Table 4.
Replicated BMI CpG sites significantly associated in both leukocyte and adipose tissue DNA from 648 females in the MuTHER, in order of MuTHER P-valuea
| CpG marker | Nearest gene | MuTHER regression coefficientb | Same direction as in blood? | MuTHER P-valuec | Function |
|---|---|---|---|---|---|
| BMI | |||||
| cg17560136 | EPB49 | 0.00233 | Yes | 4.64E − 33 | Erythrocyte membrane protein band 4.9: gene product essential for the maintenance of erythrocyte shape and membrane stability |
| cg04869770 | PBX1 | 0.00222 | Yes | 8.53E − 25 | Pre-B-cell leukemia transcription factor involved in pancreatic development and function, candidate gene SNPs associated with obesity, variants may influence porcine adipose tissue fatty acid composition |
| cg25178683 | LGALS3BP | 0.00305 | Yes | 1.68E − 18 | Lectin, galactoside-binding, soluble, 3 binding protein: a macrophage inflammatory marker, arterial expression upregulated in response to obesity in animal models |
| cg01844514 | ZNF862 | 0.00111 | Yes | 4.72E − 16 | Zinc finger protein 862: protein coding gene of unknown function, may be involved in transcriptional regulation |
| cg07136133 | PRR5L | −0.00392 | Yes | 7.85E − 15 | Proline rich 5-like: regulates cytoskeleton organization and interacts with mTOR, a central controller of cell growth, to increase apoptosis |
| cg06876354 | RALB | −0.00129 | No | 9.40E − 14 | RAS-related small GTP-ase B: involved in a variety of cellular processes including gene expression and has role in colorectal cancer oncogenesis |
| cg26033520 | Intergenic Chr. 10 | 0.00244 | Yes | 5.29E − 12 | Unknown |
| cg08857797 | VPS25 | −0.00172 | No | 5.85E − 12 | Vacuolar protein-sorting-associated protein 25: part of endosomal sorting complexes required for transport protein, II (ESCRT-II) complex involved in endosomal transport and possibly gene transcription |
| cg06946797 | Intergenic Chr. 16 | −0.00145 | Yes | 2.09E − 09 | Unknown |
| cg04816311 | C7orf50 | −0.00152 | No | 2.27E − 09 | Chromosome 7 open reading frame 50; unknown function, GWAS variants in this locus are associated with lipid levels and longevity |
| cg00574958 | CPT1A | −0.00032 | Yes | 3.40E − 08 | Carnitine palmitoyltransferase-1A: involved in mitochondrial uptake of long-chain fatty acids and triglyceride metabolism, previously associated with insulin-related DNA methylation |
| cg13123009 | LY6G6E | 0.00072 | Yes | 1.18E − 07 | Lymphocyte antigen-6 complex, locus G6E (pseudogene): one of LY6 genes located in the MHC class III region, immune function, acute lymphoblastic leukemia, hematopoiesis, cell adhesion |
| cg13708645 | KDM2B | 0.00184 | Yes | 1.74E − 07 | Lysine K-specific demethylase 2B: a H3K36 histone demethylase, involved in cellular senescence, tumor cell differentiation, part of a complex that represses preadipocyte differentiation |
| cg26403843 | RNF145 | −0.00203 | Yes | 5.59E − 07 | Ring finger protein 145: unknown function |
| cg00863378 | BBS2 | 0.00113 | Yes | 7.21E − 07 | BBS-2: member of the BBS gene family. BBS is an autosomal recessive disorder characterized by severe obesity, developmental abnormalities and mental retardation |
| cg09664445 | KIAA0664 | 0.00077 | Yes | 9.84E − 06 | Aka CLUH, clustered mitochondria homolog: regulates mitochondrial biogenesis |
| cg18568872 | ZNF710 | 0.00094 | Yes | 1.85E − 05 | Zinc finger 710: protein-coding gene, function unknown, may be involved in transcriptional regulation |
| cg15871086 | Intergenic Chr. 10 | 0.00094 | Yes | 1.46E − 03 | Unknown |
| WC | |||||
| cg17901584 | DHCR24 | 0.00162 | No | 9.07E − 13 | 3-Beta-hydroxysterol delta-24-reductase: catalyzes reduction of sterol intermediates during final step of cholesterol biosynthesis, biomarker of nonalcoholic hepatic steatosis, expression changes associated with weight loss after bariatric surgery |
aThe MuTHER includes genome-wide DNA methylation data (Illumina HumanMethylation450 array) from abdominal subcutaneous adipose tissue collected from 648 female twins (39,40).
bFixed-effects regression coefficient from linear mixed models (LMM), with probe DNA methylation beta value as the dependent variable and BMI as the primary independent variable, covariate adjusted for age, bisulfite conversion concentration, bisulfite conversion efficiency and experimental batch (Beadchip) (fixed effects), and family relationship (twin-pairing) and zygosity (random effects).
cReplication was based on P-value only because increased or decreased methylation may differ by tissue type. Threshold for replication was set at P < 1.8 × 10−3 (0.05/28 tests). There were 37 BMI-associated CpGs and 1 WC-associated CpG carried forward for replication in adipose tissue, and 10 were removed in QC procedures in MuTHER cohort and not tested.