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Biology subjects

Wright, M. N.

Publications and source records attributed to Wright, M. N..

3 recordsLinked to original sources

Adversarial random forests for omics synthesis

Data availability is critical for understanding complex disease pathways and developing robust predictive models. Although high-throughput omics technologies have improved insight into disease mechanisms, data acquisition from inaccessible tissues such as the central nervous system remains a major limitation, causing small sample sizes and complicating early prediction of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Generative modeling has emerged as a powerful approach for synthesizing data to support downstream clustering and prediction with small sample size, but existing methods rarely handle high-dimensional tabular omics data effectively. Adversarial random forests (ARFs) provide a well-performing framework for tabular data generation but are not designed for high-dimensional settings. To address this limitation, we introduce high-dimensional ARF (h-ARF), an extension of ARF optimized for integrated clinical and high-dimensional omics data. Using benchmarks across nine datasets and eight performance metrics, we show that h-ARF better preserves both feature distributions, and downstream clustering and prediction utilities compared with ARFs. The method is implemented in the open-source R package harf, available on CRAN.

bioinformatics↗

A healthy childhood environment helps to combat inherited susceptibility to obesity

ObjectivesTo investigate the degree by which the inherited susceptibility to obesity is modified by environmental factors during childhood and adolescence. DesignCohort study with repeated measurements of diet, lifestyle factors and anthropometry. SettingThe pan-European IDEFICS/I.Family cohort Participants8,609 repeated observations from 3,098 children aged 2 to 16 years, examined between 2007 and 2014. Main outcome measuresBody mass index (BMI) and waist circumference. Genome-wide polygenic risk scores (PRS) to capture the inherited susceptibility of obesity were calculated using summary statistics from independent genome-wide association studies of BMI. Gene-environment interactions of the PRS with sociodemographic (European region, socioeconomic status) and lifestyle factors (diet, screen time, physical activity) were estimated. ResultsThe PRS was strongly associated with BMI (r2 = 0.11, p-value = 7.9 x 10-81) and waist circumference (r2 = 0.09, p-value = 1.8 x 10-71) in our cohort. The associations with BMI increased from r2=0.03 in 3-year olds to r2=0.18 in 14-year olds and associations with waist circumference from r2=0.03 to r2=0.14. Being in the top decile of the PRS distribution was associated with 3.63 times higher odds for obesity (95% confidence interval (CI): [2.57, 5.14]). We observed significant interactions with demographic and lifestyle factors for BMI as well as waist circumference. The risk of becoming obese among those with higher genetic susceptibility was ~38% higher in children from Southern Europe (BMI: p-interaction = 0.0066, Central vs. Southern Europe) and ~61% higher in children with a low parental education (BMI: p-interaction = 0.0012, low vs. high). Furthermore, the risk was attenuated by a higher intake of dietary fiber (BMI: p-interaction=0.0082) and shorter screen times (BMI: p-interaction=0.018). ConclusionsOur results highlight that a healthy childhood environment might partly offset a genetic predisposition to obesity during childhood and adolescence.

genetics↗

Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e. the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally-arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of a AKR/J mouse strain (B6-mtAKR) together with a C57BL/6J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to wild-type C57BL/6J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair metabolic health and lifespan in mice.\n\nHighlightsO_LIWe identify heteroplasmy of the adenine-repeat variation (9 to 13A) in nt5172 in the origin of light-strand DNA replication (OriL) in inbred mice.\nC_LIO_LIB6-mtAKR mice carry >20% 12A heteroplasmy in the OriL, while B6 mice carry only [~] 10% heteroplasmy.\nC_LIO_LIThe level of 12A heteroplasmy correlates to mtDNA copy number, glucose metabolism, and lifespan in mice.\nC_LIO_LIGiven the established role of mtDNA heteroplasmy in regards to endurance exercise performance in athletes, these findings may impact our understanding of metabolism and aging in humans.\nC_LI

genetics↗