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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)...
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
René Luijk, Jelle J Goeman, Eline P Slagboom, Bastiaan T Heijmans, Erik W van Zwet
INTRODUCTION: An increasing number of studies investigates the influence of local genetic variation on DNA methylation levels, so-called in cis methylation quantitative trait loci (meQTLs). A common multiple testing approach in genome-wide cis meQTL studies limits the false discovery rate (FDR) among all CpG-SNP pairs to 0.05 and reports on CpGs from the significant CpG-SNP pairs. However, a statistical test for each CpG is not performed, potentially increasing the proportion of CpGs falsely reported on...
February 1, 2015: Bioinformatics
Marc Jan Bonder, Silva Kasela, Mart Kals, Riin Tamm, Kaie Lokk, Isabel Barragan, Wim A Buurman, Patrick Deelen, Jan-Willem Greve, Maxim Ivanov, Sander S Rensen, Jana V van Vliet-Ostaptchouk, Marcel G Wolfs, Jingyuan Fu, Marten H Hofker, Cisca Wijmenga, Alexandra Zhernakova, Magnus Ingelman-Sundberg, Lude Franke, Lili Milani
BACKGROUND: The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors. RESULTS: By analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A...
2014: BMC Genomics
Nicholas E Banovich, Xun Lan, Graham McVicker, Bryce van de Geijn, Jacob F Degner, John D Blischak, Julien Roux, Jonathan K Pritchard, Yoav Gilad
DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 cis methylation QTLs (meQTLs)-i...
September 2014: PLoS Genetics
Richard Leslie, Christopher J O'Donnell, Andrew D Johnson
SUMMARY: We created a deeply extracted and annotated database of genome-wide association studies (GWAS) results. GRASP v1.0 contains >6.2 million SNP-phenotype association from among 1390 GWAS studies. We re-annotated GWAS results with 16 annotation sources including some rarely compared to GWAS results (e.g. RNAediting sites, lincRNAs, PTMs). MOTIVATION: To create a high-quality resource to facilitate further use and interpretation of human GWAS results in order to address important scientific questions...
June 15, 2014: Bioinformatics
Holger Heyn, Sergi Sayols, Catia Moutinho, Enrique Vidal, Jose V Sanchez-Mut, Olafur A Stefansson, Ernest Nadal, Sebastian Moran, Jorunn E Eyfjord, Eva Gonzalez-Suarez, Miguel Angel Pujana, Manel Esteller
Epigenetic regulation and, in particular, DNA methylation have been linked to the underlying genetic sequence. DNA methylation quantitative trait loci (meQTL) have been identified through significant associations between the genetic and epigenetic codes in physiological and pathological contexts. We propose that interrogating the interplay between polymorphic alleles and DNA methylation is a powerful method for improving our interpretation of risk alleles identified in genome-wide association studies that otherwise lack mechanistic explanation...
April 24, 2014: Cell Reports
Jianxin Shi, Crystal N Marconett, Jubao Duan, Paula L Hyland, Peng Li, Zhaoming Wang, William Wheeler, Beiyun Zhou, Mihaela Campan, Diane S Lee, Jing Huang, Weiyin Zhou, Tim Triche, Laufey Amundadottir, Andrew Warner, Amy Hutchinson, Po-Han Chen, Brian S I Chung, Angela C Pesatori, Dario Consonni, Pier Alberto Bertazzi, Andrew W Bergen, Mathew Freedman, Kimberly D Siegmund, Benjamin P Berman, Zea Borok, Nilanjan Chatterjee, Margaret A Tucker, Neil E Caporaso, Stephen J Chanock, Ite A Laird-Offringa, Maria Teresa Landi
The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs...
2014: Nature Communications
Alicia K Smith, Varun Kilaru, Mehmet Kocak, Lynn M Almli, Kristina B Mercer, Kerry J Ressler, Frances A Tylavsky, Karen N Conneely
BACKGROUND: Individual genotypes at specific loci can result in different patterns of DNA methylation. These methylation quantitative trait loci (meQTLs) influence methylation across extended genomic regions and may underlie direct SNP associations or gene-environment interactions. We hypothesized that the detection of meQTLs varies with ancestral population, developmental stage, and tissue type. We explored this by analyzing seven datasets that varied by ancestry (African American vs...
2014: BMC Genomics
Degui Zhi, Stella Aslibekyan, Marguerite R Irvin, Steven A Claas, Ingrid B Borecki, Jose M Ordovas, Devin M Absher, Donna K Arnett
DNA methylation is an important molecular-level phenotype that links genotypes and complex disease traits. Previous studies have found local correlation between genetic variants and DNA methylation levels (cis-meQTLs). However, general mechanisms underlying cis-meQTLs are unclear. We conducted a cis-meQTL analysis of the Genetics of Lipid Lowering Drugs and Diet Network data (n = 593). We found that over 80% of genetic variants at CpG sites (meSNPs) are meQTL loci (P-value<10(-9)), and meSNPs account for over two thirds of the strongest meQTL signals (P-value<10(-200))...
August 2013: Epigenetics: Official Journal of the DNA Methylation Society
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