The association between prenatal famine, DNA methylation and mental disorders: a systematic review and meta-analysis

Eichenauer, Heike; Ehlert, Ulrike

doi:10.1186/s13148-023-01557-y

Table 3 Effects of prenatal exposure to famine on targeted DNA methylation of the offspring

From: The association between prenatal famine, DNA methylation and mental disorders: a systematic review and meta-analysis

References	Cohort	Sample description of groups with prenatal, non-prenatal or non-exposure	Chromosome	Gene	No. CpG	DNA methylation analysis from blood	Main results
Jiang et al. [63]	Chinese Famine*^a	Prenatal exposure N = 194, ♀ = 89, mean age 52	chr3:148416100–148416355	AGTR1	1	Bisulfite sequencing	Hypomethylation of AGTR1 (cg13528513), AGTR1 (cg20906621), and PRKCA*** after prenatal exposure compared to time controls
		Prenatal exposure N = 194, ♀ = 89, mean age 52	chr3:148418205–148418530	AGTR1	1
		Time controls N = 192, ♀ = 94, mean age 52	chr17:64649040–64649570	PRKCA	1
Wang et al. [72]^d	Chinese Famine*^a	Prenatal exposure N = 75, ♀ = 38, mean age 55	chr11:2126035–2126372	IGF2	8	EpiTYPER	Hypermethylation of IGF2 CpG2* and INSR CpG1, 4, 5 and 7 after prenatal exposure compared to time controls; no significant differences for other CpGs
		Prenatal exposure N = 75, ♀ = 38, mean age 55	chr19:7110130–7110574	INSR	9
		Time controls N = 160, ♀ = 80, mean age 55
Wang et al. [74]^d	Chinese Famine*^a	Prenatal exposure N = 75, ♀ = 38, mean age 55	chr11:68286513–68286952	CPT1A	11	EpiTYPER	Hypermethylation of INSR CpG1*, 4, 5* and 7*** after prenatal exposure compared to time controls; no significant differences for CPT1A
		Prenatal exposure N = 75, ♀ = 38, mean age 55	chr19:7110130–7110574	INSR	9
		Time controls N = 160, ♀ = 80, mean age 55
Finer et al. [59]	Bangladesh Famine*^c	Prenatal exposure N = 13	chr6:151646312–151647133	AKAP12	9	Bisulfite Pyrosequencing	Hypomethylation of VTRNA2-1* and EXD3* after prenatal exposure compared to non-prenatal exposure; hypermethylation of PAX8* and hypomethylation of ZFP57* and PRDM9*** after prenatal exposure compared to non-prenatal and non-exposure; no significant differences for other genes
		Non-prenatal exposure N = 30	chr12:57040045–57040204	ATP5B	3
		Non-exposure N = 18	chr2:74357713–74357851	BOLA	2
		Age and ♀ not stated	chr9:140311919–140311437	EXD3	3
			chr6:32729442–32729847	HLA-DQB2	15
			chr5:191242–192103	LRRC14B	11
			chr18:77918588–77918142	PARD6G	4
			chr2:113992762–113993313	PAX8	8
			chr17:17109570–17110120	PLD6	8
			chr5:23507030–23507752	PRDM9	7
			chr4:155702411–155702351	RBM46	11
			chr13:36944640–36944649	SPG20	2
			chr5:135415762–135416613	VTRNA2-1	15
			chr6:29648345–29649024	ZFP57	18
			chr4:2366672–2367137	ZFYVE28	7
			chr1:227746294–227746111	ZNF678	3
Tobi et al. [61]^d	Dutch Famine*^b	Periconceptional exposure N = 60, ♀ = 32, mean age 58	chr10:73227653–73227914	CDH23	4	EpiTYPER	Hypermethylation of CDH23 CpG1*, 2, 3–4*, CPT1A* CpG 8–10, 12, INSR CpG2*, SMAD7* CpG1*, 2, 3–4*, 5–7 and hypomethylation of KLF13 CpG2, 4- 7,9* after periconceptional exposure compared to sibling controls; no significant differences for RFTN1
		Periconceptional exposure N = 60, ♀ = 32, mean age 58	chr11:68286598–68286810	CPT1A	8
		Sibling controls N = 60, ♀ = 32, mean age 57	chr19:7110140–7110418	INSR	3
			chr18:44677194–44677679	SMAD7	7
			chr15:29425223–29425563	KLF13	6
			chr3:16394247–16394578	RFTN1	11
Tobi et al. [66]^d	Dutch Famine*^b	Periconceptional exposure N = 60, ♀ = 32, mean age 58	chr11:1975948–1976360	H19 DMR	9	EpiTYPER	Hypomethylation of IGF2 DMR0 upstr. CpG1*, 2, 3*, 4, IGF2 DMR0*, IGF2* DMR0 downstr. CpG8, 12–13*, IGF2* DMR2 CTCF CpG1,4, INSIGF* and hypermethylation of IGF2AS DMR1 CpG41** and IGF2AS DMR1 CTCF CpG20*, 22 after periconceptional exposure compared to sibling controls; no significant differences for IGF DMR2 S.L. and H19
		Periconceptional exposure N = 60, ♀ = 32, mean age 58	chr11:2138912–2139216	INSIGF	n.s.
		Sibling controls N = 60, ♀ = 32, mean age 57	chr11:2111300–2111791	IGF2 DMR2 S.L	8
			chr11:2112023–2112312	IGF2 DMR2 CTCF	3
			chr11:2117482–2117948	IGF2AS	12
			chr11:2118126–2118422	IGF2AS CTCF	12
			chr11:2125961–2126065	IGF2 DMR0 upstr	5
			chr11:2126035–2126372	IGF2 DMR0	n.s.
			chr11:2127117–2127220	IGF2 DMR0 downstr	3
Veenendaal et al. [73]	Dutch Famine*^b	Prenatal exposure N = 319	chr5:142782821–142783152	GR 1-C	n.s.	PCR	No significant differences for GR1-C, LPL, PI3kinase and PPARγ in each trimester compared to non-prenatal exposure and non-exposure
		1st trim = 73, ♀ = 42, mean age 58; 2nd trim = 112, ♀ = 68, mean age 58; 3rd trim = 134, ♀ = 75, mean age 59	chr8:19796366–19796515	LPL
			chr5:67521933–67522282	PI3kinase
			chr3:12392392–12392591	PPARy
		Non-prenatal exposure N = 235, ♀ = 127, mean age 59
		Non-exposure N = 205, ♀ = 103, mean age 57
Tobi et al. [70]^d	Dutch Famine*^b	Group 1	chr9:106730323–106730642	ABCA1	22	EpiTYPER	Group 1
		Periconceptional exposure N = 60, ♀ = 32, mean age 58	chr19:50109726–50110115	APOC1	6		Hypermethylation of ABCA1, IL-10*, LEP and GNASAS* and hypomethylation of INSIGF* after periconceptional exposure compared to sibling controls; no significant differences for other genes
		Periconceptional exposure N = 60, ♀ = 32, mean age 58	chr8:67253246–67253686	CRH	4
		Sibling controls N = 60, ♀ = 32, mean age 57	chr16:52383225–52383575	FTO	6
			chr20:56896823–56897145	GNASA/B	15
			chr20:56859210–56859503	GNASAS	17
			chr7:50818080–50818483	GRB10	7
		Group 2	chr6:160346346–160346595	IGF2R	10		Group 2
		Prenatal exposure 3rd trim N = 62, ♀ = 34, mean age 59	chr1:205012634–205012962	IL-10	4		Hypomethylation of GNASAS*** after exposure during 3rd trim compared to sibling controls; no significant differences for other genes
		Prenatal exposure 3rd trim N = 62, ♀ = 34, mean age 59	chr11:2138912–2139216	INSIGF	4
		Sibling controls N = 62, ♀ = 34, mean age 57	chr11:2677737–2678040	KCNQ1OT1	17
			chr7:127668290–127668646	LEP	9
			chr14:100361166–100361395	MEG3	9
			chr5:142763741–142764104	NR3C1	17
			chr6:2790712–2791113	TNF	7
Heijmans et al. [29]^d	Dutch Famine*^b	Group 1	chr11:2126035–2126372	IGF2	5	EpiTYPER	Group 1
		Periconceptional exposure N = 60, ♀ = 32, mean age 58					Hypomethylation of IGF2 CpG 1*, 2–3 and 5** after periconceptional exposure compared to sibling controls
		Sibling controls N = 60, ♀ = 32, mean age 57
		Group 2					Group 2
		Prenatal exposure 3rd trim N = 62, ♀ = 34, mean age 59					No significant differences for IGF2
		Sibling controls N = 62, ♀ = 34, mean age 57					No significant differences for IGF2

*^aChinese Famine: 1959–1961; *^bDutch Famine: 1944–1945; *^cBangladesh Famine: 1974–1975; ^dsample overlap between [72, 74], and between [29, 61, 66, 70]; n.s. not stated; ABCA1 ATP-binding cassette subfamily A member 1, AGTR1 Angiotensin II Receptor Type 1, AKAP12 A-kinase anchoring protein 12, APOC1 Apolipoprotein C1, ATP5B ATP synthase subunit beta, BOLA bolA family member, CDH23 Cadherin-related 23, CPT1A Carnitine palmitoyltransferase 1A, CRH Corticotropin-releasing hormone, CTCF CCCTC-Binding Factor, DMR differentially methylated region, EXD3 Exonuclease 3′-5′ domain-containing 3, FTO Alpha-ketoglutarate-dependent dioxygenase, GR 1-C Glucocorticoid receptor, GNASA/B G protein alpha S, GNASAS GNAS antisense RNA, GRB10 Growth factor receptor-bound protein 10, HLA-DQB2 Histocompatibility complex Class 2 DQ Beta 2, IGF2 Insulin-like growth factor 2, IGF2R Insulin-like growth factor 2 receptor, IL-10 Interleukin-10, INSIGF Insulin-induced gene, INSR Insulin receptor, KCNQ1OT1 KCNQ1 opposite strand/antisense transcript 1, KLF13 Kruppel-like factor 13, LEP Leptin, LPL Lipoprotein lipase, LRRC14B Leucine rich repeat containing 14B, MEG3 Maternally Expressed 3, NR3C1 Nuclear receptor subfamily 3 group C member 1, PARD6G Par-6 family cell polarity regulator gamma, PAX8 Paired box 8, PCR polymerase chain reaction, PI3kinase Phosphatidylinositol 3-kinase p85, PLD6 Phospholipase D family member 6, PPARy Peroxisome proliferator-activated receptor gamma, PRDM9 PR/SET domain 9, PRKCA Protein Kinase C Alpha, RBM46 RNA-binding motif protein 46, RFTN1 Raftlin lipid raft linker 1, SMAD7 SMAD family member 7, SPG20 Spartin gene, TNF Tumor necrosis factor, VTRNA2-1 Vault RNA 2–1, ZFP57 Zinc-finger transcription factor 57, ZFYVE28 Zinc finger FYVE-type containing 28, ZNF678 Zinc-finger protein 678; *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001

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