MRI/PET scans of individuals stratified by a common genetic variant (Val66Met) in the brain-derived neurotropic factor consistently indicate that Met66 carriers have smaller volumes of hippocampal formation in comparison to val-homozygotes (Pezawas et al, 2004 Szeszko et al, 2005, Bueller et al, 2006). This genotype has been found to be associated with cognitive performance and educational attainment in adults, but to our knowledge this has not yet been investigated in a large population based study of children.

Studies of polymorphic variation in genes such as COMT and DRD2 have demonstrated a link with brain development and psychopathology. Epigenetic variation in these genes has also been reported (Petronis 2003, Abdomaleky 2006) suggesting that either genetic or epigenetic lesions (or interaction of both) in these genes may influence phenotype. We wish to test this hypothesis with repsect to the BDNF gene.

We plan to look at the association betwee val66Met and cognitive performance among children in the ALSPAC cohort.

The BDNF gene shows variable methylation both in its first exon and promoter region. This has been verified in ALSPAC GoldenGate data from cord blood DNA in 178 children. Analysis of these data suggest a relationship between those measures of IQ listed in this proposal and DNA methylation status at birth. We therefore propose to look at these data in association with genotype to establish whether there is any interaction between genotype, epigenotype and IQ. The low numbers of individuals with methylation data will limit power but will be a worthy addition to the proposed analysis given the dearth of literature in this area.

Refs

Bueller et al. Biol Psychiatry 59: 812-815 (2006)

Pezawas et al. J Neurosci 24: 10099-10102 (2005)

Szeszko et al. Mol Psychiatry 10: 631-636 (2005)

Petronis A et al. Schizophr Bull 29:169-178 (2003)

Abdomaleky HM et al. Hum Mol Genet 15:3132-45 (2006).