BACKGROUND Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 individuals between the ages of 18 and 87 years, with replication in a further 4450 individuals between the ages of 18 and 93 years. METHODS Linear regression models were applied, with stringent genome-wide significance thresholds (p < 3.6 × 10-8) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds. RESULTS Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10, an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = - 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction. CONCLUSION The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.

中文翻译：

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性别特异性时间老化的全表观基因组关联研究。

背景技术高龄与认知和身体衰退相关，并且是多种疾病的主要危险因素。男性和女性的预期寿命也存在差距。DNA 甲基化差异已被证明与年龄和性别相关。在这里，我们调查了 2586 名年龄在 18 岁至 87 岁之间的无关人群中血液 DNA 甲基化的年龄差异，并在另外 4450 名年龄在 18 岁至 93 岁之间的个体中进行了复制。方法 应用线性回归模型，在发现和复制数据中使用严格的全基因组显着性阈值 (p < 3.6 × 10-8)。还应用了第二种高度保守的混合线性模型方法，它使用相同的全基因组显着性阈值，可以更好地控制假阳性率。结果 使用线性回归方法，将 52 个常染色体和 597 个 X 连锁 CpG 位点映射到 251 个独特基因，并在年龄与性别相互作用分析中以一致的效应大小方向进行复制。差异最大的位点映射到 X 连锁基因 GAGE10。在这里，DNA 甲基化水平在成年男性年龄范围内保持稳定（年龄 r = 0.02 的 DNA 甲基化水平），但在成年女性年龄范围内下降（年龄 r = - 0.61 的 DNA 甲基化水平）。一个具有显着年龄与性别相互作用的位点 (cg23722529) 也有一个数量性状基因座 (rs17321482)，它是前列腺癌的全基因组显着变异。混合线性模型方法确定了与年龄与性别相互作用相关的 11 个 CpG 位点。结论 性别之间与年龄相关的 DNA 甲基化轨迹的大部分差异存在于 X 染色体上。其中一些差异发生在与性二态性特征有关的基因内。