Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

“…Of these loci, 12 were also associated with adult BMI [9,10]. The remaining 3 identified genetic loci, specifically associated with childhood BMI, suggest possible age-specific differences between the two stages of life or could indicate stronger effects for these genetic loci in childhood BMI than in adult BMI [11][12][13]. Thus far, most common variants explaining the genetic variability of childhood BMI remain undetected.…”

Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits

“…However, here we show relatively frequent SNPs related to p53 affect cancer risk and anthropometric traits. Notably, the allele of a SNP in the polyadenylation signal of p53 (rs78378222[C]) which is found in approximately 1% of populations of European descent, has been shown to impair 3’- end processing of p53 mRNA, resulting in a reduction of p53 protein and an increased risk for glioma and basal cell carcinoma as well as affecting head circumference and intracranial volume 45, 46 . Here we not only validate these cancer associations in a separate cohort (non-melanomatous skin cancer, OR= 1.46 [1.34-1.60], adjusted p= 5.20E −18 , brain malignancy, OR= 3.12 [2.23-4.37], adjusted p= 1.43E −12 ) but also show that carriers of this allele tend to be taller, leaner and have a higher basal metabolic rate (standing height, adjusted-p= 2.18E −24 , beta= 0.073 ± 0.007, whole body fat free mass, adjusted-p= 8.34E −37 , beta= 0.073 ± 0.005, basal metabolic rate, adjusted-p= 1.13E −31 , beta= 0.076 ± 0.006).…”

The amplification of genetic factors for early vocabulary during children’s language and literacy development

“…However, compared to large-scale genome-wide studies of educational attainment 45 or direct assessments of language and literacy measures their predictive power is low. Indeed, anthropometric measures that are more reliably assessed, such as head circumference (known to be genetically correlated with cognitive functioning), show evidence for both amplification and innovation processes from infancy to later adolescence 46 . A further limitation of the current study is that the CDI Toddler version was developed to assess vocabulary in children up to 30 months 20 , whereas ALSPAC children were assessed at 38 months of age, potentially leading to ceiling effects.…”