Sequence Variants of the Brain-Derived Neurotrophic Factor (BDNF) Gene Are Strongly Associated with Obsessive-Compulsive Disorder

Hall, Diana; Dhilla, Alefiya; Charalambous, Anna; Gogos, Joseph A.; Karayiorgou, Maria

doi:10.1086/377003

Cited by 253 publications

(201 citation statements)

References 22 publications

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“…As rs25531 has only been previously evaluated in the single study by Hu et al (2006), which did not consider the question of comorbidity, it might be that rs25531 covertly influenced OCD-5-HTTLPR associations in earlier studies. Likewise, with regard to a possible SLC6A4-BDNF interaction in OCD, comorbidity in particular with major depressive disorder, might also help explain the lack of replication in our study with the previous strong finding of a protective effect of the BDNF Met66 allele in OCD by Hall et al (2003). TheV66M polymorphism has been reported in several studies as significantly associated with different depressive disorders (Angelucci et al, 2005), and well as with schizophrenia (Neves-Pereira et al, 2005), and anorexia nervosa (Ribases et al, 2004).…”

Section: Discussionsupporting

confidence: 39%

“…Earlier investigations have evaluated the functional 5-HTTLPR polymorphism of SLC6A4 in generally small OCD proband case-control and trio samples (and thus with low power to detect association of OCD to gene variants of small effects) with mixed results, although a recent larger study suggested that an associated promotor region SNP, rs25531, near 5-HTTLPR might have led to some of the variability (Hu et al, 2006). The only known functional BDNF variant, V66M, has been evaluated in two studies with differing results (Hall et al, 2003;Mossner et al, 2005). We addressed the lack of consistent findings by considering (1) genotyping difficulties, (2) sample size, (3) functional variants of the 5-HTTLPR L allele, (4) the …”

Section: Discussionmentioning

confidence: 99%

“…In addition, we assessed the brain-derived neurotrophic factor (BDNF) V66M polymorphism in our sample, given the recent positive finding of its involvement in OCD (Hall et al, 2003). We first validated our multiplexed SLC6A4 genotyping method (Wendland et al, 2006b) in light of a recent report showing magnesium chloridedependent preferential amplification of the S allele (Yonan et al, 2006), and then performed a number of single locus, expression grouping, haplotype, and combined genotype analyses.…”

Section: Introductionmentioning

confidence: 99%

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A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

101

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Both serotonin transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) genes have shown positive associations with obsessive-compulsive disorder (OCD) and some other psychiatric disorders, but these results have not been consistently replicated. To explore the hypothesis that this variability might result from the effects of differing combinations of overlooked variants within SLC6A4 together with small OCD and control sample sizes, we studied three common functional polymorphisms (5-HTTLPR, STin2, and the newly discovered SNP, rs25531) in the largest sample size of OCD patients (N ¼ 347) and controls (N ¼ 749) ever investigated. During methods development, we found evidence for potential SLC6A4 genotyping problems with earlier methodology, a third possible contributor to variability in earlier studies. A fourth possible explanation might be SLC6A4 Â BDNF interactions, which prompted us to investigate combined genotypes of BDNF V66M with the three SLC6A4 loci. Except for a nominal association with rs25531 alone, which did not survive correction for multiple comparisons, we found no evidence for any of these other variants being associated alone or together with OCD, and we therefore also examined clinical OCD subtypes within the sample to evaluate clinical heterogeneity. Subgroups based on the age of OCD onset, gender, familiality, factor analysis-derived symptom dimensions, or comorbidity with other psychiatric disorders failed to identify SLC6A4-or BDNF-associated phenotypes, with one exception of overall number of comorbid anxiety disorders being significantly associated with 5-HTTLPR/rs25531. We conclude that despite their attractiveness as candidate genes in OCD, our data provide no support for association in this large OCD patient sample and point toward the need to examine other genes as candidates for risk determinants in OCD.

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Section: Discussionsupporting

confidence: 39%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

101

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“…BDNF Val66Met has been widely investigated in OCD, but the results have been largely inconsistent. Hall et al (2003) observed an association between the Val-allele and childhood-onset OCD, although this result was not replicated in a later study (Mossner et al, 2005). Our group observed an association between the Met-allele and OCD in male patients with early-onset OCD (Hemmings et al, 2008).…”

Section: Introductioncontrasting

confidence: 62%

BDNF Val66Met modifies the risk of childhood trauma on obsessive-compulsive disorder

Hemmings

Löchner

Merwe

et al. 2013

Journal of Psychiatric Research

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Abstract:Childhood trauma has been linked to the development of later psychopathology, including obsessive-compulsive disorder (OCD). Although evidence exists to suggest that genetic and environmental factors are involved in the aetiology of OCD, little attention has been paid to the interactions that exist between genes and environment. The aim of this study was to investigate gene-byenvironment interactions between childhood trauma and the BDNF Val66Met variant in patients with OCD.Childhood trauma was assessed in 134 OCD patients and 188 controls using the Childhood Trauma Questionnaire (CTQ). Linear regression models were used for statistical analyses. Geneeenvironment interactions were estimated by including a combined genotype and CTQ score in the models as interaction terms. All analyses were adjusted for age, gender, CTQ minimisation-denial score and home language by including them in the logistic regression models as covariates.Childhood trauma, specifically emotional abuse and neglect, increased the odds of having OCD significantly (p < 0.001). Although no significant association was observed between BDNF Val66Met and the development of OCD, interaction analysis indicated that the BDNF Met-allele interacted with childhood emotional abuse to increase the risk of OCD significantly in a dose-dependent manner (p < 0.024). To our knowledge, this is one of the first studies to investigate geneeenvironment interactions in OCD, and the findings indicate the importance of collating genetic and environmental variables in future studies.

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“…34,45 A common theme across multiple investigations in a variety of phenotypes (excluding declarative episodic memory) suggests that when BDNF variants are associated with risk for illness, it is most often the common alleles and haplotypes that are associated with psychopathology. Hall et al 49 found the most common haplotype (C-T-val-C, P ¼ 0.007) to be associated with risk for OCD and a less common mirror haplotype (G-A-met-G, P ¼ 0.002) to be associated with protection from it. Similarly, Neves-Pereira et al 22 noted the common alleles and common haplotype (3-val, P ¼ 0.0039) to be overtransmitted and the mirror haplotype to be relatively undertransmitted (1-met, P ¼ 0.013) in bipolar disorder.…”

Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample

et al. 2005

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Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. Keywords: neurotrophic factors; mood disorder; childhood-onset; genetic association; haplotype Mood disorders rank fourth among the most significant global public health problems. 1 The prevalence of the juvenile-onset subtype of depressive disorder increases dramatically across the years of childhood and adolescence, with an estimated lifetime prevalence close to 20% by late adolescence. 2 Juvenile-onset mood disorders are associated with serious morbidity, including recurrence, impaired interpersonal functioning, and increased risks of bipolar disorder and suicide. 2,3 The influence of hereditary factors on susceptibility to major depression has been documented based on twin and adoption studies. 4 Twin studies in youth have identified significant heritability for depressive symptoms. 5,6 It has also been proposed that genetic aspects of liability to mood disorder may be more readily identified in families of childhood-and adolescentonset probands. 7 Accordingly, first-degree relatives of childhood-onset mood disorder probands have higher rates of affective disorder than do first-degree relatives of adult-onset mood disorder probands. 8 Evidence from both preclinical and clinical studies implicates brain-derived neurotrophic factor (BDNF) in mood disorders. Altered BDNF expression in stress-related depression via cellular signalling has been described in animal models. Repeated antidepressant administration, including electroconvulsive seizures, is associated with increased hippocampal BDNF expression, neuronal plasticity and neurogenesis. 9-11 Human neuroimaging 12,13 post mortem 14 and clinical [15][16][17] investigations indirectly support the hypothesis that neurotrophic factors play a key role in depression. As well, human linkage studies in

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Sequence Variants of the Brain-Derived Neurotrophic Factor (BDNF) Gene Are Strongly Associated with Obsessive-Compulsive Disorder

Cited by 253 publications

References 22 publications

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

BDNF Val66Met modifies the risk of childhood trauma on obsessive-compulsive disorder

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample

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