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Table 2 Associations between DNA methylation and cognitive impairment

From: Effects of early- and mid-life stress on DNA methylation of genes associated with subclinical cardiovascular disease and cognitive impairment: a systematic review

 

Lead Author, Publication Date

Exposure

Outcome

Gene (s) with Greatest Association

Regions Analyzed for Methylation

Methylation Assessment

Summary of Correlations

Human Studies

Alelu-Paz et al. 201536

Schizophrenia

Memory (MIS), global executive function (FAB), cognitive mental state (MMSE)

DISC1, DRD1, GABBR2, HINT1, MB-COMT, RELN, SLC6A4

CpG islands within promoter region of 19 genes analyzed

Methylation-specific PCR and bisulfite genomic sequencing

No methylated CpGs, regardless of severity of cognitive impairment

Levine et al. 201646

HIV

Learning, memory, attention, and motor (battery of tests)

–

Genome-wide

HumanMethylation450 Bead Chip

Significant positive association between DNA methylation age and diagnosis of HAND

Peter et al. 201645

Postnatal malnourishment

Attention (CAARS)

ABCF1, COMT, DCTN1-AS1, FOXP2, IFNG, INHBB, MIR200B, RAB3B, SYNGAP1, VARS, VIPR2, WT1

Genome-wide

HumanMethylation450 Bead Chip

↑ methylation in 609 and ↓ methylation in 391 CpG sites in autosomal DMRs; < 13 DMRs moderately correlated w/ADHD index; 15 X-linked DMR in males, and 1 in females, associated with attention

Intelligence (WASI)

SYNGAP1, ZBTB9

< 3 sites significantly associated with IQ scores; 15 X-linked DMR in males, and 1 in females, associated with IQ scores

Ursini et al. 201147

Obstetric complications and/or stressful life eventss

Working memory (n-back task)

COMT

CpG sites at rs4680 site (C2) analyzed

3 CpG sites within gene promoter analyzed

Pyrosequencing

C2 methylation of COMT promoter in Val/Val negatively correlated with stress and positively correlated with working memory accuracy

Animal Studies

Cordner et al. 201648

Chronic variable stress

Recognition memory (NOR)

Spatial learning and memory (Barnes maze)

Bace1, Bdnf, Gsk3b

CpGs within promoter region of Bace1 and Gsk3b analyzed

CpGs in region upstream of Bdnf exon 4 analyzed

Pyrosequencing

↓ methylation of CpGs at TSS-554 and TSS-506 of Bace1 promoter in hippocampus, of TSS-506 and TSS-518 in PFC, and of TSS-506 and TSS-554 in amygdala, and ↑ methylation of TSS-109 of Bdnf exon 4 region all associated with ↓ memory performance; no correlation with CpG sites in Gsk3b

Makhathini et al. 201749

Repetitive stress

Recognition memory (NOR)

–

Genome-wide

5-mC DNA Methylation ELISA

↓ global DNA methylation hippocampus in stressed group associated with impairment in memory recall

Zhu et al. 201750

Maternal separation

Memory (CFC), spatial learning and memory (MWZ)

Nr3c1*

17 CpG sites within promoter region of exon 17

PCR and sequencing

↑ methylation of 14 out of 17 CpG sites within promoter region of exon 17 in hippocampus and induced memory impairment after exposure to anesthesia

  1. sself-report
  2. *reported as GR in Zhu et al. 2017 study
  3. Note: complete list of identified genes is not included for study Peter et al. 2016
  4. ↑ = increased; ↓ = decreased; CAARS Conors Adult Attention Rating Scale; CFC contextual fear conditioning; DLPFC dorsolateral prefrontal cortex; DML differentially methylated loci; FAB frontal assessment battery; MIS Buschke memory impairment screen; MMSE
  5. mini-mental state examination; MWM Morris water maze; NA non-applicable; NOR novel object recognition; PFC prefrontal cortex; RM recognition memory; WASI Wechsler Abbreviated Scale of Intelligence