Population genetic study of the brain-derived neurotrophic factor (BDNF) gene

Abstract

Genetic variants in the brain-derived neurotrophic factor (BDNF) gene, predominantly the functional Val66Met polymorphism, have been associated with risk of bipolar disorder and other psychiatric disorders. However, not all studies support these findings, and overall the evidence for BDNF association with disease risk is weak. As differences in population genetic structure between patient samples could cause discrepant or spurious association results, we investigated this possibility by carrying out population genetic analyses of the BDNF genomic region. Substantial variation was detected in BDNF coding region SNP allele and haplotype frequencies between 58 global populations, with the derived Met allele of Val66Met ranging from 0–72% frequency across populations. FST analyses to assess diversity in the HapMap populations determined that the Val66Met FST value was at the 99.8th percentile among all SNPs in the genome. As the BDNF population genetic differences may be due to local selection, we performed the long-range haplotype (LRH) test for selection using 68 SNPs spanning the BDNF genomic region in 12 European-derived pedigrees. Evidence for positive selection was found for a high frequency Val-carrying haplotype, with a relative extended haplotype homozygosity (REHH) value above the 99th percentile compared to HapMap data (P=4.6 ×10−4). In conclusion, we observed considerable BDNF allele and haplotype diversity among global populations and evidence for positive selection at the BDNF locus. These phenomena can have a profound impact on detection of disease susceptibility genes and must be considered in gene association studies of BDNF.

No gene-by-environment interaction of BDNF Val66Met polymorphism and childhood maltreatment on anxiety sensitivity in a mixed race adolescent sample

“…The following genotype frequencies were evident in our mixed race sample: Val66Val (75.65%, 233/308), Val66Met (22.08%, 68/308) and Met66Met (2.3%, 7/308). These frequencies are generally in line with those determined in Caucasian samples (Carver et al, 2011; Gatt et al, 2009; Pivac et al, 2009; Surtees et al, 2007; Zeni et al, 2013) and in South African mixed race samples (Dalvie et al, 2014), and confirm the low rates of Met66 allele carriers evident in ethnic groups in sub-Saharan Africa (Petryshen et al, 2009). Given the low frequency of Met66Met genotype carriers, Val66Met and Met66Met genotypes were combined (24.35%, 75/308) for genotypic analyses to increase statistical power.…”

“…adversity, negative stressors, recent life events) on psychopathology, such as increased levels of neuroticism, harm avoidance and depression (Chen et al, 2013; Kim et al, 2009; Lehto et al, 2016). Apart from the possible confounding effects of age and gender, discrepant results across studies may in part be due to population-driven differences in BDNF Val66Met frequencies, given that the Met66 allele has consistently been found to be more common in Asian populations than in Caucasian populations (Chen et al, 2013; Petryshen et al, 2009). A further confounding factor may include phenotype heterogeneity and methodological (assessment) differences (Hong et al, 2012).…”

Association between brain-derived neurotrophic factor Val66Met and obesity in children and adolescents

“…Gender has been proposed to affect the association between BDNF Val66Met and BMI (Arija et al, 2010;Beckers et al, 2008), however multiple regression analysis in our study excluded the possible effect of gender, at least in our sample, presumably due to the fact that most of them were pre-pubertal and did not reach neurodevelopmental maturity, as emphasized in previous studies (Arija et al, 2010). Since we detected significant differences in the distribution of the BDNF Val66Met variants between Caucasian (Croatian) and Asian (South Korean) healthy adult subjects (Pivac et al, 2009), and there is substantial global population diversity in the BDNF Val66Met polymorphism (Petryshen et al, 2010), to exclude population genetic differences in BDNF, we selected only Caucasian children and adolescents of Croatian origin. Furthermore, although the present study included a relatively small group of children and adolescents (N=300), this group had an analogous distribution of the BDNF Val66Met variants to larger groups of 556 and 402 subjects from our previous studies (Pivac et al, 2009;Pivac et al, 2011).…”

“…The divergent results might be attributed to different study designs, different study groups (obese versus healthy), or the population genetic differences in BDNF Val66Met (Petryshen et al, 2010), that may lead to the conflicting association results between studies, evaluating the role of BDNF Val66Met in various psychiatric disorders and altered behaviors.…”

“…Most of the studies evaluated the role of BDNF Val66Met in eating disorders, and found either a significant association (Akkermann et al, 2011;Gratacos et al, 2007), or no association (Arija et al, 2010;Friedel et al, 2005) between the Met allele and eating disorders. The ethnic (Pivac et al, 2009), as well as population-related genetic differences (Petryshen et al, 2010) might explain the conflicting association results showing either that BDNF Val66Met Met/Met genotype was more frequently found in adult women with higher (Beckers et al, 2008) or with lower (Shugart et al, 2009) BMI. Therefore, the aim of this study was to determine the association between BDNF Val66Met variants and obesity in healthy Caucasian children and adolescents of the same ethnic background of Croatian origin, subdivided according to the BMI measures.…”