BDNF Variation and Mood Disorders: A Novel Functional Promoter Polymorphism and Val66Met are Associated with Anxiety but Have Opposing Effects

Abstract

The brain-derived neurotrophic factor (BDNF) gene is critical for neuronal function and survival, and is likely to be important in psychiatric disorders. In this study, we used single-nucleotide polymorphism (SNP) discovery, functional analyses, and genetic association studies to better understand the potential role of BDNF sequence variation in behavior. Screening 480 unrelated individuals for SNPs and genotyping was performed in US Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) was administered to measure anxious temperament (harm avoidance (HA)) and novelty seeking (NS). A novel SNP (À281 C4A) in promoter 1 was discovered that had decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the À281 A allele was 0.03 in a Caucasian sample, but was virtually absent in other populations. Association analyses in a community-based sample showed that individuals with the À281 A allele (13 heterozygotes) had lower TPQ HA (F ¼ 4.8, po0.05). In contrast, the Met 66 allele was associated with increased HA (F ¼ 4.1, p ¼ 0.02) and was most abundant in individuals with both anxiety disorders and major depression (po0.05). Among the Val66Val homozygotes, individuals who were -281 CA heterozygotes had significantly lower HA than the -281 CC homozygotes (po0.01). Our results suggest that in this population, the low activity -281 A allele may be protective against anxiety and psychiatric morbidity, whereas Met 66 may be a risk allele.

Is it time to reassess the BDNF hypothesis of depression?

“…93 Evidence for-Met Met allele associated with increased risk avoidance in 208 Caucasian subjects. 102 Increased Met allele expression in 110 depressed elderly Chinese subjects. 103 Met allele associated with expression of suicidal and psychotic symptoms in 154 depressed Japanese subjects.…”

“…These findings provide additional support for a link between a BDNF singlenucleotide polymorphism, behaviour co-morbid with depression and possibly SSRI resistance. However, the conclusion that it is an increase in Met as opposed to Val expression which is associated with depression vulnerability, argues directly against the hypothesized 'protective' role of Met, as proposed by Sen et al 92 This has also been reported in a number of human studies, with the Met allele most associated with increased risk avoidance behaviour (a measure of anxious temperament) 102 and showing greatest expression in individuals suffering from anxiety disorders and depression. 102,103 It has also been reported that Met expression is not associated with the development of depression per se, but with clinical features such as psychosis and suicidal behaviour.…”

Molecular epidemiology of major depressive disorder

“…A functional polymorphism of the BNDF Val66Met influences and reduces trafficking and secretion of BNDF protein in the brain and is thought to be associated with low BDNF levels in major depressive disorder [108][109][110]. Some did associate the BDNF Val66Met genotype with depression [111], but other groups found only weak or no associations [112][113][114][115].…”

Impact of Genetic Variant BDNF (Val66Met) on Brain Structure and Function

“…Several recent studies have looked at the relationship between BDNF Met and trait anxiety. The results have been conflicting, with the Val allele associated with vulnerability in one study and the Met allele designated as the 'risk' allele in another study (Sen et al 2003, Jiang et al 2005, Lang et al 2005. Inconsistency across genetic studies may be attributable to sampling and measurement issues, genetic heterogeneity due to differential sampling of populations or low frequency of homozygous Met carriers, which may lessen the effect size of any particular association.…”