Journal club
"various Epigenome-wide Association Studies (EWAS) findings related to smoking and pollution effects, featuring studies on passive smoking, prenatal smoke exposure, cannabis use, obesity, neuropathy, depression, Alzheimer's disease, and genetic risk of dementia. Additionally, a federated analysis infrastructure for a child cohort network is discussed, aiming to identify markers of early-life stressors affecting health trajectories."
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Journal club September 7, 2020 Categories Number EWAS 12 Candidate gene 1 Cohort network 1 Biomarker of cancer 1 Epigenetics 1 Chromatin interactions 1 Transcription factor binding 2
EWAS Phenotype Tissue Population Study N CpGs Note PMID Journal Partner smoking Peripheral blood Understanding Society Little evidence for associations with passive smoking. Top sites not enriched for CpG sites associated with own smoking. Adults 769 0 32745538Environ Res Prenatal and passive smoke Peripheral blood 18 (prenatal); 0 (passive) Gene expression associated with 5 of 18 CpG sites but those genes only weakly associated with prenatal smoking. Child age 8 HELIX 1203 1730 32811491BMC Med Am J Med Genet B Neuropsychiatr Genet Peripheral blood (853 for rep) Cannabis use Maternal blood lead (by trimester) Women Sister Study 150-CpG predictor AUC = 0.54 32803843 ELEMENT (Mexico) 3 (1st), 1 (3rd trimester)No overlap between trimesters Cord blood Children 89 32734142Epigenet Insights Peripheral blood Children 6-20 Latino Asthma population 1136 2Some' top associations replicated in non-Latino populations 32799603Epigenetics Peripheral blood Mothers (22- 38 weeks) 8 (none replicated) Birthweight Isle of Wight 122 32754889Reprod Sci Peripheral blood Korean 7 of the 48 sites had similar associations in adipose tissue and were associated with gene expression BMJ Open Diabetes Res Care Obesity Adults population 902 48 32788176 Adults with diabetic neuropathy Sural nerves (in the calf) EWAS of two clusters obtained from gene expression with different average levels of HbA1c. HbA1c 53 929 32787975Clin Epigenetics Major Peripheral blood Dorsal lateral prefrontal Teens age 15- Monozygotic 6 of 17 DMRs overlapped with genetic loci associated with major depression Depression 20 twins 150 17 DMRs 32843619Transl Psychiatry Adults age 4 of these sites near the YOD1 gene, plays a role in inflammatory responses with links to depression Depression cortex ~86 ROS/MAP 608 7 32733030Transl Psychiatry Alzheimer s disease Peripheral blood Adults age European population ~75 284 0 32745807Neurobiol Aging Genetic risk of dementia Peripheral blood Generation Scotland All be 1 CpG site near one or more of the 26 genomic loci in the genetic risk score. Alzheimers Dement (Amst) Adults ~10K 68 32789163
Pollution and smoking have similar effects Tantoh DM, Wu MC, Chuang CC, et al. AHRR cg05575921 methylation in relation to smoking and PM2.5 exposure among Taiwanese men and women. Clin Epigenetics. 2020;12(1):117. n=948 adults from the Taiwan Biobank project Whole blood Self-report smoking PM2.5 estimated by residential address AHRR cg05575921, AHRR cg23576855, F2RL3 cg03636183, and F2RL3 cg21911711 independently associated with smoking and PM2.5 AHRR cg05575921 associations remain even when adjusting for F2RL3 cg03636183 (they didn t consider adjustments with/for other CpG sites)
Is this the end of PACE? Jaddoe VWV, Felix JF, Andersen AN, et al. The LifeCycle Project-EU Child Cohort Network: a federated analysis infrastructure and harmonized data of more than 250,000 children and parents. Eur J Epidemiol. 2020;35(7):709-724. Aim: to enable analytic access to multiple pregnancy and childhood cohort studies to allow identification of novel markers of early-life stressors affecting health trajectories throughout the life course, and to translate findings into policy recommendations for targeted prevention strategies. Main exposures: Socioeconomic, migration, urban environment, lifestyle and nutrition related factors, genome-wide association screen Main mediators: Epigenetics, metabolomics, allergy, brain development Main outcomes: Cardio-metabolic (body mass index (BMI), body composition, blood pressure, cardiac structure and function, lipids, insulin, glucose); respiratory (allergy, wheezing, infections, lung function, asthma), mental (behaviour, cognition, education, ASD, ADHD, anxiety, depression) Analyses will use DataSHIELD 19 cohorts with 250,000 children (includes ALSPAC and Born In Bradford)
Deriving biomarkers using multi-omic data Wu L, Yang Y, Guo X, et al. An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk. Nat Commun. 2020;11(1):3905. Hypothesis: SNP -> methylation -> gene expression -> prostate cancer SNP->methylation: Derive genetic models of DNA methylation (n=1595, Framingham Heart Study) R2 >= 0.01 for 81K CpG sites SNP->methylation->prostate cancer: Identify differences of CpG estimates in 79194 cases and 61112 controls (PRACTICAL consortia) Differences at 759 CpG sites Methylation->gene expression 42 CpG sites associated with adjacent gene expression Gene expression->prostate cancer 22 of these genes associated with prostate cancer Hypothesis supported for 25 CpG sites and 14 genes
Genes regulate the regulator Hop PJ, Luijk R, Daxinger L, et al. Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference. Genome Biol. 2020;21(1):220. Aim: identify genes that regulate DNA methylation in blood Step1. Build genetic models of gene expression (n=8644 genes) Step2. Identify gene models associated with trans DNA methylation in blood (n=818 genes) (avoid LD/pleiotropy by adjusting for expression of neighboring gene estimates and removing cases where multiple genes associated with the same CpG site) Genes enriched for transcription factors, those associated with multiple CpG sites had consistent effects, target CpG sites tended to coincide with factor binding sites
3D genome is cell-type specific Grubert F, Srivas R, Spacek DV, et al. Landscape of cohesin-mediated chromatin loops in the human genome. Nature. 2020;583(7818):737-743. Phase III of Encyclopedia of DNA Elements (ENCODE): investigate the 3D organization of the genome in 24 cell types Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) of cohesion-bound chromatin loops Results 28% of all loops vary across cell types Loop variation strongly associated with cell type Loop variation modestly correlated with gene expression Housekeeping genes have few contacts Dosage-sensitive genes more likely to be connected to enhancers
Footprints reveal a race Aug 18 July 29 Funk CC, Casella AM, Jung S, et al. Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data across 27 Tissue Types. Cell Rep. 2020;32(7):108029. Applied genomic footprinting algorithms to ENCODE Dnase-seq data Predict binding of 1515 human TFs in 27 cell types Predictions validated by ChIP-seq data We demonstrate that the locations, depth, and tissue specificity of footprints predict effects of genetic variants on gene expression and capture a substantial proportion of genetic risk for complex traits. Vierstra J, Lazar J, Sandstrom R, et al. Global reference mapping of human transcription factor footprints. Nature. 2020;583(7818):729-736 Generated Dnase-seq for 243 cell types TFs mostly bind alone TFs occupy hypermutable DNA (often due to CpG sites) Variants in TF binding sites are major contributors to trait heritability .
Im planning to have a look at these reviews McGuire AL, Gabriel S, Tishkoff SA, et al. The road ahead in genetics and genomics. Nat Rev Genet. 2020;1-16. In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Suhre K, McCarthy MI, Schwenk JM. Genetics meets proteomics: perspectives for large population-based studies. Nat Rev Genet.
