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Brain Derived Neurotrophic Factor (BDNF) is a member of the neurotrophin family which plays a pivotal role in the development and plasticity of the brain. BDNF has been implicated in several neuropsychiatric disorders and multiple lines of evidence suggest an involvement in autism. Direct evidence comes from reports of high serum BDNF levels in small samples of autism patients and the identification, in a large autism whole genome-linkage scan, of a linkage peak on chromosome 11p12-13, where the BDNF gene maps.
Objectives:
In this study, circulating BDNF levels were compared between autistic patients and controls, and the genetic factors that might regulate BDNF distribution and contribute to autism etiology were examined.
Methods:
BDNF levels in platelet rich plasma were measured in 146 autistic patients, 88 parents and 50 controls in the same age range. Markers selected in candidate genes, including BDNF, NTRK2 (encoding the BDNF receptor TrkB), and nine genes involved in the serotonin metabolic and neurotransmission pathways (SLC6A4, HTR2A, MAOA, HTR2C, HTR1D, HTR1A, HTR5A, TPH1 and ITGB3) were tested for association with BDNF levels. These genes were also tested for association with autism in 301 Portuguese and 168 Irish trios.
Results:
BDNF levels in autistic children were significantly higher than in control children (P<0.0001) and positively correlated with serotonin levels (P=0.004), and showed an heritability of 30%. Five polymorphisms in the HTR1A genomic region were associated with BDNF levels. While in the overall population association with autism was detected with four different markers in this region, in the subset of patients with high BDNF levels, four of the polymorphisms that were associated with BDNF levels were also associated with autism. These markers map not in HTR1A but in a neighbour gene, RNF180, which was very recently identified and encodes a zinc ring finger protein which functions as an E3 ubiquitin ligase. In NTRK2 five SNPs (0.0027<P<0.041) and multiple two and three marker haplotypes (0.0006<P<0.04) were significantly associated with autism in the Portuguese population, but none were associated with BDNF levels. In the combined Portuguese and Irish sample (N=491), association was found for the same 5 SNPs, two becoming more significant, with rs1187352 and rs1187321 surviving Bonferroni correction. Although association of NTRK2 markers could not be replicated independently in the smaller Irish sample, we found a frequent trend for overtransmission of the same alleles. No association with autism or BDNF levels of any of the other genes tested was found.
Conclusions:
We report an increase of BDNF plasma levels in 25% of the autistic children in this population sample, the largest tested thus far, corroborating previous results in smaller samples. In addition, we show that BDNF levels are heritable and that its determination is associated with genetic polymorphisms in the chromosome 5q11.2-q13 region. We also provide evidence for an involvement of the NTRK2 gene in autism which, taken together with the findings of increased BDNF levels, suggests that BDNF/TrkB signalling is altered in autism, possibly underlying an abnormal development of the serotonergic and glutamatergic/GABAergic systems commonly associated with autism.