the meta-analysis if: (i) studies based on pedigree data (ii) study was review, letter to editor or editorial and (iii) other genes variants are analysed in OCD patients.
The following data was extracted from each included study: (i) first author’s family name, (ii) country name and ethnicity, (iii) number of cases and controls and (iv) number of alleles and/or number of genotypes in both cases and controls for recalculation of ORs with 95% CI (Confidence Interval).
Pooled OR with corresponding 95% confidence Interval (CI) was used as association measure to assess the risk between Met allele and OCD susceptibility. A pooled OR was estimated on the basis of the individual ORs. OR was estimated either by using fixed effects [15], or random effects [16], model depending upon heterogeneity (I2 ). If I2 > 50% then random effect model was used. Pooled ORs were calculated using different genetic models, viz.: (i) allelic contrast model (A vs.G), (ii) homozygote model (AA vs. GG), (iii) dominant model (AA+ GA vs. GG), and (iv) recessive model (AA vs. GA+ GG) [17]. Method of Guo et al. [18], was adopted for quality score assessment. The quality scores ranged from 0 to 10 and studies with score <5 was defined as low quality, and studies with score ≥7 was defined as high quality. Meta-analysis was undertaken by free program MetaDiSc (version 1.4), developed by Zamora et al. [19]. All P values are two-tailed with a significance level at 0.05
RESULTS AND DISCUSSION
After applying inclusion and exclusion criteria, total 13 studies were found to be eligible for present meta-analysis [1,20-31] (Table 1). In one study [22], authors analysed cases from two countries viz.- South Africa and The Netherland, so both samples were included separately in the meta-analysis. Hence, total studies included in current metaanalysis was fourteen. In included meta-analysis, samples with several countries/population were analysed like-America [20], Brazil [24], China [23, 27, 29], India [1], Japan [31], Mexico [28], South Africa [21,26], The Netherlands [22], and Turkey [25] (Table 1).
Table 1: Details of included fourteen studies in present meta-analysis
In total 14 included studies, the number of cases were 2765 and number of controls was 5585. GG, GA and AA genotypes number in cases are 1434, 1028, and 303, respectively. In controls, GG, GA, AA genotypes number were 2571, 2320 and 694, respectively (Table 1) (Figure 3). In cases and controls T allele frequencies were 29.55 % and 33.2%. Meta-analysis of samples of 14 studies, adopting allele contrast model (A vs. G) showed no significant association with both fixed and random effects models. Higher heterogeneity was observed (I2 = 71.5%), so random effect model was adopted. The random effect pooled ORAvs G was 0.96 (95% CI= 0.82-1.12; p= 0.000) and Cochran Q was 45.55 (df = 13; p=0.000). The tau squared is 0.0596 (Figure 4)
Figure 1 : BDNF gene structure showing Val66Met polymorphism .
Figure 2 : Flow diagram of article selection
Figure 3 : Bar diagram showing number of GG, GA and AA genotypes in case and control samples of included studies.
Figure 4 : Allele contrast forest plot adopting random effect model
Association between OCD and Val66Met polymorphism using homozygote (AA vs GG; homozygote model), was also not found (ORAAvs GG= 0.79; 95%CI= 0.59-1.06; p= 0.0058; Cochran Q=29.35), higher heterogeneity (I2 =55.7%) was present, so random effect was adopted (Figure 5). Results of meta-analysis using dominant models (ORAA+GAvs GG= 0.96; 95%CI= 0.86-1. 06; p= 0.17; Cochran Q=15.56; I2 =25.9) did not show significant association. Egger’s test were performed to estimate the risk of publication bias. Except allele contrast and homozygote model, publication bias was absent (G vs. A: P Egger’s test= 0.03; AG vs. AA: P Egger’s test= 0.29; GG vs. AA: P Egger’s test P= 0.03; Dominant model GG+AG vs. AA: P Egger’s test= 0.06; Recessive model GG vs. AG+GG: P Egger’s test= 0.05) It is very well established fact that BDNF is required for overall brain/neuron health and mutation in this gene affects brain activities and modulates moods, hence is reported a risk factor for psychiatric as well as neurodegenerative disorders including anxiety disorders [32], obsessive-compulsive disorder [33], depression [34, 35], bipolar disorder[34], schizophrenia [34,36], eating disorders [37], as well as alcohol and substance-use disorders [38], Alzheimer’s disease [39], Parkinson’s disease [40], and multiple sclerosis [41].
Figure 5 : Homozygote contrast forest plot adopting random effect model.
The results of present metaanalysis suggested that Met (A) allele is not risk for OCD, instead A/met allele protects against OCD During past thirty years, meta-analysis is used for summarization and revalidation of results of individual case –control studies. Metaanalysis are continuously published to evaluate disease risk of small effect genes like- tuberculosis [42], Cleft lip and Palate [43], NTD [44], Down syndrome [45-47], Obsessive compulsive disorder [48], depression [49,50], schizophrenia [51], bipolar disorder [52,53], autism [54], alcohol dependence [55-57], migraine [58], epilepsy [59], Alzheimer’s disease [60], male infertility [61], osteoporosis [62], recurrent pregnancy loss [63], uterine leiomyoma [64], lung cancer [65], digestive tract cancer [66], breast cancer risk [67,68], esophageal cancer [69], prostate cancer [70- 72], endometrial cancer [73], ovary cancer [74], and MTRR [75].
Present meta-analysis had few limitations also, that should also be acknowledged- (i) case sample size is small, (ii) used crude ORs without adjustment, (iii) single BDNF polymorphism is considered and (iv) gene environment interaction is not considered. In conclusion, the present meta-analysis reported no association between the BDNF Val66Met polymorphism and OCD risk. Met allele is not a risk for OCD, instead plays a protective role. However, due to presence of higher heterogeneity, results should be cautiously interpreted. In future, well-designed meta-analysis considering cofounding factors and gene-environment interactions should be performed to confirm exact associations in different ethnic populations.
ACKNOWLEDGMENTS
Authors acknowledge the funding received from UP higher Education Council (Centre of Excellence-9/2022/447/ seventy-4-2022-04(17)/2021; Date 15-03-2022).
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Citation
Rai V, Kumar P, Kannojiya A (2025). Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and Obsessive Compulsive Disor der Risk. SM J Neurol Neurosci 11: 7.