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Head Size-Related Genetic Variants Coincide With Cancer Genes, Pathways

NEW YORK – New research suggests that genetic variants, genes, and pathways involved in large head size overlap with those involved in cancer risk, providing clues to shared biology and screening possibilities.

As they reported in Cell Reports Medicine on Friday, researchers from the Netherlands, US, France, and other international centers relied on a genome-wide association study meta-analysis involving 80,890 individuals for whom head circumference or brain imaging measurements were available to search for loci linked to head size.

"The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped," co-senior and corresponding author Hieab Adams, a researcher at Radboud University Medical Center in the Netherlands, and his co-authors wrote.

In the process, the team tracked down 90 head size-associated genetic variants at 67 loci in participants with European ancestry, including 17 variants with ties to the size of specific parts of the brain. At least four dozen variants with ties to head size in the European participants showed similar association directionality in smaller subsets of study participants of Asian and African ancestry.

The investigators explored the functional consequences of the head size-linked variants with a series of follow-up studies, including expression quantitative trait locus analyses, assessments of published single-cell gene expression data from human cortex cell types, and a transcriptome-wide association study that brought together 21 available gene expression panels and GWAS summary statistics from European ancestry participants.

Along with an overrepresentation of variants in and around genes implicated in syndromes marked by large head size, or macrocephaly, the researchers' results revealed an enrichment of variants and loci in parts of the genome previously implicated in cancer.

"[W]e performed the largest head size GWAS to date and found that associated genetic variants significantly locate to cancer genes and cancer-associated pathways," the authors wrote, noting that their gene set enrichment analyses likewise highlighted signaling pathways with ties to cancer, including p53, WNT, and ErbB pathways.

The results line up with findings from past studies that found ties between head circumference at birth and the risk of developing cancers ranging from pediatric brain cancer to breast or stomach cancer, the team explained. On the other hand, they also provide a more nuanced view to prior observational studies linking cancer risk and height in adults, hinting that such associations may be reflecting larger head size in taller individuals.

"Genes near head size variants were enriched for high-fidelity cancer genes even after adjustment for height," authors of the study reported, "suggesting a specific association of head growth with cancer, rather than general growth."

Based on their latest findings, together with results from previous studies, the authors suggested that additional research is needed to dig into the apparent relationship between head size and cancer. The results may help with understanding and screening for cancer development in individuals with larger head sizes.

"[W]e were not able to account for environmental factors such as socioeconomic status and diet, especially during childhood, which would be important to adjust for in future studies," they wrote, noting that "clinical implications of the findings of our study need to be investigated, for example if patients with clinical macrocephaly syndromes need to be screened for cancer more extensively."