# Genome-Wide Analysis of DNA Methylation Signatures Linking Prenatal Exposure to the Chinese Great Famine and Blood Lipids in Late Adulthood: The Genomic Research of the Chinese Famine (GRECF) Study

## TL;DR

This study found that prenatal exposure to a severe famine in China is linked to long-term changes in DNA methylation that affect blood lipid levels in adulthood.

## Contribution

The study identifies six new genes associated with lipid metabolism through epigenetic changes caused by prenatal famine exposure.

## Key findings

- Seven DNA methylation sites showed significant associations with prenatal famine exposure.
- Five pathways related to lipid metabolism were identified as significant after FDR correction.
- Six novel genes (GBA2, ATF2, GRB2, PIK3R1, PIGQ, MAN1C1) were linked to blood lipid levels via epigenetic changes.

## Abstract

Background/Objectives: Prenatal exposure to famine can lead to lasting health effects through changes in DNA methylation. This study aims to evaluate the impact of prenatal exposure to the Chinses Great Famine (1959–1961) on human epigenome and the subsequent influence on blood lipids. Methods: We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and prenatal exposure to the Chinese Great Famine as well as blood lipids among eight participants exposed to famine and eight sex-matched participants (born ≤ 3 years after the famine). Genome-wide DNA methylation sites were profiled using the Illumina EPIC BeadChip, which covers 850K methylation positions. Results: After EWAS analyses, seven probes in genes C8orf31, ELAVL1, U6, GBA2, SHOX2, SLC1A4, and NPHP4 reached p < 1 × 10−5. Of these, famine exposure was associated with decreased methylation levels of a GBA2 exonic probe cg08258661 (p = 4.9 × 10−6). After false discovery rate (FDR) correction, pathway enrichment analyses for genes harboring nominally significant (p < 0.05) probes identified 44 significant pathways (q < 0.05), and 5 pathways were related to lipid metabolism. After FDR correction in each pathway, probes cg02622866 (5’UTR of ATF2, p = 1.09 × 10−3), cg07316730 (body of GRB2, p = 1.32 × 10−3), and cg01105385 (body of PIK3R1, p = 1.94 × 10−3) in the PI2K-Akt signaling pathway were associated with blood LDL-C (q ≤ 0.04); probes cg09180702 (3’UTR of PIGQ, p = 9.21 × 10−5, and q = 0.04) and cg01421548 (body of HS3ST4, p = 5.23 × 10−5, and q = 0.01) in the metabolism pathway were associated with blood LDL-C and HDL-C, respectively; In addition, probe cg08460387 (5’UTR of MAN1C1, p = 1.09 × 10−4, and q = 0.02) in the vesicle-mediated transport pathway was associated with log-transformed blood triglycerides. Conclusions: Through an epigenetic study of the Chinese Great Famine, we identified six novel genes involved in lipid metabolism.