The project would be two genetic association studies assessing the effects of variations in two genes (BDNF and ACE) on normal variation in cognitive function in ALSPAC. This would be an extension of our previous, successful collaboration in which we have investigated the effects of SNPs in the COMT, 5HTTP and MAOA genes (Barnett et al 2007). Analyses are hypothesis-driven (see below). Outcome measures would be cognitive scores from ages 8 (attention and IQ) and ten years (working memory). Genotype data would be required for the ACE and BDNF genes, which we understand has already been completed in the cohort.

Brain-derived neurotrophic factor (BDNF) is one of the group of neurotrophins which affect cell survival, axonal and dendritic growth and synaptic plasticity among dopaminergic and other neurons (Bath and Lee 2006). The BDNF gene on 11p13 contains a common Val-Met substitution at codon 66. The Met allele is associated with smaller hippocampal volume (Pezawas et al 2004; Szeszko et al 2005) and better memory (Egan et al 2003; Hariri et al 2003; Dempster et al 2005; Tan et al 2005; Ho et al 2006) but not attention, processing speed, language or planning abilities (Ho et al 2006). The relative rarity of Met/Met homozygotes (about 4% of the US population, (Shimizu et al 2004)) means that the cognitive status of Met/Met individuals is effectively unknown. There have been no studies, to our knowledge, of the effect of BDNF genotype on children's cognitive function, despite the obvious importance of BDNF in neurodevelopment.

Angiotension-converting enzyme (ACE) is a central enzyme of the renin-angiotensin system (RAS) and is primarily involved in blood pressure regulation. It is widely distributed throughout the brain, and particularly associated with cerebral blood vessels, and astrocytes of the periventricular nuclei. Raised RAS activity through elevated ACE is thought to impair cellular metabolism (Williams et al 2000) and amplify free radical and pro-inflammatory responses (Harding et al 2005). ACE may therefore play a role in neurodevelopmental progress and subsequent cognitive development (Harding et al 2005) as well as late-life cognitive decline (Amouyel et al 1996). This hypothesis is supported by demonstrations that ACE inhibitors improve cognitive function (Amenta et al 2002; Tzourio et al 2003).

The ACE gene on 17p23 contains a 287bp insertion/deletion polymorphism in intron 16. Both tissue and circulating ACE levels are higher in individuals with two copies of the deletion allele (Tiret et al 1992). The insertion allele appears to confer a slightly increased risk for Alzheimer's disease (Narain et al 2000) while the deletion allele has been repeatedly associated with increased risk for age-related cognitive impairment and dementia (Amouyel et al 1996; Palumbo et al 1999; Bartres-Faz et al 2000; Richard et al 2000; Stewart et al 2004). Deletion allele carriers are reported to show greater cognitive impairment in moderate and severe traumatic brain injury (Ariza et al 2006), less improvement after shunt surgery in normal pressure hydrocephalus (del Mar Matarin et al 2005), and reduced cognitive impairment in alcoholism (Bartres-Faz et al 2002). However three epidemiological studies have found no associations between ACE genotype and normal cognitive ageing (Visscher et al 2003, Frederiksen et al 2003, Yip et al 2002). Two studies have investigated the effects of ACE genotype on cognitive function in children (Gao et al 2006, Harding et al 2005). Both studies were negative, however both were limited by sample size and by the relatively crude cognitive measure they employed.