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Zhi D.,University of Alabama at Birmingham | Aslibekyan S.,University of Alabama at Birmingham | Irvin M.R.,University of Alabama at Birmingham | Claas S.A.,University of Alabama at Birmingham | And 4 more authors.
Epigenetics | Year: 2013

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). Beyond direct effects on the methylation of the meSNP site, the CpG-disrupting allele of meSNPs were associated with lowered methylation of CpG sites located within 45 bp. The effect of meSNPs extends to as far as 10 kb and can contribute to the observed meQTL signals in the surrounding region, likely through correlated methylation patterns and linkage disequilibrium. Therefore, meSNPs are behind a large portion of observed meQTL signals and play a crucial role in the biological process linking genetic variation to epigenetic changes. © 2013 Landes Bioscience. Source

Love C.,Duke University | Sun Z.,Duke University | Jima D.,Duke University | Li G.,Duke University | And 27 more authors.
Nature Genetics | Year: 2012

Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene. © 2012 Nature America, Inc. All rights reserved. Source

Hidalgo B.,University of Alabama at Birmingham | Irvin M.R.,University of Alabama at Birmingham | Sha J.,University of Alabama at Birmingham | Zhi D.,University of Alabama at Birmingham | And 6 more authors.
Diabetes | Year: 2014

Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing heritability in T2D and related metabolic traits. We conducted an epigenome-wide association study for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study, divided into discovery (N = 544) and replication (N = 293) stages. Cytosine guanine dinucleotide (CpG) methylation at ;470,000 CpG sites was assayed in CD4+ T cells using the Illumina Infinium HumanMethylation 450 Beadchip. We fit a mixed model with the methylation status of each CpG as the dependent variable, adjusting for age, sex, study site, and T-cell purity as fixed-effects and family structure as a random-effect. A Bonferroni corrected P value of 1.1 3 1027 was considered significant in the discovery stage. Significant associations were tested in the replication stage using identical models. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin (P = 1.83 3 1027) and HOMA-IR (P = 1.60 3 1029). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P = 1.29 3 1027 and P = 3.36 3 1026, respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 3 1023 and P = 3.35 3 1022, respectively). Our findings suggest that methylation of a CpG site within ABCG1 is associated with fasting insulin and merits further evaluation as a novel disease risk marker. © 2014 by the American Diabetes Association. Source

Aslibekyan A.,University of Alabama at Birmingham | Wiener H.W.,University of Alabama at Birmingham | Havel P.J.,University of California at Davis | Stanhope K.L.,University of California at Davis | And 5 more authors.
Journal of Nutrition | Year: 2014

A large body of evidence links a high dietary intake of n-3 (ω-3) polyunsaturated fatty acids (PUFAs) with improved cardiometabolic outcomes. Recent studies suggested that the biologic processes underlying the observed associations may involve epigenetic changes, specifically DNA methylation. To evaluate changes in methylation associated with n-3 PUFA intake, we conducted an epigenome-wide methylation association study of long-chain n-3 PUFA intake and tested associations between the diabetes-and cardiovascular disease-related traits. We assessed DNA methylation at;470,000 cytosine-phosphate-guanine (CpG) sites in a cross-sectional study of 185 Yup'ik Alaska Native individuals representing the top and bottom deciles of PUFA intake. Linear regression models were used to test for the associations of interest, adjusting for age, sex, and community group. We identified 27 differentially methylated CpG sites at biologically relevant regions that reached epigenome-wide significance (P < 1 × 10-27). Specifically, regions on chromosomes 3 (helicase-like transcription factor), 10 (actin a 2 smooth muscle/Fas cell surface death receptor), and 16 (protease serine 36/C16 open reading frame 67) each harbored 2 significant correlates of n-3 PUFA intake. In conclusion, we present promising evidence of association between several biologically relevant epigenetic markers and long-term intake of marine-derived n-3 PUFAs. © 2014 American Society for Nutrition. Source

Arrington C.B.,University of Utah | Matsunami N.,University of Utah | Bonnell G.D.,University of Utah | Otterud B.E.M.,University of Utah | And 5 more authors.
Circulation: Cardiovascular Genetics | Year: 2012

Background-A number of single gene defects have been identified in patients with isolated or nonsyndromic congenital heart defects (CHDs). However, due to significant genetic heterogeneity, candidate gene approaches have had limited success in finding high-risk alleles in most cases. The purpose of this study was to use exome sequencing to identify high-risk gene variants in a family with highly penetrant pleiotropic CHD. Methods and Results-DNA samples from 2 members of a family with diverse CHD were analyzed by exome sequencing. Variants were filtered to eliminate common variants and sequencing artifacts and then prioritized based on the predicted effect of the variant and on gene function. The remainder of the family was screened using polymerase chain reaction, high-resolution melting analysis, and DNA sequencing to evaluate variant segregation. After filtering, >2000 rare variants (including single nucleotide substitutions and indels) were shared by the 2 individuals. Of these, 46 were nonsynonymous, 3 were predicted to alter splicing, and 6 resulted in a frameshift. Prioritization reduced the number of variants potentially involved in CHD to 18. None of the variants completely segregated with CHD in the kindred. However, 1 variant, Myh6 Ala290Pro, was identified in all but 1 affected individual. This variant was previously identified in a patient with tricuspid atresia and large secundum atrial septal defect. Conclusions-It is likely that next-generation sequencing will become the method of choice for unraveling the complex genetics of CHD, but information gained by analysis of transmission through families will be crucial. © 2012 American Heart Association, Inc. Source

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