Genome-wide DNA methylation analysis of cognitive function in middle and old-aged Chinese monozygotic twins

Cognitive ability plays an important role in mental and physical well-beings in the increasingly ageing populations. Here, based on a sample of 30 cognitive function-discordant monozygotic twin pairs, we aimed to detect specific epigenetic variants potentially related to cognitive function by conducting an epigenome-wide association study (EWAS). Association between methylation level of single CpG site with cognitive function score was tested by linear mixed effect model. Functions of cis-regulatory regions and ontology enrichments were predicted by Genomic Regions Enrichment of Annotations Tool (GREAT). Differentially methylated regions (DMRs) were detected by comb-p python library. A list of 28 CpG sites were identified to reach the level of P < 1 × 10^-4, and the strongest association (cor = 0.138, P = 2.549 × 10^-6) was detected for DNA CpG site (Chr17: 40,700,490 bp) located at HSD17B1P1. The identified 14,065 genomic CpG sites (P < 0.05) were mapped to 2646 genes, especially HSD17B1P1, CUL4A, INTS8, GFI1B, ZNF467, CDH15, and PSMA1. GREAT ontology enrichments mainly highlighted nicotine pharmacodynamics pathway, GABA-B receptor II/nicotinic acetylcholine receptor/hedgehog/endothelin/Wnt signaling pathways, Parkinson disease, Huntington disease, glycolysis, neuronal system, and toll-like receptor binding. We detected 15 DMRs located at/near 16 genes, especially LINC01551, LINC02282, and FAM32A. And 32 cognitive function-associated differentially methylated genes could be replicated, such as SHANK2, ABCA2, PRDM16, NCOR2, and INPP5A. Our EWAS in monozygotic twins identify specific epigenetic variations which are significantly involved in functional genes, biological function and pathways that mediate cognitive function. The findings provide clues to further identify new diagnostic biomarkers and therapeutic targets for cognitive dysfunction.