Waterfield Scott, Yousefi Paul, Suderman Matt
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Clin Epigenetics. 2024 Dec 21;16(1):189. doi: 10.1186/s13148-024-01802-y.
Multiple studies have shown that DNA methylation (DNAm) models of protein abundance can be informative about exposure, phenotype and disease risk. Here we investigate and provide descriptive details of the capacity of DNAm to capture non-genetic variation in protein abundance across the lifecourse.
We evaluated the performance of 14 previously published DNAm models of protein abundance (episcores) in peripheral blood from a large adult population using the Avon Longitudinal Study of Parents and Children (ALSPAC) at ages 7-24 and their mothers antenatally and in middle age (N range = 145-1464). New age-specific episcores were trained in ALSPAC and evaluated at different ages. In all instances, episcore-protein associations were evaluated with and without adjustment for genetics. The association between longitudinal protein stability and longitudinal episcore projection was also evaluated, as was sex-specificity of episcores derived solely in female participants.
Of the 14 Gadd episcores, 10 generated estimates associated with abundance in middle age, 9 at age 24, and none at age 9. Eight of these episcores explained variation beyond genotype in adulthood (6 at age 24; 7 at midlife). At age 9, the abundances of 22 proteins could be modelled by DNAm, 7 beyond genotype of which one trained model generated informative estimates at ages 24 and in middle age. At age 24, 31 proteins could be modelled by DNAm, 19 beyond genotype, of which 5 trained models generated informative estimates at age 9 and 8 in middle age. In middle age, 23 proteins could be modelled, 13 beyond genotype, of which 3 were informative at age 9 and 7 at age 24.
We observed that episcores performed better at older ages than in children with several episcores capturing non-genetic variation at all ages.
多项研究表明，蛋白质丰度的DNA甲基化（DNAm）模型可用于了解暴露情况、表型和疾病风险。在此，我们研究并详细描述了DNAm在整个生命过程中捕捉蛋白质丰度非遗传变异的能力。
我们使用雅芳亲子纵向研究（ALSPAC），评估了14个先前发表的蛋白质丰度DNAm模型（表观评分）在7至24岁的大量成年人群外周血中的表现，以及他们母亲在产前和中年时的表现（样本量范围为145 - 1464）。在ALSPAC中训练了新的年龄特异性表观评分，并在不同年龄进行评估。在所有情况下，均在调整和未调整基因的情况下评估表观评分与蛋白质的关联。还评估了纵向蛋白质稳定性与纵向表观评分预测之间的关联，以及仅在女性参与者中得出的表观评分的性别特异性。
在14个加德表观评分中，10个在中年时产生了与丰度相关的估计值，9个在24岁时相关，9岁时均无相关。其中8个表观评分解释了成年期基因型以外的变异（24岁时6个；中年时7个）。在9岁时，22种蛋白质的丰度可用DNAm建模，其中7种超出基因型，其中一个训练模型在24岁和中年时产生了有参考价值的估计值。在24岁时，31种蛋白质可用DNAm建模，19种超出基因型，其中5个训练模型在9岁时产生了有参考价值的估计值，8个在中年时产生了有参考价值的估计值。在中年时，23种蛋白质可用DNAm建模，13种超出基因型，其中3种在9岁时具有参考价值，7种在24岁时具有参考价值。
我们观察到，表观评分在年龄较大时比在儿童中表现更好，有几个表观评分在所有年龄段都能捕捉到非遗传变异。
