Background/Objectives: Separate genetic variants are associated with larger body size in childhood and adulthood. Whether these variants predominantly influence adiposity, and whether these truly differ by life stage is unknown. We examined how genetic variants influence total body fat and total lean mass trajectories from childhood to young adulthood. Methods: Data were from the Avon Longitudinal Study of Parents and Children birth cohort. Sex-specific genetic risk scores (GRS) for childhood and adulthood body size were generated, and dual-energy X-ray absorptiometry scans were used to measure total body fat and lean mass 6 times between ages 9-25y. We used mutually-adjusted multilevel linear spline models to examine the independent sex-specific associations of childhood and adulthood body size GRSs with fat and lean mass trajectories from 9 -25y. Results: In males, the childhood and adulthood GRS were associated with similar differences in fat mass from 9 to 18y; 8.3% (95% confidence interval (CI): 5.1,11.6)) and 7.5% (95% CI: 4.3,10.8) higher fat mass at 18y per standard deviation (SD) higher childhood and adulthood GRS respectively. At 25y, childhood GRS associations with fat mass attenuated while adulthood GRS associations remained similar to those at 18y for males. Among females, associations for the childhood GRS were almost two-fold stronger than the adulthood GRS from 9 to 18y: 10.5% (95% CI: 8.5, 12.4) higher fat mass at 9y per SD higher childhood GRS compared with 5.1% (95% CI 3.2, 6.9) per SD higher adulthood GRS. At 25y, associations of the childhood and adulthood GRS with fat mass were similar; 5.0% (95% CI: 2.5, 7.5) and 5.8% (95% CI: 3.3, 8.3) higher fat mass per SD higher childhood and adulthood GRS respectively: Lean mass effect sizes were much smaller. Conclusions: Genetic variants for body size are more strongly associated with adiposity than lean mass from childhood to early adulthood; childhood variants are more strongly associated with adiposity in females until early adulthood whereas childhood and adulthood variants are similarly associated with adiposity across early life in males. Findings may inform selection of instruments for life stage- specific adiposity in future Mendelian randomization studies.
Background: Small intestinal neuroendocrine tumours (siNETs) are rare neoplasms which present with low mutational burden and can be subtyped based on copy number variation (CNV). Currently, siNETs can be molecularly classified as having chromosome 18 loss of heterozygosity (18LOH), multiple CNVs (MultiCNV), or no CNVs. 18LOH tumours have better progression free survival when compared to MultiCNV and NoCNV tumours, however the mechanism underlying this is unknown, and clinical practice does not currently consider CNV status. Methods: Here, we use genome-wide tumour DNA methylation (n=54) and gene expression (n=20 matched to DNA methylation) to better understand how gene regulation varies by 18LOH status. We then use multiple cell deconvolution methods to analyse how cell composition varies between 18LOH status, and determine potential associations with progression free survival. Results: We identified 27,464 differentially methylated CpG sites and 12 differentially expressed genes between 18LOH and non-18LOH (MultiCNV + NoCNV) siNETs. Although few differentially expressed genes were identified, these genes were highly enriched with the differentially methylated CpG sites compared to the rest of the genome. We identified differences in tumour micro-environment between 18LOH and non-18LOH tumours, including CD14+ infiltration in a subset of non-18LOH tumours which had the poorest clinical outcomes. Conclusions: We identify a small number of genes which appear to be linked to the 18LOH status of siNETs, and find evidence of potential epigenetic dysregulation of these genes. We also find a potential prognostic marker for worse progression free outcomes in the form of higher CD14 infiltration in non-18LOH siNETs.
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