OBJECTIVE
This study aimed to examine the associations of longitudinal obesity trajectories and polygenic risk with sex-specific brain aging.
METHODS
We analyzed 35,092 UK Biobank participants (16,484 males and 18,608 females). Sex-specific XGBoost models estimated multimodal brain age. We derived 16-year longitudinal obesity trajectories from repeatedly collected anthropometric measurements. Polygenic risk scores were constructed based on 55 independent genetic loci. Multivariable logistic regression examined associations of obesity trajectories and genetic risk with brain age acceleration.
RESULTS
A total of 8198 (49.73%) males and 9089 (48.84%) females had accelerated brain aging. High genetic risk significantly increased brain age acceleration odds (males: OR = 1.39; females: OR = 1.34). Crucially, the high-stable obesity trajectory exerted a stronger effect in males (OR = 1.90, 95% CI: 1.64-2.21) than in females (OR = 1.25, 95% CI: 1.12-1.40), with the joint presence of high genetic risk and high-stable obesity amplifying risk to an OR of 2.78 in males and 1.57 in females. Conversely, shifting from obesity to non-obesity reduced risk by 30% in males and 18% in females.
CONCLUSIONS
These findings underscore long-term obesity as a critical, sex-dimorphic driver of accelerated brain aging, and midlife weight management offers robust neuroprotection even in genetically susceptible individuals.
Miao-Miao Zhu, Fan Yang, Jia Guo et al.· Obesity· 0 citations
BACKGROUND
The identification and reporting of actionable genotypes in the American College of Medical Genetics and Genomics (ACMG)-recommended secondary findings (SF) genes represent a key preventive strategy for hereditary diseases. Robust evidence quantifying their association with lifespan remains limited, particularly for non-coding regulatory variants, due to functional interpretation challenges.
METHOD
Using data from the UK Biobank, we investigated associations between genetic variants and all-cause mortality in 490 086 participants with whole-genome sequencing. We systematically interpreted pathogenic or likely pathogenic coding variants in the 81 genes listed in the ACMG SF V.3.2. In parallel, we conducted saturation mutagenesis combined with a massively parallel reporter assay on the core promoters of these genes to generate a functional map of every potential variant, which we then used to interpret the functionally promoter variants in the cohort and evaluated their associations with mortality and disease incidence.
RESULTS
Coding actionable genotypes were present in 3.40% of participants and were associated with increased all-cause mortality (HR in females, 1.42; 95% CI 1.34 to 1.52; HR in males, 1.31; 95% CI 1.24 to 1.39). All rare variants within the core promoter regions of these genes revealed no significant association with survival. Functionally promoter variants with downregulating activity of cancer genes were associated with elevated mortality risk (HR in females, 1.15; 95% CI 1.01 to 1.31; HR in males, 1.12; 95% CI 1.00 to 1.26). Furthermore, our findings provide clues that functional promoter variants may merit consideration when expanding actionable genotype lists.
CONCLUSIONS
Our findings demonstrate that functionally verified promoter variants represent a previously unrecognised determinant of mortality risk, highlighting the potential value of looking beyond coding sequences in future studies.
Congcong Chen, Jiawen Zhu, Ziye Xu et al.· Journal of Medical Genetics· 0 citations
De novo mutations (DNMs) are an important source of congenital diseases. With delayed parenthood and assisted reproductive technology (ART) use increasing, it is essential to elucidate how these reproductive factors influence DNMs and whether resulting mutations influence offspring health. Here we performed whole-genome sequencing of 24,030 individuals from 7,851 parent-offspring families, identifying 390,924 de novo single-nucleotide variants (dnSNVs). Paternal and maternal aging exhibited distinct mutational patterns, with maternal DNM accumulation accelerating at advanced ages. Increased paternal dnSNVs partially accounted for the association between advanced parental age and shorter gestational duration. Moreover, ART showed age-independent, procedure-specific effects: intracytoplasmic sperm injection (ICSI) and ovarian stimulation were associated with increased paternal and maternal dnSNVs, respectively, and ICSI-associated paternal dnSNVs also partially accounted for the association between ICSI and shorter gestational duration. In vitro embryo manipulation was associated with increased early post-zygotic mosaic mutations, particularly C > A substitutions linked to delayed neurocognitive development at 1 year. Collectively, these findings advance understanding of the determinants and consequences of de novo mutagenesis.
N. Qin, Juncheng Dai, Yue Jiang et al.· Nature Medicine· 0 citations
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