BDNF Gene's Role in Schizophrenia: From Risk Allele to Methylation Implications

Background: Schizophrenia (SZ) is a severe chronic mental disorder with complex genetic mechanisms. Brain-derived neurotrophic factor (BDNF) is one of promising candidate genes for SZ, and rs6265 is a non-synonymous single nucleotide polymorphism (SNP) in BDNF.Methods: In this study, we performed a case-control association study of rs6265 in a cohort of Han Chinese population from eastern China, including 1,407 SZ patients and 1,136 healthy controls; and carried out a cis-mQTL (Methylation Quantitative Trait Loci) analysis for BDNF rs6265.Results: We found a positive association of rs6265 with SZ (P = 0.037), with the minor allele (A) of rs6265 conferring a protecting effect for SZ (OR = 0.89). Furthermore, cis-mQTL analysis indicates that rs6265 is associated with several methylation loci surrounding BDNF.Conclusions: Together, our findings provide further evidence to support the involvement of BDNF gene in the genesis of SZ.

Download Full-text

Single nucleotide polymorphism of BDNF Val66Met (rs6265) and its association to neuropsychiatric disorders

Neuroscience Research Notes ◽

10.31117/neuroscirn.v3i3.50 ◽

2020 ◽

Vol 3 (3) ◽

pp. 9-26

Author(s):

Asraa Faris ◽

Pike-See Cheah ◽

King-Hwa Ling

Keyword(s):

Single Nucleotide Polymorphism ◽

Positive Association ◽

Neuropsychiatric Disorders ◽

Post Traumatic Stress ◽

Nucleotide Polymorphism ◽

Bdnf Level ◽

Obsessive Compulsive ◽

Single Nucleotide ◽

Compulsive Disorder ◽

Bdnf Rs6265

Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the central nervous system and was shown to be involved in neuronal growth, differentiation and synaptic plasticity. A single nucleotide polymorphism at the pro-region of the BDNF gene (rs6265) has been reported to alter the amino acid from valine to methionine at codon 66 and was associated with neuropsychiatric disorders in several studies. To date, the results on the association of BDNF rs6265 to the aetiology of the neuropsychiatric illnesses have been inconsistent with some studies reporting a positive association and others reporting no association. Concerning the past inconsistent reports, this mini-review aims at determining the association of BDNF rs6265 and neuropsychiatric disorders among the different studies. Firstly, we discuss the findings on studies reporting the association of BDNF rs6265 with depression whereby a positive association between the BDNF variant and depression was obtained in several studies on the Caucasian, German, Chinese, and Malaysian population but not in studies on the Korean and other populations. Likewise, some studies found the occurrence of the SNP to be associated with a reduction in the BDNF level in depressed cases, but others found no effect at all. We then reported findings on the association of BDNF rs6265 with anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, bipolar disorder, and schizophrenia. Val allele has been found associated with these disorders, whereas some studies reported the involvement of the Met allele, and some reported no association at all. Similarly, the association of the BDNF variant with the BDNF level remains controversial. It is, therefore, essential to conduct more studies with larger sample sizes and look at the haplotype level to determine the association.

Download Full-text

The Association of IL-1 and HRAS Gene Polymorphisms with Breast Cancer Susceptibility in a Jordanian Population of Arab Descent: A Genotype–Phenotype Study

Cancers ◽

10.3390/cancers12020283 ◽

2020 ◽

Vol 12 (2) ◽

pp. 283 ◽

Cited By ~ 2

Author(s):

Laith N. AL-Eitan ◽

Bashar H. Al-Ahmad ◽

Fouad A. Almomani

Keyword(s):

Breast Cancer ◽

Single Nucleotide Polymorphism ◽

Genetic Polymorphisms ◽

Genetic Association ◽

Risk Allele ◽

Variable Number Tandem Repeat ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Jordanian Population ◽

The Impact

Breast cancer (BC) pathogenesis is poorly understood and not yet completely determined. BC susceptibility genes are responsible for 20% to 25% of breast cancer risk. The main objective of this study is to identify the genetic polymorphisms within the Harvey rat sarcoma viral oncogene homolog (HRAS1) and interleukin-1 receptor antagonist (IL1-Ra) genes in Jordanian BC female patients and to investigate the genetic association of these polymorphisms with BC. Samples were collected from 150 Jordanian BC patients and 187 healthy age-matched controls. PCR and PCR-RFLP techniques were used to identify genetic polymorphisms within these candidate genes. The single nucleotide polymorphism single nucleotide polymorphism (SNP) association web tool SNPStats (v. 3.6) was used to investigate the allelic and genotypic association with BC. Different statistical analyses were used to study the correlation between the investigated genetic variants and several prognosis factors of BC. A genetic association between BC susceptibility and Il-1β rs1143634 was found specifically at the allelic level of E1 as a risk allele (72% in the cases vs. 64.2% in the controls). Another genetic association was found in the IL-Ra gene (86-VNTR (variable number tandem repeat)), which presented one repeat allele (24.1% in cases vs. 15.59% in controls) and could be considered as a risk allele in Jordanian women. In contrast, this study found that there is no genetic association between Il-1β SNP rs16944 and BC. In addition, a significant association was found between the allelic level of the HRAS1 gene and BC susceptibility. Since this study is the first to be conducted on the genetic susceptibility of these genes to BC in the Jordanian population, more investigations on the link between BC and these variants are recommended to determine the impact of these polymorphisms on other ethnic groups.

Download Full-text

Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458510376778 ◽

2010 ◽

Vol 16 (11) ◽

pp. 1303-1307 ◽

Cited By ~ 3

Author(s):

Naghmeh Jafari ◽

Linda Broer ◽

Ilse A Hoppenbrouwers ◽

Cornelia M van Duijn ◽

Rogier Q Hintzen

Keyword(s):

Multiple Sclerosis ◽

Single Nucleotide Polymorphism ◽

Infectious Mononucleosis ◽

Risk Allele ◽

Hla Class I ◽

Class I ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Major Class ◽

A Minor

Background: Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism. Objectives: Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis. Methods: Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501. Results: HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10 -5). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 ( p = 0.003) for HLA-A. Conclusions: HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.

Download Full-text

Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC

10.1101/2020.01.28.917401 ◽

2020 ◽

Author(s):

A.K. Sorial ◽

I.M.J Hofer ◽

M. Tselepi ◽

K. Cheung ◽

E. Parker ◽

...

Keyword(s):

Peripheral Blood ◽

Mechanical Forces ◽

Allelic Expression Imbalance ◽

Nucleotide Polymorphism ◽

Fat Pad ◽

Functional Effect ◽

Single Nucleotide ◽

Epigenetic Analysis ◽

Locus Mapping ◽

Methylation Quantitative Trait Loci

ObjectiveOsteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates with differential expression of PLEC, and methylation quantitative trait loci (mQTLs) at PLEC CpGs in cartilage. This implies that methylation links chondrocyte genotype and phenotype, thus driving the functional effect. PLEC encodes plectin, a cytoskeletal protein that enables tissues to respond to mechanical forces. We sought to assess whether PLEC functional effects were cartilage specific.MethodCartilage, fat pad, synovium and peripheral blood were collected from patients undergoing arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) was performed. We focussed on previously reported mQTL clusters neighbouring cg19405177 and cg14598846. Plectin was knocked down in a mesenchymal stem cell (MSC) line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing.ResultsNovel mQTLs were discovered in fat pad, synovium and peripheral blood at both clusters. The genotype-methylation effect of rs11780978 was stronger in cg14598846 than in cg19405177 and stronger in joint tissues than in peripheral blood. We observed AEI in synovium in the same direction as for cartilage. Knocking-down plectin impacted on pathways reported to have a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune regulation.ConclusionsSynovium is also a target of the rs11780978 OA association functionally operating on PLEC. In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting the functional effect is not joint-wide. Our study highlights interplay between genetic risk, DNA methylation and gene expression in OA, and reveals clear differences between tissues from the same diseased joint.

Download Full-text

BDNF rs6265 Polymorphism and Its Methylation in Patients with Stroke Undergoing Rehabilitation

International Journal of Molecular Sciences ◽

10.3390/ijms21228438 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8438

Author(s):

Massimo Santoro ◽

Mariacristina Siotto ◽

Marco Germanotta ◽

Elisa Bray ◽

Alessia Mastrorosa ◽

...

Keyword(s):

Barthel Index ◽

Univariate Analysis ◽

Biological Marker ◽

Stroke Recovery ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Rehabilitation Treatment ◽

Cpg Site ◽

Preliminary Study ◽

Bdnf Rs6265

Brain-Derived Neurotrophic Factor (BDNF) and its rs6265 single nucleotide polymorphism (SNP) play an important role in post-stroke recovery. We investigated the correlation between BDNF rs6265 SNP and recovery outcome, measured by the modified Barthel index, in 49 patients with stroke hospitalized in our rehabilitation center at baseline (T0) and after 30 sessions of rehabilitation treatment (T1); moreover, we analyzed the methylation level of the CpG site created or abolished into BDNF rs6265 SNP. In total, 11 patients (22.4%) were heterozygous GA, and 32 (65.3%) and 6 (12.2%) patients were homozygous GG and AA, respectively. The univariate analysis showed a significant relationship between the BDNF rs6265 SNP and the modified Barthel index cut-off (χ2(1, N = 48) = 3.86, p = 0.049), considering patients divided for carrying (A+) or not carrying (A−) the A allele. A higher percentage of A− patients obtained a favorable outcome, as showed by the logistic regression model corrected by age and time since the stroke onset, compared with the A+ patients (OR: 5.59). At baseline (T0), the percentage of BDNF methylation was significantly different between GG (44.6 ± 1.1%), GA (39.5 ± 2.8%) and AA (28.5 ± 1.7%) alleles (p < 0.001). After rehabilitation (T1), only patients A− showed a significant increase in methylation percentages (mean change = 1.3, CI: 0.4–2.2, p = 0.007). This preliminary study deserves more investigation to confirm if BDNF rs6265 SNP and its methylation could be used as a biological marker of recovery in patients with stroke undergoing rehabilitation treatment.

Download Full-text

The FTO rs17817449 Polymorphism is Not Associated With Sedentary Time, Physical Activity, or Cardiorespiratory Fitness: Findings From the GENADIO Cross-Sectional Study

Journal of Physical Activity and Health ◽

10.1123/jpah.2021-0076 ◽

2021 ◽

pp. 1-6

Author(s):

Miquel Martorell ◽

Lorena Mardones ◽

Fanny Petermann-Rocha ◽

Maria Adela Martinez-Sanguinetti ◽

Ana Maria Leiva-Ordoñez ◽

...

Keyword(s):

Physical Activity ◽

Single Nucleotide Polymorphism ◽

Cardiorespiratory Fitness ◽

Sedentary Time ◽

Risk Allele ◽

Cross Sectional Study ◽

Sectional Study ◽

Nucleotide Polymorphism ◽

Cross Sectional ◽

Single Nucleotide

Background: Genetic variants within the FTO gene have been associated with increased adiposity and metabolic markers; however, there is limited evidence regarding the association of FTO gene variants with physical activity-related variables. The authors aimed to investigate the association of the rs17817449 single-nucleotide polymorphism of FTO with physical activity, sedentary time, and cardiorespiratory fitness in Chilean adults. Methods: A total of 409 participants from the GENADIO study were included and genotyped for the rs17817449 single-nucleotide polymorphism of FTO in this cross-sectional study. Physical activity and sedentary time were measured with ActiGraph accelerometers. Cardiorespiratory fitness was assessed using the Chester step test. The associations were assessed by using multivariate regression analyses. Results: No associations were found for FTO variant with physical activity levels and cardiorespiratory fitness. The risk allele (G) of the FTO was found to be associated with sedentary time in the minimally adjusted model (β = 19.7 min/d; 95% confidence interval, 4.0 to 35.5, per each copy of the risk allele; P = .006), but the association was no longer significant when body mass index was included as a confounder (P = .211). Conclusion: The rs17817449 single-nucleotide polymorphism of the FTO gene was not associated with the level of physical activity, cardiorespiratory fitness, and sedentary behaviors in Chilean adults.

Download Full-text

Multiple sclerosis and the CTLA4 autoimmunity polymorphism CT60: no association in patients from Germany, Hungary and Poland

Multiple Sclerosis Journal ◽

10.1177/1352458507082357 ◽

2007 ◽

Vol 14 (2) ◽

pp. 153-158 ◽

Cited By ~ 15

Author(s):

Bernhard Greve ◽

Rostislav Simonenko ◽

Zsolt Illes ◽

Agnes Peterfalvi ◽

Nada Hamdi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Diseases ◽

Autoimmune Diabetes ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Regional Control ◽

Ctla4 Gene ◽

Cell Expression ◽

Control Association

Polymorphisms in the CTLA4 gene region have been associated with susceptibility to autoimmune diseases. The recently described single nucleotide polymorphism CT60, located in the 3' untranslated region of CTLA4 is associated with Graves' disease, thyroiditis, autoimmune diabetes and other autoimmune diseases. A case-control association study was conducted in German, Hungarian and Polish multiple sclerosis (MS) patients and regional control individuals for the CTLA4 CT60 and + 49A/G polymorphisms. No significant association of these polymorphisms or respective haplotypes with MS was found. No association of CT60 genotypes with T cell expression of ICOS and CTLA-4 after in vitro stimulation was detected. Multiple Sclerosis 2008; 14: 153—158. http://msj.sagepub.com

Download Full-text

Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with personality traits in healthy individuals

European Psychiatry ◽

10.1016/j.eurpsy.2008.03.004 ◽

2008 ◽

Vol 23 (5) ◽

pp. 344-349 ◽

Cited By ~ 17

Author(s):

Axel Krug ◽

Valentin Markov ◽

Dirk Leube ◽

Klaus Zerres ◽

Thomas Eggermann ◽

...

Keyword(s):

Personality Traits ◽

Psychiatric Disorders ◽

Healthy Subjects ◽

Risk Allele ◽

Risk Haplotype ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Personality Differences ◽

Potential Risk Factors ◽

The Impact

AbstractBackgroundDifferences in personality traits have long been acknowledged as potential risk factors in developing psychiatric disorders. Lately, several susceptibility genes of different psychiatric disorders have been linked to personality traits. This has not been done for schizophrenia yet. Neuregulin1 has been repeatedly shown to be associated with schizophrenia and is involved in numerous neurodevelopmental functions such as neuronal migration and myelination. The impact of this gene might also modulate personality traits in healthy subjects.MethodsThe NRG1 status of 523 healthy subjects was determined with a single nucleotide polymorphism (SNP8NRG221533) which has been described as a tagging marker being part of the core at-risk haplotype for schizophrenia. Genotype was correlated with personality traits using the NEO-FFI questionnaire.ResultsSubjects with the NRG1 risk allele scored higher on neuroticism (p <.05) and lower on conscientiousness (p <.05). Further, interactions of genotype by gender for extraversion (p <.05), openness (p <.05) and conscientiousness (p <.05) were found with men carrying the risk allele scoring the lowest.ConclusionsThe data indicate that the NRG1 gene which has found to be associated with schizophrenia may also influence personality differences in healthy subjects.

Download Full-text

Single nucleotide polymorphism (SNP) characterization of drought-responsive genes to estimate genetic variation of Populus tremula var. davidiana and eight other Populus species

Canadian Journal of Forest Research ◽

10.1139/cjfr-2017-0387 ◽

2018 ◽

Vol 48 (6) ◽

pp. 689-696 ◽

Cited By ~ 2

Author(s):

Yong-Yul Kim ◽

Soon-Ho Kwon ◽

Aruna Jo ◽

Yang-Gil Kim ◽

Jei-Wan Lee ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Genetic Variation ◽

Expectation Maximization Algorithm ◽

Snp Genotyping ◽

Populus Tremula ◽

Taqman Probe ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Genetic Mechanisms ◽

Populus Species

To reveal the genetic mechanisms behind drought tolerance, we attempted to identify the drought-responsive genes in Populus tremula var. davidiana (Dode) C.K. Schneid. and eight other species of Populus. Nine drought-responsive genes were assayed by single nucleotide polymorphism (SNP) genotyping using TaqMan probe-based real-time PCR. A total of 346 SNPs were found from the 101 sequences of the nine genes. Among them, 57 primers were selected for SNP genotyping and haplotype determination. For the SNP genotyping, 56 assays were applicable to section Leuce Duby, 53 to section Aigeiros Duby, 50 to Populus maximowiczii Henry, and 52 to Populus simonii Carrière. The expectation maximization algorithm was implemented to determine haplotypes among species and sections. A total of 78 haploid types were estimated from nine drought-responsive gene loci, and the average number of haploid types per locus was 8.67. The analysis of genetic diversity revealed that P. tremula var. davidiana had substantial levels of genetic variation for the nine drought-responsive genes, which was higher than the eight other species. The means of observed number of alleles (NA) and heterozygosity (Ho) were 5.33 and 0.6609, respectively. Analysis of the genetic differentiation of P. tremula var. davidiana showed that 7.52% of genetic variation was among populations and the remaining was within a population.

Download Full-text

Fuchs Endothelial Corneal Dystrophy: Strong Association with rs613872 Not Paralleled by Changes in Corneal EndothelialTCF4mRNA Level

BioMed Research International ◽

10.1155/2015/640234 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 14

Author(s):

Monika Ołdak ◽

Ewelina Ruszkowska ◽

Monika Udziela ◽

Dominika Oziębło ◽

Ewelina Bińczyk ◽

...

Keyword(s):

Mrna Level ◽

Strong Association ◽

Positive Association ◽

Transcript Level ◽

Corneal Dystrophy ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Amino Terminal ◽

Risk Alleles ◽

Strong Positive Association

Fuchs endothelial corneal dystrophy (FECD) is a common corneal endotheliopathy with a complex and heterogeneous genetic background. Different variants in theTCF4gene have been strongly associated with the development of FECD.TCF4encodes the E2-2 transcription factor but the link between the strong susceptibility locus and disease mechanism remains elusive. Here, we confirm a strong positive association betweenTCF4single nucleotide polymorphism rs613872 and FECD in Polish patients (OR = 12.95, 95% CI: 8.63–19.42,χ2=189.5,p<0.0001). We show thatTCF4expression at the mRNA level in corneal endothelium (n=63) does not differ significantly between individuals with a particularTCF4genotype. It is also not altered in FECD patients as compared to control samples. The data suggest that changes in the transcript level containing constitutiveTCF4exon encoding the amino-terminal part of the protein seem not to contribute to disease pathogenesis. However, considering the strong association ofTCF4allelic variants with FECD, genotyping ofTCF4risk alleles may be important in the clinical practice.

Download Full-text