全基因组范围内鉴定影响人类海马体 DNA 甲基化和基因表达的遗传决定因素。
Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus.
机构信息
Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.
Department of Genomics, Life & Brain Center, Institute of Human Genetics, University of Bonn, 53127, Bonn, Germany.
出版信息
Nat Commun. 2017 Nov 15;8(1):1511. doi: 10.1038/s41467-017-01818-4.
Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the cis-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis-meQTLs at 14,118 CpG methylation sites and cis-eQTLs for 302 3'-mRNA transcripts of 288 genes. Hippocampal cis-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cis-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.
新兴证据强调了调控基因组元件在神经发育过程和大脑疾病复杂途径中的强大影响。本全基因组数量性状基因座分析研究了 110 个人类海马体活检样本中单核苷酸多态性（SNP）对 DNA 甲基化（meQTL）和基因表达（eQTL）的顺式调控作用。我们在 14118 个 CpG 甲基化位点和 288 个基因的 302 个 3' -mRNA 转录本中发现了顺式-meQTL。海马顺式-meQTL-CpG 富含活跃启动子侧翼区域、CpG 岛岸、转录因子 CTCF 结合位点和大脑 eQTL。海马体 meQTL 和 eQTL 的顺式作用 SNP 与精神分裂症相关 SNP 显著重叠。发现 34 个基因的 CpG 甲基化和 RNA 表达存在相关性。我们的海马顺式作用 meQTL 和 eQTL 的综合图谱为疾病相关 SNP 和调控基因组之间提供了联系，这将提高在大脑疾病的分子遗传学分析中非编码遗传变异的功能解释。
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