@article {7261, title = {Epigenetic Signatures of Cigarette Smoking.}, journal = {Circ Cardiovasc Genet}, volume = {9}, year = {2016}, month = {2016 Oct}, pages = {436-447}, abstract = {

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1{\texttimes}10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1{\texttimes}10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001506}, author = {Joehanes, Roby and Just, Allan C and Marioni, Riccardo E and Pilling, Luke C and Reynolds, Lindsay M and Mandaviya, Pooja R and Guan, Weihua and Xu, Tao and Elks, Cathy E and Aslibekyan, Stella and Moreno-Macias, Hortensia and Smith, Jennifer A and Brody, Jennifer A and Dhingra, Radhika and Yousefi, Paul and Pankow, James S and Kunze, Sonja and Shah, Sonia H and McRae, Allan F and Lohman, Kurt and Sha, Jin and Absher, Devin M and Ferrucci, Luigi and Zhao, Wei and Demerath, Ellen W and Bressler, Jan and Grove, Megan L and Huan, Tianxiao and Liu, Chunyu and Mendelson, Michael M and Yao, Chen and Kiel, Douglas P and Peters, Annette and Wang-Sattler, Rui and Visscher, Peter M and Wray, Naomi R and Starr, John M and Ding, Jingzhong and Rodriguez, Carlos J and Wareham, Nicholas J and Irvin, Marguerite R and Zhi, Degui and Barrdahl, Myrto and Vineis, Paolo and Ambatipudi, Srikant and Uitterlinden, Andr{\'e} G and Hofman, Albert and Schwartz, Joel and Colicino, Elena and Hou, Lifang and Vokonas, Pantel S and Hernandez, Dena G and Singleton, Andrew B and Bandinelli, Stefania and Turner, Stephen T and Ware, Erin B and Smith, Alicia K and Klengel, Torsten and Binder, Elisabeth B and Psaty, Bruce M and Taylor, Kent D and Gharib, Sina A and Swenson, Brenton R and Liang, Liming and DeMeo, Dawn L and O{\textquoteright}Connor, George T and Herceg, Zdenko and Ressler, Kerry J and Conneely, Karen N and Sotoodehnia, Nona and Kardia, Sharon L R and Melzer, David and Baccarelli, Andrea A and van Meurs, Joyce B J and Romieu, Isabelle and Arnett, Donna K and Ong, Ken K and Liu, Yongmei and Waldenberger, Melanie and Deary, Ian J and Fornage, Myriam and Levy, Daniel and London, Stephanie J} } @article {7583, title = {DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Dec 07}, pages = {888-902}, abstract = {

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0~{\texttimes} 10-7; replication: N = 7,182, p~<~1.6~{\texttimes} 10-3). The replicated methylation sites are heritable (h2 > 30\%) and independent of known BP genetic variants, explaining an additional 1.4\% and 2.0\% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

}, keywords = {Aged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.028}, author = {Richard, Melissa A and Huan, Tianxiao and Ligthart, Symen and Gondalia, Rahul and Jhun, Min A and Brody, Jennifer A and Irvin, Marguerite R and Marioni, Riccardo and Shen, Jincheng and Tsai, Pei-Chien and Montasser, May E and Jia, Yucheng and Syme, Catriona and Salfati, Elias L and Boerwinkle, Eric and Guan, Weihua and Mosley, Thomas H and Bressler, Jan and Morrison, Alanna C and Liu, Chunyu and Mendelson, Michael M and Uitterlinden, Andr{\'e} G and van Meurs, Joyce B and Franco, Oscar H and Zhang, Guosheng and Li, Yun and Stewart, James D and Bis, Joshua C and Psaty, Bruce M and Chen, Yii-Der Ida and Kardia, Sharon L R and Zhao, Wei and Turner, Stephen T and Absher, Devin and Aslibekyan, Stella and Starr, John M and McRae, Allan F and Hou, Lifang and Just, Allan C and Schwartz, Joel D and Vokonas, Pantel S and Menni, Cristina and Spector, Tim D and Shuldiner, Alan and Damcott, Coleen M and Rotter, Jerome I and Palmas, Walter and Liu, Yongmei and Paus, Tom{\'a}{\v s} and Horvath, Steve and O{\textquoteright}Connell, Jeffrey R and Guo, Xiuqing and Pausova, Zdenka and Assimes, Themistocles L and Sotoodehnia, Nona and Smith, Jennifer A and Arnett, Donna K and Deary, Ian J and Baccarelli, Andrea A and Bell, Jordana T and Whitsel, Eric and Dehghan, Abbas and Levy, Daniel and Fornage, Myriam} }