count: false class: left, bottom # Journal club ## March 29, 2021   <img src="bristol-logo.png" width="20%"> <img src="ieu-logo.png" width="17%"> --- layout: true .logo[.mrcieu[ MRC Integrative Epidemiology Unit     ]] --- ## EWAS: gene expression > Yao C, ... Levy D.**Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases**. *Clin Epigenetics*. 2021 Mar 22;13(1):60. **tissue** whole blood **size** n=6000 **dataset** matching DNA methylation and gene expression **cohorts** FHS, KORA, InCHIANTI, BLSA **results** - 148-1741 gene-CpG pairs per cohort - closer pair = larger effect - 36% of pairs share the same causal genetic variant - MR shows reduced methylation and expression of CHRNA5 causally linked to COPD and lung cancer (validated in lung tissue) --- ## EWAS: lung cancer > Sun Yi-Qian, Richmond RC, ... Relton CL, Mai XM. **Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT study**. *Int J Epidemiol*. 2021 Mar 17:dyab044. **variable** lung cancer risk and smoking **tissue** whole blood **size** 140 lung cancer cases and 140 controls **cohorts** HUNT2 **results** - 76 associations with smoking (16 novel) - MR: smoking cases DNA methylation changes - no associations with future lung cancer - MR: no evidence DNA methylation changes (smoking or otherwise) cause lung cancer --- ## EWAS: opioid intoxication > Shu C, ... Maher BS. **Epigenome-wide study of brain DNA methylation following acute opioid intoxication**. *Drug Alcohol Depend*. 2021 Feb 26;221:108658. **variable** death from acute opioid intoxication **tissue** dorsolateral prefrontal cortex **size** 153 (72 cases, 53 psychiatric controls, 28 controls) **results** - No associations - PhenoAge accelerated by 2.24 years (p=0.045) --- ## EWAS: birthweight > Moccia C, ... Richiardi L. **Birthweight DNA methylation signatures in infant saliva**. *Clin Epigenetics*. 2021 Mar 19;13(1):57. **variable** birthweight **tissue** infant saliva at average age 10.8 months **size** 135 **results** - 44 associations - 44 associations with small for gestational age (1 overlap with birthweight) - no overlap with PACE cord blood study --- ## EWAS: maternal smoking and birthweight > Xu R, ... Ji H. **DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother-newborn pairs**. *Clin Epigenetics*. 2021 Mar 4;13(1):47. **variable** maternal smoking **tissue** cord blood **cohort** "a US predominantly urban, low-income multi-ethnic birth cohort" **size** 954 **results** - 38 associations with maternal smoking - ... of which 8 associated with birthweight - ... these explain 67.8% of maternal smoking-birthweight association - ... most linked to the GFI1 gene and also found to be mediators in Kupers et al (PMID 25862628) --- ## DNAm age: weight-loss intervention > Yaskolka Meir A, ... Shai I. **Lifestyle weight-loss intervention may attenuate methylation aging: the CENTRAL MRI randomized controlled trial**. *Clin Epigenetics*. 2021 Mar 4;13(1):48. **intervention** 18-month low fat vs mediterranean/low carbohydrate diets + physical activity (aerobic) **sample size** 30 LF, 30LF+PA, 30 MED/LC, 30 MED/LC+PA **dataset** DNAm age calculated from 240 CpG sites (Li et al EHP 2018) and blood DNA methylation measured at baseline and 18 months later **results** - DNAm age increased between baseline and 18 months - DNAm age increase did not differ between groups - DNAm age increase doubled in those who failed to lose weight (1.1 vs 0.6, p=0.04) - DNAm age increase tripled in those with fatty liver (1.8 vs 0.6, p=0.0003) --- ## DNAm age: CVD in African Americans > Ammous F, ... Smith JA. **Epigenetic age acceleration is associated with cardiometabolic risk factors and clinical cardiovascular disease risk scores in African Americans**. *Clin Epigenetics*. 2021 Mar 16;13(1):55. **sample size** 1100 hypertensive AA **cohort** Genetic Epidemiology Network of Arteriopathy (GENOA) **results** Increased epigenetic age acceleration was associated with: - higher systolic blood pressure (IEAA), - higher pulse pressure (EEAA and GrimAA), - higher fasting glucose (PhenoAA and GrimAA), - higher fasting insulin (EEAA), - lower low density cholesterol (GrimAA), and - higher triglycerides (GrimAA). five-year increase in GrimAA = CVD incidence HR=1.54 (95% CI 1.22-2.01) (partly independent of CVD risk factors) -- *"Our findings are in line with the literature in cohorts of European ancestry, showing that GrimAA outperforms other measures in its association with CVD incidence"* --- ## Need more cell types in blood references? > Pellegrino-Coppola D, ... Franke L. **Correction for both common and rare cell types in blood is important to identify genes that correlate with age**. *BMC Genomics*. 2021 Mar 15;22(1):184. **data** 3165 gene expression profiles (RNA-seq) from blood (age 18-81) **methods** - model 1: counts for 5 major blood cell types - model 2: counts for 5 major + 33 additional white blood cell types **results** Model 1 has **2808** vs model 2 **625** genes associated with age (511 in common). *Is this just a power difference?* Model 2 has - lower mean-squared errors in regression models - more normally distributed residuals - 'less' heteroskedasticity - model 1 age-associated genes show evidence of differential methylation between cell types - functional enrichment of genes from each model generally distinct --- ## Reference data: peripheral cells and tissues > Hannon E, ... Mill J. **Assessing the co-variability of DNA methylation across peripheral cells and tissues: Implications for the interpretation of findings in epigenetic epidemiology**. *PLoS Genet*. 2021 Mar 19;17(3):e1009443. **tissues** whole blood (monocytes, granulocytes, CD4+ T cells, CD8+ T cells, and B cells), buccal epithelial and nasal epithelial cells **cohort** E-Risk **size** thirty individuals **results** - lots of cell-type specific methylation levels and variation - DNAm estimates of age and smoking varied by cell type - variance in blood cell types *weakly* predictive of variance in blood - for some CpG sites, variation occurs in a single blood cell type (useful for determining cell-type-specific associations) --- ## Reference data: placenta > Rondinone O, ... Miozzo M. **Extensive Placental Methylation Profiling in Normal Pregnancies**. *Int J Mol Sci*. 2021 Feb 21;22(4):2136. **sample size** 154 placentas and cord blood samples **results** - placenta methylation more variable *Unclear how to access the data. Possibly ask "Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy"*