The mammalian brain has undergone significant expansion in its evolution to man, and is over 3 times bigger than our closest primate relatives (1). Head circumference is highly correlated with brain size, and is used clinically as a proxy measurement for brain volume. Major work has been done in the identification and functional analysis of genes causing marked reduction in head circumference/brain size (Primary Microcephaly/Seckel syndrome,ref. 2-6). Several genes have been identified, all of which have centrosomal functions (6-8). Two of these, ASPM and MCPH1 have been found to undergo significant adaptive evolution in primates (9,10). However, to date, variants in these genes have not been found to be associated with normal population variation in head circumference/brain size (11).

Following on from the identification of Mendelian genes for these disorders of extreme reduction in head circumference (-4 to -10sd), it is now of interest to identify the factors responsible for variation in head circumference and brain size in the general population, especially during early development. Given the wide variation in growth of head cicumference during early childhood, all measures will be standardised using the GrowthAnalyzer (http://www.growthanalyser.org) to obtain the best possible reference standards within each sample. Measures at birth will be adjusted for gestational age.

A meta-analysis on variation in early head circumference at birth and early childhood (0 to 4 years) is proposed as part of the EGG/EAGLE consortium with a follow-up of genome-wide/ near genome-wide significant signals within the remainder of the ALSPAC sample.

Once identified and validated, such genes will contribute to the understanding of developmental pathways that influence cognitive and brain development and address whether common variants are acting in developmental pathways already implicated by mendelian genetics in brain size determination.