Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus

Abstract

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.

Fig. 1

DNA methylation in context of genetic determination. a Distribution of the degree of methylation (β-value) of CpGs. The 14,118 meQTL-CpG sites display a rather intermediate distribution of their median β-values (red) compared to the bimodal distribution observed for all 344,106 CpG sites (black). b The relationship of explained variance R ² to the genomic distance of 14,118 meQTL-SNPs and their associated CpG site

Fig. 2

Genomic organization of hippocampal cis-meQTLs at the ADARB2 locus. Regional plot of hippocampal cis-meQTL P-values and CpG co-methylation patterns in the chromosomal region 10p15.3 (chr10:1,130,405–1,815,625, hg19) encompassing the RNA-editing adenosine deaminase-2 gene (ADARB2). We display gene symbols (Ensembl), CpG islands (UCSC), the Roadmap Hippocampus middle (E071) 15-chromatin-states: active TSS (#1 TssA, black), flanking active TSS (#2 TssAFlnk, gray), enhancer (#7 Enh, black), genic enhancers (#6 EnhG, gray) and cis-meQTL-SNPs. The plot was created using coMET

Fig. 3

Genetically driven correlation of CpG methylation with PIGP gene expression. The a correlation of PIGP 3′-expression with methylation states of CpG cg21832243 in the promoter flanking region (explained variance: 33.5%) is based on b a cis-eQTL (ILMN_1774949; P = 1.44 × 10⁻²², explained variance: 57.1%) and c a cis-meQTL (cg21832243; P = 9.58 × 10⁻²⁰, explained variance: 50.9%) both driven by a shared SNP rs9974798. Previously, we reported an association of the SNP rs9305614 in the PIGP promoter with pharmacoresistance of seizures for the antiepileptic drug levetiracetam in a partial overlapping sample of TLE patients