Within our study, we aim to analyse common and rare genetic variation for association with head circumference within a total sample of 6284 unrelated 7-year-old ALSPAC children with phenotypic information (mean(SD)=52.5(1.5) cm). For this, we will carry out a meta-analysis in collaboration with other cohorts such as GenR, HELIC and QIMR. Specifically, we aim at the detection of novel rare but also single point variants. In addition, we will search for an enrichment of signals according to cell type and syndromic loci, where disorders have been linked to abnormal head shape (holoprosencephaly, oral clefts and others). This will be complemented by analyses of SNP heritability and genetic correlation analyses with other anthropometric traits in ALSPAC during childhood and adolescent development.

Exposure variables in ALSPAC: The analysis will be carried out within the framework of a UK10K Project (UK10K approval has already been obtained). This includes the investigation of 1867 individuals from the Avon Longitudinal Study of Parents & Children (ALSPAC), which have been whole genome sequenced (WGS) to ~6.5x coverage. The analysis will also include the remaining ALSPAC children with genome-wide SNP data (total N=8365). These data were jointly imputed using variants discovered by WGS together with those from 1000 Genomes. Outcome variables in ALSPAC: The investigated phenotype is head circumference at 7 years of age. Genetic relationships will also be explored with respect other anthropometric and bone-related variables, as well as cognitive functioning (height, weight) during childhood and adolescence (birth to 17 years).