Table 2.
Genome-wide epigenetic studies of retinal disease, risk factors, and related pathologies.
| STUDY | SYSTEM | DISEASE | METHODOLOGY | RNA EXPRESSION | SAMPLE SIZE | TISSUE SAMPLE(S) | DEATH/COLLECTION TO PRESERVATION TIME | NUMBER OF DIFFERENTIALLY METHYLATED PROBES OR REGIONS (DMPs OR DMRs)/GENES | PATHWAYS IDENTIFIED IN DMR LOCI | VALIDATED LOCI WITH DIFFERENTIAL METHYLATION |
|---|---|---|---|---|---|---|---|---|---|---|
| Aavik et al, 2015173 | Cardiovascular | Atherosclerosis | MeCP2-seq | Affymetrix HGU133 Plus2 microarray; qPCR; immunohisto-chemistry; western blots | Femoral artery ather-ectomy samples (22); mammary arteries (9) | Femoral artery atherectomy samples; mammary arteries | Not provided | 4779 promoter DMPs/3740 genes, 8604 exonic DMPs/4939 genes, 17782 intronic DMPs/7972 genes | Intermediate filament-related genes, ATP-binding proteins, cytoskeleton, chromatin regulators, cell adhesion, morphogenesis | RTL1 |
| Allione et al, 2015174 | Multiple | Smoking | Illumina Infinium Human-Methylation450K BeadChip | None | 20 MZ twin pairs | Whole blood | Not provided | 22 DMPs | GTPase regulatory activity, phospholipid binding, vitamin D response element binding, transcriptional repressor complex | None |
| Bell et al, 2010175 | Endocrine | Type 2 diabetes | MeDIP-chip Nimblegen; H3K4me1/2/3, CTCF, and H3K9me1 ChIP-chip | RNAseq | Discovery: 30 cases, 30 controls; validation: original 60 + 20 plus 14 donor brain tissue | Whole blood; donor brain tissue | Not provided | 0 DMR between T2D and controls | None | None |
| Binder et al, 2015176 | Endocrine | Gestational diabetes mellitus (GBM) | Discovery: Illumina Infinium HumanMethylation450K BeadChip; targeted replication with bisulfite-pyrosequencing | Affymetrix Human Transcriptome Array 2.0 | Discovery: 41 cases, 41 controls; validation: not provided | Placental tissues (maternal side) | Not provided | Not provided | Immune response, cellular metabolism, response to external stimuli | CCDC181, HLA-H/HLA-J, HLA-DOA, SNRPN/SNURF |
| Boks et al, 200963 | Multiple | Age, gender, genotype | Illumina GoldenGate DNA Methylation Cancer Panel 1 assay | None | 23 MZ twin pairs, 23 DZ twin pairs, 96 controls | Whole blood | Not provided | Age: 58 DMPs; gender: 56 auto-somal DMPs; heritability: 96 DMPs; genotype: 11 DMPs | None | None |
| Dayeh et al, 2014155 | Endocrine | Type 2 diabetes | Illumina Infinium Human-Methylation450K BeadChip | Affymetrix GeneChip Human Gene 1.0 ST arrays | 15 cases, 34 controls | Donor pancreatic islets | Cultured 2.7 days prior to DNA/RNA extraction | 1649 DMPs/853 genes | Cancer, axon guidance, MAPK signaling, focal adhesion, ECM-receptor interactions, regulation of actin cytoskeleton | None |
| Guida et al, 2015178 | Multiple | Smoking | Illumina Infinium Human-Methylation450K BeadChip | Illumina HumanWG-6 chip v3; Illumina HT-12 chip | 745 women | Whole blood | Not provided | 461 DMPs between current smokers and never smokers; 3 DMPs between former smokers and never smokers; 751 DMPs associated with time since cessation of smoking | None | None |
| Haas et al, 2013179 | Cardiovascular | Dilated cardiomyopathy | Discovery: Illumina Infinium HumanMehtylation27 Bead-Chip; replication: MassArray and bisulfite sequencing | RT-qPCR | Discovery: 9 cases, 8 controls; replication: 30 cases, 128 controls | Left ventricular tissue | Immediately washed and flash frozen | 90 genes | Cardiovascular disease, nutritional & metabolic diseases, pathological conditions, signs and symptoms | LY75, ERBB3, HOXB13, ADORA2A |
| Hannum et al, 201365 | Multiple | Aging | Illumina Infinium Human-Methylation450K BeadChip | Used data from Emilsson et al, 2008177 | Discovery: 482; validation: 174 additional individuals; verification: Heyn et al, 201264 data | Whole blood | Not provided | 70,387 | AD, cancer, tissue degradation, DNA damage, oxidative stress | None-used validation sets to validate their model of aging from initial set |
| Heyn et al, 201264 | Multiple | Aging | Discovery: whole genome bisulfite sequencing (WGBS); replication 1: WGBS and Illumina Infinium HumanMethylation450K BeadChip; replication 2: Illumina Infinium Human-Methylation450K BeadChip: validation of discovery + replication 1 combined and replication 2: targeted bisulfite sequencing validation | RT-qPCR | Discovery: 1 new-born, 1 centenarian; replication 1: 1 middle aged person; replication 2: 19 newborns, 19 nonagenarians | Discovery & replication 1: CD4+ T cells; replication 2: cord blood for newborns and peripheral blood mononuclear cells for nonagenarians | Not provided | Discovery & replication 1: 1149 DMPs/615 genes; replication 2: confirmed 214 DMPs plus additional 5774 DMPs | Not provided | AIM2, TNFRSF9, IGSF9B, PTPRE, ZRP-1, FHL2, miR-21 |
| Hidalgo et al, 2014180 | Renal | Diabetes | Illumina Infinium Human-Methylation450K BeadChip | None | Discovery: 544; replication: 293 | CD4+ T cells | From frozen | Presented top 5 DMPs | Not provided | ABCG1 |
| Irvin et al, 2014182 | Multiple | Fasting VLDL and TGs | Illumina Infinium Human-Methylation450K BeadChip | Discovery: RT-qPCR of single hit; replication: Affymetrix HumanExon 1.0 ST GeneChip | Discovery: 991; replication 1261 | CD4+ T cells | Not provided | 4 DMPs/1 gene | Lipid metabolism | CPT1A |
| Ko et al, 2013183 | Renal | Kidney fibrosis | Discovery: HELP-Nimblegen whole genome covering microarray; validation: bisulfite-Sequenom MassArray EpiTYPER; replication: Illumina Infinium HumanMethylation450K BeadChip | None | Discovery/validation: 12 hypertensive or diabetic chronic kidney disease, 14 controls; replication: 21 diabetic chronic kidney disease, 66 controls | Human kidney tubule epithelial cell tissue samples from healthy living transplants or surgical nephrectomies | Not provided | Discovery: 4751 DMRs/1535 genes; replication: 1061 genes | Cell adhesion, development | COLIVA1, DSCAM, DPT |
| Markunas et al, 2014184 | Multiple | Maternal smoking | Discovery: Illumina Infinium HumanMethylation450K BeadChip; replication using Joubert et al, 2012181 published data | None | 287 infants whose mothers smoked during 1st trimester, 602 infants whose mothers did not smoke during pregnancy | Whole blood | Not provided | 185 DMPs/110 genes | Nicotine dependence, smoking cessation, placental & embryonic development | FRMD4A, ATP9A, GALNT2, MEG3, GNG12, Loc284998, VGLL4, CUX2, FTO, KIF26B |
| McClay et al, 201467 | Multiple | Aging | Discovery: MBD-seq; replication: pyrosequencing | None | Discovery: 718 aged 25–92 years; replication: 558 | Whole blood | Not provided | 11 DMRs | Protocadherins, homeo-box genes, MAPKs, ryanodine receptors | LSAMP, ZEB2, MEIS7, GRIA2 |
| Menni et al, 201366 | Multiple | Aging | Discovery: Illumina Infinium HumanMehtylation27 BeadChip; replication: Illumina Infinium Human-Methylation450K BeadChip | None | Discovery: 172 female twins; replication: 350 twins | Fasting whole blood | Not provided | 3 DMPs associated with C-glyTrp levels (an age-associated metabolite) | Protein synthesis, cell cycle, embryonic development, renal inflammation & hypertension, age-related retinal degeneration | WDR85 |
| Miao et al, 2008185 | Endocrine | Type 1 diabetes | H3K9me2 ChIP-chip, including human 12 k cDNA array, human 12 k CpG island array, and Nimblegen human promoter tiling array | None | 9 T1D, 7 controls | Blood lymphocytes and monocytes | Not provided | Lymphoblasts: 193 DMPs 12 k cDNA array, 213 DMPx 12 k CpG island array, not specified for the tiling array; monocytes: none | Autoimmunity, inflammation, TGFbeta, NFkappa-B, p38 MAPK, toll-like receptor, IL-6 pathways, T1D genes | HOX13B, NKXB, CPLX4, CXCR4, FAM19A5, AR, PLAZG4B, CD55, IGSF4B, CTLA4 |
| Milenkovic et al, 2014186 | Cardiovascular | Flavanols & cardiovascular disease | Discovery: Illumina Infinium HumanMethylation450K BeadChip; validation with pyrosequencing | Agilent G4845A Human GE 4×44K v2 microarray | 13 male smokers before and after flavanol treatment | Leukocytes | Freshly stored in RNALater | None | None | CXCL12, SCRIB, PDGFRL, FERMT3, ICAM1, VCAM1 (not significantly DM at 10% change) |
| Monick et al, 2012187 | Multiple | Smoking | Illumina Infinium Human-Methylation450K BeadChip | RT-qPCR (transformed lymphoblasts) | 10 smokers, 9 controls | Lung alveolar macrophage | Not provided | 1381 DMPs | Wound healing, inflammation, G-protein/Ras signaling | AHRR |
| Movassagh et al, 2010188 | Cardiovascular | Cardiomyopathy | Discovery: MeDIP-chip with the Nimblegen CpG island and promoter microarray; validation: bisulfite PCR and sequencing | RT-qPCR | Discovery: 3 (ischemic & idiopathic) cardiomyopathic tissue from transplant surgeries; 1 normal tissue from donors; validation: 4 (ischemic & idiopathic) cardiomyopathic tissue from transplant surgeries; 4 normal tissue from donors | Left ventricular tissue | Not provided | 3 genes | Angiogenesis | AMOTL2, ARH-GAP24, PECAM1 |
| Movassagh et al, 2011189 | Cardiovascular | Cardiomyopathy | MeDIP-seq; H3K36me3 ChIP-seq | RT-qPCR | 4 (ischemic & idiopathic) cardiomyopathic tissue from transplant surgeries; 4 normal tissue from donors | Left ventricular tissue | Not provided | Not provided | Not provided | DUX4 |
| Nazarenko et al, 2015190 | Cardiovascular | Coronary Heart Disease | Illumina Infinium HumanMehtylation27 BeadChip; pyrosequencing validation | No | 3 tissues from 6 patients for microarray; 3 tissues from 21 patients for validation | Human right coronary artery in the area of advanced atherosclerotic plaques (CAP); internal mammary arteries (IMA); great saphenous veins (GSV) | Processed and snap frozen immediately after surgery | 22 (CAP-IMA); 27 (GSV-IMA) | Inflammation and immune response; development | HOXD4 |
| Nilsson et al, 2014191 | Endocrine | Type 2 diabetes | Illumina Infinium Human-Methylation450K BeadChip | RT-qPCR; Affymetrix GeneChip Human Gene 1.0 ST arrays | 14 discordant MZ twin pairs; cohort 1: 120 case-controls; cohort 2: 28 cases, 28 controls | Subcutaneous adipose tissue biopsies | Frozen immediately in liquid nitrogen | 15,627 DMPs/7,046 genes in cohort 2, 1410 of which DMPs also in MZ twins | Oxidative phosphorylation; mitogen-activated protein kinase signaling; carbohydrate, amino acid, and lipid metabolism; inflammation; Wnt signaling; glycan degradation; cancer | None |
| Nitert et al, 2012192 | Endocrine & musculoskel et al | Diabetes & exercise | Discovery: MeDIP-chip; replication: Illumina Infinium HumanMethylation450K BeadChip; validation: bisulfite-Sequenom Epi-TYPER, luciferase assays with or without methylation | Affymetrix Custom-Array NuGO-Hs1a520180 GeneChip | Discovery: 15 men with 1st degree relative with diabetes (FH+)/13 men w/o relative with diabetes (FH-); replication: 9 MZ twin pairs discordant for T2D | Skeletal muscle biopsies from vastus lateralis after fasting and without exercise for 48 hrs prior to biopsy | Not provided | 65 genes DM FH+/FH-before exercise; 38 genes DM FH+/FH-after exercise; 134 genes DM before/after exercise combined FH+/− | FH+/−: MAP signaling, insulin signaling, calcium signaling, Wnt signaling, starch and sucrose metabolism, sphingolipid metabolism; before/after exercise: purine metabolism, retinol metabolism, calcium signaling, muscle, T2D, gly/ser/thr metabolism, glycolysis, gluconeogenesis, starch and sucrose metabolism, insulin signaling | MSI2, THADA, MEF2A, RUNX1, NDUFC2 |
| Olsson et al, 2014193 | Endocrine | Insulin secretion | Discovery: Illumina Infinium HumanMethylation450K BeadChip; validation: pyrosequencing | Affymetrix GeneChip Human Gene 1.0 ST | 89 pancreatic islet donors | Human pancreatic islets | Cultured in vitro 4 days | 14 DMPs potentially mediating relationship between SNPs and mRNA level | Pancreatic islet function, type 1 diabetes, cell adhesion, ECM interaction, folate biosynthesis | GPX7, GST-1, SNX19 |
| Rakyan et al, 2011194 | Endocrine | Type 1 diabetes | Illumina Infinium HumanMehtylation27 BeadChip | None | 19 discordant MZ twin pairs; 7 singletons before and after diagnosis | CD14+ monocytes | Not provided | 132 DMPs | Type 2 diabetes, immune responses | HLA-DQB1, RFXAP, NFKB1A, TNF, GAD2 |
| Ronn et al, 2015195 | Endocrine, etc. | Aging, BMI, HbA1c | Discovery: Illumina Infinium HumanMethylation450K BeadChip; validation: pyrosequencing | Affymetrix GeneChip Human Gene 1.0 ST | Discovery: 96 males, 94 females; validation: 37 males, 67 females | Discovery: human adipose tissue biopsies (fasted state); validation: human adipose tissue biopsies and blood (fasted state) | Not provided | Age: 1050 genes methylation and expression; BMI: 2825 genes methylation and expression; HbA1c: 711 genes methylation | Cancer, type 2 diabetes, cardiovascular disease; signal transduction | None |
| Sapienza et al, 2011196 | Endocrine | Diabetes | Illumina Infinium HumanMehtylation27 BeadChip | None | 23 diabetics with end stage renal disease; 23 diabetics without nephropathy | Saliva | Not provided | 389 DMPs | Inflammation, oxidative stress, ubiquitination, fibrosis, drug metabolism, cancer, cardiotoxicity, hepatotoxicity, nephrotoxicity | None |
| Sharma et al, 2014197 | Cardiovascular | Coronary artery disease | Discovery: 12 k Human CpG Island Microarray; replication: bisulfite deep sequencing | None | Discovery: 18 cases, 18 controls; replication: 48 cases, 48 controls | Peripheral blood | Within 1 hour | 72 DMRs | Signal transduction, transcription regulation, organelle development, transport, cell regulation, ion channel activity, E-box binding, mitochondria, plasma membrane, nuclear chromatin | STRADA, C1QL4, HSP90B3P |
| Steenaard et al, 2015198 | Cardiovascular | Tobacco smoking (coronary artery disease) | Illumina Infinium HumanMethylation450K BeadChip | Illumina HumanHT12v4 Expression BeadChip | 724 subjects: 195 current smokers, 201 never smokers, 328 prior smokers | Whole blood | Not provided | 15 DMPs of 3669 CpGs/1169 CAD genes analyzed | Only looked at CAD related genes | None |
| Stringhini et al, 2015199 | Immune System | Inflammation | Illumina Infinium Human-Methylation450K BeadChip | None | 857 | Whole blood | Not provided | 41 DMPs/10 genes associated with household occupational position; 12 DMPs/6 genes associated with socioeconomic trajectories | Only looked at candidate genes involved in socio-economic status-related inflammation | None |
| Sun et al, 201468 | Multiple | Aging | Illumina Infinium HumanMethylation450K BeadChip | None | 100 male, 100 female nonagenarians/centenarians | Peripheral blood mononuclear cells | Not provided | 850 DMPs/564 genes | Hormone regulation, neuron projection, disease-related pathways, cellular component organization, cell morphogenesis, cell-cell junctions, CNS development, ECM-receptor interactions, axon guidance, cell adhesion molecules | None |
| Suter et al, 2011200 | Multiple | Maternal tobacco exposure | Discovery: Illumina Infinium HumanMehtylation27 BeadChip; validation: bisulfite PCR sequencing | Illumina HG-12, RT-qPCR | Discovery: 18 smokers, 18 non-smokers; validation: 9 smokers, 9 non-smokers | Placental tissues | Collected immediately after delivery and flash frozen | 1024 DMPs | Oxidative stress pathways, oxidative phosphorylation, mitochondrial dysfunction, HIF1alpha signaling, cell death, cell morphology, cell-to-cell signaling | PURA, GTF2H2, GCA, GPR135, HKR1 |
| Tsaprouni et al, 2014201 | Multiple | Smoking | Illumina Infinium HumanMethylation450K BeadChip | RNAseq | Discovery: 22 current smokers, 263 former smokers, 179 never smokers; replication: 41 current, 104 former, 211 never | Peripheral blood | Not provided | 30 DMPs/15 loci | Cardiovascular disease; cancer; connective tissue and developmental disorders; cell death, cell survival, and cell-cell interactions; heme biosynthesis; aryl hydrocarbon receptor signaling | None |
| Wan et al, 2012202 | Multiple | Smoking | Discovery: Illumina Infinium HumanMethylation27 BeadChip: validation: bisulfite pyrosequencing | None | Discovery: 1085; replication: 369 | Peripheral blood leukocytes | Not provided | 15 DMPs current vs. former smokers; 2 DMPs cumulative exposure; 3 DMPs time since quitting | Not provided | F2RL3, GPR15 |
| Wang et al, 2013203 | Cardiovascular | Hypertension | Discovery: Illumina Infinium HumanMehtylation27 BeadChip; replication: bisulfite sequencing | None | Discovery: 8 cases, 8 controls 14–23 years old; replication 1: 36 cases, 60 controls 14–30 years old; replication 2: 36 cases, 34 controls 15.8–40 years old | Blood leukocytes | Not provided | 1 gene | Inflammation | SULF1 |
| Xiao et al, 201569 | Multiple | Aging | Discovery: MeDIP-seq; replication: whole genome bisulfite sequencing | None | Discovery: 4 centenarians, 4 middle aged; replication: additional 1 centenarian, 1 middle aged | Peripheral blood | Not provided | Discovery: 626 DMRs/251 genes; replication: 156 genes | Age-related diseases: T2D, cardiovascular disease, stroke, coronary artery disease, AD; developmental processes; cell adhesion; signal transduction; cell communication; cell adhesion; cadherin signaling; Wnt signaling; AD-presenilin | None |
| Xu et al, 2013204 | Multiple | Obesity | Illumina Infinium Human-Methylation450K BeadChip | None | 48 obese cases, 28 lean controls, all 14–20 years old | Fasting peripheral blood leukocytes | Not provided | 23305 DMPs | DNA binding, development, regulation of neurogenesis, cell differentiation, transcription regulation, obesity-related diseases | None |
| Yang et al, 201570 | Neurological | Aging | Illumina Infinium Human-Methylation450K BeadChip | None | 740 aged 66 to 108 years old | Postmortem dorsolateral prefrontal cortex | Not provided | 4263 DMPs associate with age | Not provided | None |
| Yuan et al, 2014205 | Endocrine | Type 2 diabetes | Discovery: MeDIP-seq; replication: Illumina Infinium HumanMethylation450K BeadChip | Illumina HumanHT12v3 Expression BeadChip | Discovery: 27 MZ twin pairs (17 T2D discordant, 2 T2D concordant, 7 control concordant pairs); replication: 42 unrelated T2D cases, 221 controls | Whole blood | Blood drawn into EDTA tubes | 1355 DMRs | T2D GWAS genes, imprinted genes | GPR61, PRKCB, MALT1 |
| Zaina et al, 2014206 | Cardiovascular | Atherosclerosis | Discovery: whole-genome shotgun bisulfite sequencing; replication: Illumina Infinium HumanMethylation450K BeadChip; validation: pyrosequencing and conventional bisulfite sequencing | RT-qPCR | Discovery: 1 matched pair of atherosclerotic and normal tissue from the same donor; replication: 15 matched pairs of atherosclerotic and normal tissues each from the same donor; validation: (multiple) 5 aortas/24 donor pairs/15 donor pairs from original cohort/1 donor pair | Postmortem aortas and carotid tissues | 3–26 hours | Discovery: 54625 DMRs; replication: 1895 DMPs | Genes related to processes related to endothelial cells and vascular smooth muscle cells; vascular smooth muscle cell contraction; extracellular matrix formation | HOX family members, PDGFA, PLAT, PRRX1, PXDN, MIR23b |
| Zawada et al, 2012207 | Cardiovascular | Chronic kidney disease-associated cardiovascular disease | Discovery: SuperTAG methylation-specific digital karyotyping; validation: bisulfite pyrosequencing | RT-qPCR | 10 cases, 10 controls | Peripheral blood | Not provided | 4288 DMRs | Lipid metabolism & transport, cell proliferation, cell-cycle regulation, angiogenesis, inflammation | METTL2B |