Rs6265, also called Val66Met or G196A, is a gene variation, a

single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

(SNP) in the

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

that codes for

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the can ...

. Well over a hundred research studies have examined the polymorphism.

Association with neuropsychiatric disorders

Numerous studies have examined the role of this polymorphism in risk of

neuropsychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s, including (but not limited to)

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

and depression. It is generally thought that some variants of the polymorphism lead to memory impairment and susceptibility to neuropsychiatric disorders, and a 2007

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

of case-control studies found a relationship between the SNP and

substance-related disorder Substance-related disorders is a class of mental disorders that affect a person's brain and behavior, leading to their inability to control their use of substances like drugs, alcohol, or medications. The disorders can lead to large societal probl ...

eating disorder An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's health, physical or mental health, mental health. These behaviors may include eating too much food or too little food. Types of eatin ...

s, and

. Another 2007

could, however, find no association between the SNP and

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

. Meta-analyses of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

also indicate that the SNP has little or no association with these diseases. Also inconsistencies in association studies with depression have been noted. The reason for these inconsistent results have been suggested to stem from several sources, with one recent review arguing that statistical artefact, sampling bias, population stratification and uncontrolled gene-environment interactions are likely to underscore this effect. These same authors recently published a report which found that transgenic mice engineered to express human BDNF as well as carry the Val66Met permutation are selectively sensitive to the glucocorticoid stress hormone corticosterone (rodent equivalent of cortisol), which in turn primes the fear circuitry and hippocampus-dependent memory function of Met/Met homozygous mice. As hippocampal function is a core component of several psychiatric conditions, and stress is a non-specific but substantial risk factor for affective, anxiety, eating and psychotic disorders, Notaras et al. argue that "''there is a long-term effect of glucocorticoids in 66Met carriers that potentiates the fear circuitry into adulthood, which may increase susceptibility to trauma, events with negative emotional valence and related psychopathology''". This interpretation is consistent with a suggested role of BDNF and the Val66Met polymorphism in post-traumatic stress disorder, where it has been shown that 66Met variant perturbs extinction learning in both man and mouse. The Val66Met polymorphism alters vulnerability to stress in mice and humans, which likely contributes to PTSD risk. In treatment response studies val/val homozygotes may respond better than met allele carriers with drug resistant depression treated with

repetitive transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation technique in which a changing magnetic field is used to induce an electric current in a targeted area of the brain through electromagnetic induction. A device called a sti ...

Subject variables in healthy humans

One study has reported that met/met carriers tend to have lower

body mass index Body mass index (BMI) is a value derived from the mass (Mass versus weight, weight) and height of a person. The BMI is defined as the human body weight, body mass divided by the square (algebra), square of the human height, body height, and is ...

compared to the two other genotypes. Another study showed that subjects with the val/val genotype had higher mean

intelligence Intelligence has been defined in many ways: the capacity for abstraction, logic, understanding, self-awareness, learning, emotional knowledge, reasoning, planning, creativity, critical thinking, and problem-solving. It can be described as t ...

. The same study found no association with

personality trait In psychology, trait theory (also called dispositional theory) is an approach to the study of human personality. Trait theorists are primarily interested in the measurement of ''traits'', which can be defined as habitual patterns of behavior, thou ...

s as measured with the

Tridimensional Personality Questionnaire Tridimensional Personality Questionnaire (TPQ) is a personality test. It was devised by C. Robert Cloninger. A newer version of the questionnaire is called Temperament and Character Inventory. As the name indicates TPQ seeks to measure three dimen ...

. Also a Polish 2007 study observed no significant relationship between the polymorphism and personality in healthy females. A German 2005 study could though find an association with personality traits measured with

NEO-Five Factor Inventory The Revised NEO Personality Inventory (NEO PI-R) is a personality inventory that assesses an individual on five dimensions of personality. These are the same dimensions found in the Big Five personality traits. These traits are openness to experi ...

, with val/val subjects scoring higher on

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

and

neuroticism Neuroticism is a personality trait associated with negative emotions. It is one of the Big Five traits. Individuals with high scores on neuroticism are more likely than average to experience such feelings as anxiety, worry, fear, anger, shame ...

dimensions. Large studies and a meta-analysis inclusive of over 15,000 subjects, however, found no association between the Val66Met and Neuroticism.

Other studies

A study in

transgenic mice A genetically modified mouse, genetically engineered mouse model (GEMM) or transgenic mouse is a mouse (''Mus musculus'') that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly use ...

has found that met/met mice exhibits increased anxiety-related behaviors.

References

{{Reflist SNPs on chromosome 11 Biology of bipolar disorder