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Haoyang Zeng, David K Gifford
DNA methylation plays a crucial role in the establishment of tissue-specific gene expression and the regulation of key biological processes. However, our present inability to predict the effect of genome sequence variation on DNA methylation precludes a comprehensive assessment of the consequences of non-coding variation. We introduce CpGenie, a sequence-based framework that learns a regulatory code of DNA methylation using a deep convolutional neural network and uses this network to predict the impact of sequence variation on proximal CpG site DNA methylation...
March 16, 2017: Nucleic Acids Research
Frédéric Guénard, André Tchernof, Yves Deshaies, Simon Biron, Odette Lescelleur, Laurent Biertho, Simon Marceau, Louis Pérusse, Marie-Claude Vohl
A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites...
February 2, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
Arunima Shilpi, Yingtao Bi, Segun Jung, Samir K Patra, Ramana V Davuluri
INTRODUCTION: Breast cancer being a multifaceted disease constitutes a wide spectrum of histological and molecular variability in tumors. However, the task for the identification of these variances is complicated by the interplay between inherited genetic and epigenetic aberrations. Therefore, this study provides an extrapolate outlook to the sinister partnership between DNA methylation and single-nucleotide polymorphisms (SNPs) in relevance to the identification of prognostic markers in breast cancer...
2017: Cancer Informatics
Yuping Tang, Bo Jin, Lingling Zhou, Weifeng Lu
Earlier GWAS has identified that rs17782313 near MC4R was associated with obesity. However, subsequent studies showed conflicting results, especially among childhood. Besides, the mechanisms underlying the association between rs17782313 and childhood obesity remain largely unexplored, and genetic and epigenetic may interact and together affect the development of childhood obesity. We conducted a comprehensive meta-analysis to assess the association between rs17782313 and childhood obesity. MeQTL and eQTL analysis was applied to explore the effect of rs17782313 on DNA methylation and MC4R expression...
January 10, 2017: Oncotarget
Anke Hoffmann, Michael Ziller, Dietmar Spengler
Genome-wide association studies (GWAS) have remarkably advanced insight into the genetic basis of schizophrenia (SCZ). Still, most of the functional variance in disease risk remains unexplained. Hence, there is a growing need to map genetic variability-to-genes-to-functions for understanding the pathophysiology of SCZ and the development of better treatments. Genetic variation can regulate various cellular functions including DNA methylation, an epigenetic mark with important roles in transcription and the mediation of environmental influences...
November 24, 2016: Genes
Åsa K Hedman, Mihkel Zilmer, Johan Sundström, Lars Lind, Erik Ingelsson
BACKGROUND: Oxidative stress has been related to type 2 diabetes (T2D) and cardiovascular disease (CVD), the leading global cause of death. Contributions of environmental factors such as oxidative stress on complex traits and disease may be partly mediated through changes in epigenetic marks (e.g. DNA methylation). Studies relating differential methylation with intermediate phenotypes and disease endpoints may be useful in identifying additional candidate genes and mechanisms involved in disease...
November 25, 2016: BMC Medical Genomics
Sandeep K Singh, Philip J Lupo, Michael E Scheurer, Anshul Saxena, Amy E Kennedy, Boubakari Ibrahimou, Manuel Alejandro Barbieri, Ken I Mills, Jacob L McCauley, Mehmet Fatih Okcu, Mehmet Tevfik Dorak
Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012...
November 2016: Medicine (Baltimore)
Kenneth Day, Lindsay L Waite, Arnald Alonso, Marguerite R Irvin, Degui Zhi, Krista S Thibeault, Stella Aslibekyan, Bertha Hidalgo, Ingrid B Borecki, Jose M Ordovas, Donna K Arnett, Hemant K Tiwari, Devin M Absher
DNA methylation at CpG sites is both heritable and influenced by environment, but the relative contributions of each to DNA methylation levels are unclear. We conducted a heritability analysis of CpG methylation in human CD4+ cells across 975 individuals from 163 families in the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN). Based on a broad-sense heritability (H2) value threshold of 0.4, we identified 20,575 highly heritable CpGs among the 174,445 most variable autosomal CpGs (SD > 0.02). Tests for associations of heritable CpGs with genotype at 2,145,360 SNPs using 717 of 975 individuals showed that ~74% were cis-meQTLs (< 1 Mb away from the CpG), 6% of CpGs exhibited trans-meQTL associations (>1 Mb away from the CpG or located on a different chromosome), and 20% of CpGs showed no strong significant associations with genotype (based on a p-value threshold of 1e-7)...
2016: PloS One
Juan de Toro-Martín, Frédéric Guénard, André Tchernof, Yves Deshaies, Louis Pérusse, Frédéric-Simon Hould, Stéfane Lebel, Picard Marceau, Marie-Claude Vohl
BACKGROUND: The TOMM20 gene was previously identified as differentially expressed and methylated between severely obese subjects with and without metabolic syndrome (MS). Since metabolic complications do not affect all obese patients to the same extent, the aim of this study was to identify methylation quantitative trait loci (meQTL) potentially associated with MS-related complications within the TOMM20 locus. METHODS: Methylation profiling, SNP genotyping and meQTL association tests (general linear models) were performed in a population of 48 severely obese subjects...
2016: Diabetology & Metabolic Syndrome
Kaipeng Xie, Cheng Liang, Qin Li, Caiwang Yan, Cheng Wang, Yayun Gu, Meng Zhu, Fangzhi Du, Hui Wang, Juncheng Dai, Xiao'an Liu, Guangfu Jin, Hongbing Shen, Hongxia Ma, Zhibin Hu
The aim of this article was to evaluate whether genetic variants in autophagy-related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets...
October 1, 2016: International Journal of Cancer. Journal International du Cancer
Joseph L McClay, Andrey A Shabalin, Mikhail G Dozmorov, Daniel E Adkins, Gaurav Kumar, Srilaxmi Nerella, Shaunna L Clark, Sarah E Bergen, Christina M Hultman, Patrik K E Magnusson, Patrick F Sullivan, Karolina A Aberg, Edwin J C G van den Oord
BACKGROUND: Genetic influence on DNA methylation is potentially an important mechanism affecting individual differences in humans. We use next-generation sequencing to assay blood DNA methylation at approximately 4.5 million loci, each comprising 2.9 CpGs on average, in 697 normal subjects. Methylation measures at each locus are tested for association with approximately 4.5 million single nucleotide polymorphisms (SNPs) to exhaustively screen for methylation quantitative trait loci (meQTLs)...
December 23, 2015: Genome Biology
Andrew E Jaffe, Yuan Gao, Amy Deep-Soboslay, Ran Tao, Thomas M Hyde, Daniel R Weinberger, Joel E Kleinman
DNA methylation (DNAm) is important in brain development and is potentially important in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape and overlap regions of genetic risk for schizophrenia. A quarter of published genome-wide association studies (GWAS)-suggestive loci (4,208 of 15,930, P < 10(-100)) manifest as significant methylation quantitative trait loci (meQTLs), including 59...
January 2016: Nature Neuroscience
Michael D Rushton, Louise N Reynard, David A Young, Colin Shepherd, Guillaume Aubourg, Fiona Gee, Rebecca Darlay, David Deehan, Heather J Cordell, John Loughlin
Osteoarthritis (OA) is a common, painful and debilitating disease of articulating joints resulting from the age-associated loss of cartilage. Well-powered genetic studies have identified a number of DNA polymorphisms that are associated with OA susceptibility. Like most complex trait loci, these OA loci are thought to influence disease susceptibility through the regulation of gene expression, so-called expression quantitative loci, or eQTLs. One mechanism through which eQTLs act is epigenetic, by modulating DNA methylation...
December 20, 2015: Human Molecular Genetics
Anu Loukola, Jadwiga Buchwald, Richa Gupta, Teemu Palviainen, Jenni Hällfors, Emmi Tikkanen, Tellervo Korhonen, Miina Ollikainen, Antti-Pekka Sarin, Samuli Ripatti, Terho Lehtimäki, Olli Raitakari, Veikko Salomaa, Richard J Rose, Rachel F Tyndale, Jaakko Kaprio
Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70-0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort...
2015: PLoS Genetics
Michelle R Jones, Meredith A Brower, Ning Xu, Jinrui Cui, Emebet Mengesha, Yii-Der I Chen, Kent D Taylor, Ricardo Azziz, Mark O Goodarzi
Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS...
August 2015: PLoS Genetics
Dana B Hancock, Jen-Chyong Wang, Nathan C Gaddis, Joshua L Levy, Nancy L Saccone, Jerry A Stitzel, Alison Goate, Laura J Bierut, Eric O Johnson
Nicotine dependence is influenced by chromosome 15q25.1 single nucleotide polymorphisms (SNPs), including the missense SNP rs16969968 that alters function of the α5 nicotinic acetylcholine receptor (CHRNA5) and noncoding SNPs that regulate CHRNA5 mRNA expression. We tested for cis-methylation quantitative trait loci (cis-meQTLs) using SNP genotypes and DNA methylation levels measured across the IREB2-HYKK-PSMA4-CHRNA5-CHRNA3-CHRNB4 genes on chromosome 15q25.1 in the BrainCloud and Brain QTL cohorts [total N = 175 European-Americans and 65 African-Americans (AAs)]...
October 15, 2015: Human Molecular Genetics
Jean Shin, Celine Bourdon, Manon Bernard, Michael D Wilson, Eva Reischl, Melanie Waldenberger, Barbara Ruggeri, Gunter Schumann, Sylvane Desrivieres, Alexander Leemans, Michal Abrahamowicz, Gabriel Leonard, Louis Richer, Luigi Bouchard, Daniel Gaudet, Tomas Paus, Zdenka Pausova
DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3 kb). Here, we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300 kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs...
October 15, 2015: Human Molecular Genetics
Lynn M Almli, Jennifer S Stevens, Alicia K Smith, Varun Kilaru, Qian Meng, Janine Flory, Duna Abu-Amara, Rasha Hammamieh, Ruoting Yang, Kristina B Mercer, Elizabeth B Binder, Bekh Bradley, Steven Hamilton, Marti Jett, Rachel Yehuda, Charles R Marmar, Kerry J Ressler
Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N = 147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N = 147, β = 31...
July 2015: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Mathieu Lemire, Syed H E Zaidi, Maria Ban, Bing Ge, Dylan Aïssi, Marine Germain, Irfahan Kassam, Mike Wang, Brent W Zanke, France Gagnon, Pierre-Emmanuel Morange, David-Alexandre Trégouët, Philip S Wells, Stephen Sawcer, Steven Gallinger, Tomi Pastinen, Thomas J Hudson
The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P<3.2 × 10(-13); FDR<5%). These trans-meQTLs include 1,657 SNP-CpG pairs from different chromosomes and 262 pairs from the same chromosome that are >1 Mb apart...
2015: Nature Communications
Margus Putku, Mart Kals, Rain Inno, Silva Kasela, Elin Org, Viktor Kožich, Lili Milani, Maris Laan
CDH13 encodes T-cadherin, a receptor for high molecular weight (HMW) adiponectin and low-density lipoprotein, promoting proliferation and migration of endothelial cells. Genome-wide association studies have mapped multiple variants in CDH13 associated with cardiometabolic traits (CMT) with variable effects across studies. We hypothesized that this heterogeneity might reflect interplay with DNA methylation within the region. Resequencing and EpiTYPER™ assay were applied for the HYPertension in ESTonia/Coronary Artery Disease in Czech (HYPEST/CADCZ; n = 358) samples to identify CDH13 promoter SNPs acting as methylation Quantitative Trait Loci (meQTLs) and to investigate their associations with CMT...
March 2015: Human Genetics
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