Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2
Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2
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DOI：
10.1038/s41386-019-0500-y
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发表时间：
2020-02-01
影响因子：
7.6
通讯作者：
Lohoff, Falk W.
中科院分区：
文献类型：
--
作者：
Luo, Audrey;Jung, Jeesun;Lohoff, Falk W.
为了研究酒精使用障碍（AUD）在衰老过程中的潜在作用，我们使用Levine的表观遗传时钟（DNAm PhenoAge）来估计331名AUD患者和201名健康对照（HC）的DNA甲基化年龄。我们使用临床生物标志物，包括肝功能测试酶（LFTs）和临床测量，评估了重度慢性饮酒对表观遗传年龄加速（EAA）的影响。为了描述可能导致AUD患者EAA的潜在遗传变异，我们对EAA进行了全基因组关联研究（GWAS），包括通路分析。我们利用BRAINEAC数据库对相关的顶级发现进行了生物功能的计算机表达定量性状位点（eQTL）分析。在调整性别和血细胞组成后，与对照组相比，AUD的年龄加速2.22岁（p = 1.85 x 10(-5)）。在调整种族、体重指数和吸烟状况后，这种关联仍然显著（1.38年，p = 0.02）。二次分析显示，与aud相关的表型越严重的个体，EAA越明显，包括γ -羟戊基转移酶（GGT）和谷丙转氨酶（ALT）升高，酗酒天数越长（p < 0.05）。AUD患者EAA的全基因组荟萃分析显示，载脂蛋白L2 （APOL2）在全基因组水平上存在显著的单核苷酸多态性（SNP） rs916264 （p = 5.43 × 10(-8)）。rs916264的次要等位基因A与EAA相关，且与海马mRNA表达增加相关（p = 0.0015）。我们的数据证实了EAA在AUD中的作用，并表明疾病的严重程度进一步加速了表观遗传衰老。EAA与APOL2的遗传变异有关，提示AUD患者年龄加速的潜在新的生物学机制。
To investigate the potential role of alcohol use disorder (AUD) in aging processes, we employed Levine's epigenetic clock (DNAm PhenoAge) to estimate DNA methylation age in 331 individuals with AUD and 201 healthy controls (HC). We evaluated the effects of heavy, chronic alcohol consumption on epigenetic age acceleration (EAA) using clinical biomarkers, including liver function test enzymes (LFTs) and clinical measures. To characterize potential underlying genetic variation contributing to EAA in AUD, we performed genome-wide association studies (GWAS) on EAA, including pathway analyses. We followed up on relevant top findings with in silico expression quantitative trait loci (eQTL) analyses for biological function using the BRAINEAC database. There was a 2.22-year age acceleration in AUD compared to controls after adjusting for gender and blood cell composition (p = 1.85 x 10(-5)). This association remained significant after adjusting for race, body mass index, and smoking status (1.38 years, p = 0.02). Secondary analyses showed more pronounced EAA in individuals with more severe AUD-associated phenotypes, including elevated gammaglutamyl transferase (GGT) and alanine aminotransferase (ALT), and higher number of heavy drinking days (all ps < 0.05). The genome-wide meta-analysis of EAA in AUD revealed a significant single nucleotide polymorphism (SNP), rs916264 (p = 5.43 x 10(-8)), in apolipoprotein L2 (APOL2) at the genome-wide level. The minor allele A of rs916264 was associated with EAA and with increased mRNA expression in hippocampus (p = 0.0015). Our data demonstrate EAA in AUD and suggest that disease severity further accelerates epigenetic aging. EAA was associated with genetic variation in APOL2, suggesting potential novel biological mechanisms for age acceleration in AUD.