NEW YORK (GenomeWeb) – A genome-wide association study involving tens of thousand of children and adults has identified genetic variants associated with head size across the lifespan, including low-frequency variants in TP53 and other cancer-related genes.
"Our findings show that genome-wide approaches combining genetically and developmentally related phenotypes may enhance the power to identify even relatively rare genetic variation with large effect," co-first author Simon Haworth, a researcher in the University of Bristol MRC Integrative Epidemiology Unit, said in a statement.
As they reported online yesterday in Nature Communications, Haworth and colleagues used whole-genome sequences and genotypes imputed with the help of data from projects such as UK10K, the 1000 Genomes Project, and the haplotype reference consortium for a two-stage GWAS focused on finding common, low-frequency, and rare variants associated with head circumference or intracranial volume, a brain volume measurement.
"[U]sing measures of the developing skull as an accurate and easily accessible proxy for intracranial volume may enable us to investigate cost-effectively genetic factors that also affect brain growth," corresponding author Beate St Pourcain, an integrative epidemiology, language, and genetics researcher affiliated with the University of Bristol, the Max Planck Institute for Psycholinguistics, and Radboud University, said in a statement.
The team's search led to nine previously unappreciated loci that are linked to head size, including low-frequency variants in TP53, along with variants previously implicated in head size in infancy. In particular, the team estimated that variants linked to head traits in infancy or at age 7 explained at least 60 percent of the phenotypic variation observed in these traits by age 15.
"We know very little about genetic factors influencing head circumference scores beyond infancy," St. Pourcain explained. "Studying head circumference in older children and adults is important, as it is a permanent measure of our peak brain size that is robust to aging."
For their two-stage head circumference GWAS, the researchers started with low-coverage whole-genome sequence data or array-based genotyping profiles for 10,600 children between the ages of six and nine and nearly 8,300 adults 44 to 61years old from the Avon Longitudinal Study of Parents and Children and 10 other population-based cohorts.
The team's analyses and meta-analyses of the cohorts, together with follow-up genotyping data for 973 individuals, provided a look at the variants impacting head circumference or intracranial volume across the lifespan.
In the pediatric cohort, the team identified a known head circumference-associated variant on chromosome 12, along with a new variant on chromosomes 4 near the INTU gene and a chromosome 6 SNP in linage disequilibrium with the major histocompatibility region. The latter variant was associated with head circumference in a combined analysis of adult and pediatric individuals.
The researchers' adult-pediatric analysis also unearthed a chromosome 17 variant in TP53 that coincided with an average head size difference of 0.5 cm. On the other hand, several known head size-related variants showed potential ties to the trait in the adult-only cohort, but did not reach statistical significance.
The team unearthed eight more head size-related loci in a follow-up GWAS meta-analysis of both head circumference and intracranial volume in the 18,881 adults and children from the original GWAS and another 26,577 individuals. That set included a cancer-related, low-frequency variant influencing TP53 transcript isoforms.
"Collectively, these findings provide insight into the genetic effects influencing cranial growth during childhood and adolescence," the authors wrote, "while yielding additional genetic associations which enhance our understanding of the biological mechanisms underlying these complex developmental processes."