Evaluating a Genome-Wide Polygenic Score for Handgrip Strength and Its Interplay with Leisure-Time Physical Activity Across the IGEMS Twin Cohorts.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting heterozygous carriers of a mutant copy of the neurofibromin gene (), accounting for around 1 in 3000 births [, ]. As a negative regulator of the Ras-MAPK [] and PI3K-Akt-mTOR pathways [], neurofibromin plays a central role across many tissues in the regulation of cell proliferation and is considered a tumour-suppressing protein. Notably, individuals with NF1 show a range of multisystemic symptoms of varying severity. In somatic tissues, neurofibromin deficiency is thought to be compounded by secondary loss of heterozygosity, leading to uncontrolled cell proliferation. This can lead to cell malformations including tumours across many tissues of the body, the most common of which are plexiform neurofibromas (affecting nerve sheaths), Lisch nodules (affecting the iris) and café-au-lait macules (affecting epidermal melanocytes). Other common symptoms include bone abnormalities and hypertension. While mostly benign, arising tumours can lead to chronic pain, cosmetic disfigurement, may impede the normal growth of critical structures (e.g. airway or spinal cord), and can reduce overall functional outcomes. Furthermore, malignancies may develop in a significant subset of individuals with NF1, greatly reducing life expectancy []. Neurofibromin is widely expressed throughout the brain across early development and adulthood [, ]. The prevailing view is that neurofibromin protein deficiency leads to neurodevelopmental and neurophysiological abnormalities that contribute to the cognitive, behavioural, and psychiatric symptom complexes seen in many individuals with NF1 [, ]. A downward shift in intellectual functioning is a robust finding and specific deficits in executive function, attention and visuospatial perception have been widely reported [, ]. These cognitive complications contribute to elevated autistic traits [] and attention deficit hyperactivity disorder (ADHD) symptoms [], with approximately 25% of children with NF1 meeting diagnostic threshold for autism [] and 38% for ADHD []. Additionally, a majority of individuals with NF1 present with learning difficulties [, ]. Rates of depression and anxiety are also significantly higher in those with NF1 than in the general population, although exact estimates vary [, ]. Despite the negative impact on quality of life [], no targeted treatments for cognitive deficits and psychiatric symptoms in NF1 are currently available. Heterozygous mice have been used to model cognitive and behavioural symptoms in this condition []. This preclinical model does not develop malignancies until an advanced age [], thus avoiding the confounding factor of tumour formation on relevant outcomes. Research using the mouse has repeatedly revealed deficits in spatial learning [, –] and several other cognitive domains [–], although there have also been a number of inconsistent results [, , ]. In addition, behavioural alterations highly relevant to the autism-associated symptoms seen in individuals with NF1 have been reported in mice, including significant changes in early ultrasonic vocalization [], suggesting communication deficits, as well as impairments in social recognition [, , ]. Other phenotypes in mice pertinent to NF1 clinical presentation include morphometric MRI findings of several brain regions []. In humans, enlarged brains and brain subregions have been reported consistently [–], and some studies have reported a correlation between these structural abnormalities and the severity of specific neuropsychological traits [, ]. Neurodevelopmental disorders such as autism and other syndromes that have overlapping symptoms with NF1—such as fragile X syndrome—are also associated with increased brain size [–], which points toward a potential significance of this trait in the shared pathophysiology. In mice, increased prefrontal cortex volumes in were found to be inversely correlated with social recognition performance, while striatum volumes inversely predicted spatial learning performance for a subgroup of mice []. While these associations do not constitute proof of a causal role for brain size in the emergence of these behavioural traits, they provide convincing support for further investigations into the role of altered brain structure in NF1 neurobehavioural phenotypes.