Genetics and Genomics Commons^™

Impact Of Home Visit Capacity On Genetic Association Studies Of Late-Onset Alzheimer's Disease, David W. Fardo, Laura E. Gibbons, Shubhabrata Mukherjee, M. Maria Glymour, Wayne Mccormick, Susan M. Mccurry, James D. Bowen, Eric B. Larson, Paul K. Crane

Biostatistics Faculty Publications

INTRODUCTION—Findings for genetic correlates of late-onset Alzheimer's disease (LOAD) in studies that rely solely on clinic visits may differ from those with capacity to follow participants unable to attend clinic visits.

METHODS—We evaluated previously identified LOAD-risk single nucleotide variants in the prospective Adult Changes in Thought study, comparing hazard ratios (HRs) estimated using the full data set of both in-home and clinic visits (n = 1697) to HRs estimated using only data that were obtained from clinic visits (n = 1308). Models were adjusted for age, sex, principal components to account for ancestry, and additional health indicators.

RESULTS …

Alzheimer's Disease Genetics And Abca7 Splicing, Jared B. Vasquez, James F. Simpson, Ryan Harpole, Steven Estus

Physiology Faculty Publications

Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer’s disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended …

Whole-Genome Dna Methylation Status Associated With Clinical Ptsd Measures Of Oif/Oef Veterans., R Hammamieh, N Chakraborty, A Gautam, S Muhie, R Yang, D Donohue, R Kumar, B J Daigle, Y Zhang, D A Amara, S-A Miller, S Srinivasan, J Flory, R Yehuda, L Petzold, O M Wolkowitz, S H Mellon, L Hood, F J Doyle, C Marmar, M Jett

Articles, Abstracts, and Reports

Emerging knowledge suggests that post-traumatic stress disorder (PTSD) pathophysiology is linked to the patients' epigenetic changes, but comprehensive studies examining genome-wide methylation have not been performed. In this study, we examined genome-wide DNA methylation in peripheral whole blood in combat veterans with and without PTSD to ascertain differentially methylated probes. Discovery was initially made in a training sample comprising 48 male Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) veterans with PTSD and 51 age/ethnicity/gender-matched combat-exposed PTSD-negative controls. Agilent whole-genome array detected ~5600 differentially methylated CpG islands (CpGI) annotated to ~2800 differently methylated genes (DMGs). The majority (84.5%) of these CpGIs …

Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt, Manana Melikishvili, Michael G. Fried

Center for Structural Biology Faculty Publications

Human O⁶-alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O⁶-alkylguanine and O⁴-alkylthymine adducts in single-stranded and duplex DNAs. The search for these lesions, through a vast excess of competing, unmodified genomic DNA, is a mechanistic challenge that may limit the repair rate in vivo. Here, we examine influences of DNA secondary structure and twist on protein–protein interactions in cooperative AGT complexes formed on lesion-free DNAs that model the unmodified parts of the genome. We used a new approach to resolve nearest neighbor (nn) and long-range (lr) components from the ensemble-average cooperativity, ω_ave. We found …

Meta-Analysis Of Five Genome-Wide Association Studies Identifies Multiple New Loci Associated With Testicular Germ Cell Tumor., Zhaoming Wang, Katherine A Mcglynn, Ewa Rajpert-De Meyts, D Timothy Bishop, Charles C Chung, Marlene D Dalgaard, Mark H Greene, Ramneek Gupta, Tom Grotmol, Trine B Haugen, Robert Karlsson, Kevin Litchfield, Nandita Mitra, Kasper Nielsen, Louise C Pyle, Stephen M Schwartz, Vésteinn Thorsson, Saran Vardhanabhuti, Fredrik Wiklund, Clare Turnbull, Stephen J Chanock, Peter A Kanetsky, Katherine L Nathanson

Articles, Abstracts, and Reports

The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10

Genetic Associations With Lipoprotein Subfraction Measures Differ By Ethnicity In The Multi-Ethnic Study Of Atherosclerosis (Mesa), Zhe Wang, Ani Manichukal, David C. Goff, Samia Mora, Jose M. Ordovas, Nicholas M. Pajewski, Wendy S. Post, Jerome I. Rotter, Michele M. Sale, Stephanie A. Santorico, David Siscovick, Michael Y. Tsai, Donna K. Arnett, Stephen Rich, Alexis C. Frazier-Wood

Epidemiology and Environmental Health Faculty Publications

A recent genome-wide association study associated 62 single nucleotide polymorphisms (SNPs) from 43 genomic loci, with fasting lipoprotein subfractions in European–Americans (EAs) at genome-wide levels of significance across three independent samples. Whether these associations are consistent across ethnicities with a non-European ancestry is unknown. We analyzed 15 lipoprotein subfraction measures, on 1677 African–Americans (AAs), 1450 Hispanic–Americans (HAs), and 775 Chinese–Americans (CHN) participating in the multi-ethnic study of atherosclerosis (MESA). Genome-wide data were obtained using the Affymetrix 6.0 and Illumina HumanOmni chips. Linear regression models between genetic variables and lipoprotein subfractions were adjusted for age, gender, body mass index, smoking, study …

C/D-Box Snornas Form Methylating And Non-Methylating Ribonucleoprotein Complexes: Old Dogs Show New Tricks, Marina Falaleeva, Justin R. Welden, Marilyn J. Duncan, Stefan Stamm

Molecular and Cellular Biochemistry Faculty Publications

C/D box snoRNAs (SNORDs) are an abundantly expressed class of short, non‐coding RNAs that have been long known to perform 2′‐O‐methylation of rRNAs. However, approximately half of human SNORDs have no predictable rRNA targets, and numerous SNORDs have been associated with diseases that show no defects in rRNAs, among them Prader‐Willi syndrome, Duplication 15q syndrome and cancer. This apparent discrepancy has been addressed by recent studies showing that SNORDs can act to regulate pre‐mRNA alternative splicing, mRNA abundance, activate enzymes, and be processed into shorter ncRNAs resembling miRNAs and piRNAs. Furthermore, recent biochemical studies have shown that a given SNORD …

Modulation Of Bax And Mtor For Cancer Therapeutics., Rui Li, Chunyong Ding, Jun Zhang, Maohua Xie, Dongkyoo Park, Ye Ding, Guo Chen, Guojing Zhang, Melissa Gilbert-Ross, Wei Zhou, Adam I Marcus, Shi-Yong Sun, Zhuo G Chen, Gabriel L Sica, Suresh S Ramalingam, Andrew T Magis, Haian Fu, Fadlo R Khuri, Walter J Curran, Taofeek K Owonikoko, Dong M Shin, Jia Zhou, Xingming Deng

Articles, Abstracts, and Reports

A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 …

Single-Trait And Multi-Trait Genome-Wide Association Analyses Identify Novel Loci For Blood Pressure In African-Ancestry Populations, Jingjing Liang, Thu H. Le, Digna R. Velez Edwards, Bamidele O. Tayo, Kyle J. Gaulton, Jennifer A. Smith, Yingchang Lu, Richard A. Jensen, Guanjie Chen, Lisa R. Yanek, Karen Schwander, Salman M. Tajuddin, Tamar Sofer, Wonji Kim, James Kayima, Colin A. Mckenzie, Ervin Fox, Michael A. Nalls, J. Hunter Young, Yan V. Sun, Jacqueline M. Lane, Sylvia Cechova, Jie Zhou, Hua Tang, Myriam Fornage, Solomon K. Musani, Heming Wang, Juyoung Lee, Adebowale Adeyemo, Albert W. Dreisbach, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10⁻⁸) for either systolic and …

Discovering And Linking Public Omics Data Sets Using The Omics Discovery Index., Yasset Perez-Riverol, Mingze Bai, Felipe Da Veiga Leprevost, Silvano Squizzato, Young Mi Park, Kenneth Haug, Adam J Carroll, Dylan Spalding, Justin Paschall, Mingxun Wang, Noemi Del-Toro, Tobias Ternent, Peng Zhang, Nicola Buso, Nuno Bandeira, Eric W Deutsch, David S Campbell, Ronald C Beavis, Reza M Salek, Ugis Sarkans, Robert Petryszak, Maria Keays, Eoin Fahy, Manish Sud, Shankar Subramaniam, Ariana Barbera, Rafael C Jiménez, Alexey I Nesvizhskii, Susanna-Assunta Sansone, Christoph Steinbeck, Rodrigo Lopez, Juan A Vizcaíno, Peipei Ping, Henning Hermjakob

Articles, Abstracts, and Reports

No abstract provided.

Optimal Nutrition And The Ever-Changing Dietary Landscape: A Conference Report., A Shao, A Drewnowski, D C Willcox, L Krämer, Christopher G Lausted, M Eggersdorfer, J Mathers, J D Bell, R K Randolph, R Witkamp, J C Griffiths

Articles, Abstracts, and Reports

The field of nutrition has evolved rapidly over the past century. Nutrition scientists and policy makers in the developed world have shifted the focus of their efforts from dealing with diseases of overt nutrient deficiency to a new paradigm aimed at coping with conditions of excess-calories, sedentary lifestyles and stress. Advances in nutrition science, technology and manufacturing have largely eradicated nutrient deficiency diseases, while simultaneously facing the growing challenges of obesity, non-communicable diseases and aging. Nutrition research has gone through a necessary evolution, starting with a reductionist approach, driven by an ambition to understand the mechanisms responsible for the effects …

A Longitudinal Cline Characterizes The Genetic Structure Of Human Populations In The Tibetan Plateau, Choongwon Jeong, Benjamin M. Peter, Buddha Basnyat, Maniraj Neupane, Geoff Childs, Sienna Craig, John Novembre, Anna Di Rienzo

Dartmouth Scholarship

Indigenous populations of the Tibetan plateau have attracted much attention for their good performance at extreme high altitude. Most genetic studies of Tibetan adaptations have used genetic variation data at the genome scale, while genetic inferences about their de- mography and population structure are largely based on uniparental markers. To provide genome-wide information on population structure, we analyzed new and published data of 338 individuals from indigenous populations across the plateau in conjunction with world- wide genetic variation data. We found a clear signal of genetic stratification across the east- west axis within Tibetan samples. Samples from more eastern locations …

Discovery And Fine-Mapping Of Adiposity Loci Using High Density Imputation Of Genome-Wide Association Studies In Individuals Of African Ancestry: African Ancestry Anthropometry Genetics Consortium, Maggie C. Y. Ng, Mariaelisa Graff, Yingchang Lu, Anne E. Justice, Poorva Mudgal, Ching-Ti Liu, Kristin Young, Lisa R. Yanek, Mary F. Feitosa, Mary K. Wojczynski, Kristin Rand, Jennifer A. Brody, Brian E. Cade, Latchezar Dimitrov, Qing Duan, Xiuqing Guo, Leslie A. Lange, Michael A. Nalls, Hayrettin Okut, Salman M. Tajuddin, Bamidele O. Tayo, Sailaja Vedantam, Jonathan P. Bradfield, Guanjie Chen, Wei-Min Chen, Alessandra Chesi, Marguerite R. Irvin, Badri Padhukasahasram, Jennifer A. Smith, Wei Zheng, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Genome-wide association studies (GWAS) have identified > 300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHR_adjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHR_adjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified …

Longitudinal Peripheral Blood Transcriptional Analysis Of A Patient With Severe Ebola Virus Disease., John C Kash, Kathie-Anne Walters, Jason Kindrachuk, David Baxter, Kelsey Scherler, Krisztina B Janosko, Rick D Adams, Andrew S Herbert, Rebekah M James, Spencer W Stonier, Matthew J Memoli, John M Dye, Richard T Davey, Daniel S Chertow, Jeffery K Taubenberger

Articles, Abstracts, and Reports

The 2013-2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration-approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily …

Csf Protein Changes Associated With Hippocampal Sclerosis Risk Gene Variants Highlight Impact Of Grn/Pgrn, David W. Fardo, Yuriko Katsumata, John S. K. Kauwe, Yuetiva Deming, Oscar Harari, Carlos Cruchaga, Alzheimer’S Disease Neuroimaging Initiative, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs).

Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes.

Results—The GRN risk …

Evolutionary History Of Tibetans Inferred From Whole-Genome Sequencing., Hao Hu, Nayia Petousi, Gustavo Glusman, Yao Yu, Ryan Bohlender, Tsewang Tashi, Jonathan M Downie, Jared C Roach, Amy M Cole, Felipe R Lorenzo, Alan R Rogers, Mary E Brunkow, Gianpiero Cavalleri, Leroy Hood, Sama M Alpatty, Josef T Prchal, Lynn B Jorde, Peter A Robbins, Tatum S Simonson, Chad D Huff

Articles, Abstracts, and Reports

The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 …

Mir-144 Attenuates The Host Response To Influenza Virus By Targeting The Traf6-Irf7 Signaling Axis., Carrie M Rosenberger, Rebecca L Podyminogin, Alan H Diercks, Piper M Treuting, Jacques J Peschon, David Rodriguez, Madhumati Gundapuneni, Mitchell J Weiss, Alan Aderem

Articles, Abstracts, and Reports

Antiviral responses must rapidly defend against infection while minimizing inflammatory damage, but the mechanisms that regulate the magnitude of response within an infected cell are not well understood. miRNAs are small non-coding RNAs that suppress protein levels by binding target sequences on their cognate mRNA. Here, we identify miR-144 as a negative regulator of the host antiviral response. Ectopic expression of miR-144 resulted in increased replication of three RNA viruses in primary mouse lung epithelial cells: influenza virus, EMCV, and VSV. We identified the transcriptional network regulated by miR-144 and demonstrate that miR-144 post-transcriptionally suppresses TRAF6 levels. In vivo ablation …

Discovery And Validation Of Information Theory-Based Transcription Factor And Cofactor Binding Site Motifs., Ruipeng Lu, Eliseos J Mucaki, Peter K Rogan

Biochemistry Publications

Data from ChIP-seq experiments can derive the genome-wide binding specificities of transcription factors (TFs) and other regulatory proteins. We analyzed 765 ENCODE ChIP-seq peak datasets of 207 human TFs with a novel motif discovery pipeline based on recursive, thresholded entropy minimization. This approach, while obviating the need to compensate for skewed nucleotide composition, distinguishes true binding motifs from noise, quantifies the strengths of individual binding sites based on computed affinity and detects adjacent cofactor binding sites that coordinate with the targets of primary, immunoprecipitated TFs. We obtained contiguous and bipartite information theory-based position weight matrices (iPWMs) for 93 sequence-specific TFs, …

Cpt1a Methylation Is Associated With Plasma Adiponectin, S. Aslibekyan, A. N. Do, H. Xu, S. Li, M. R. Irvin, D Zhi, H. K. Tiwari, D. M. Absher, A. R. Shuldiner, T. Zhang, W. Chen, K. Tanner, C. Hong, B. D. Mitchell, G. Berenson, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background and Aims—Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood.

Methods and Results—We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression …

Micrornas, Heart Failure, And Aging: Potential Interactions With Skeletal Muscle, Kevin A. Murach, John J. Mccarthy

Center for Muscle Biology Faculty Publications

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting mRNAs for degradation or translational repression. MiRNAs can be expressed tissue specifically and are altered in response to various physiological conditions. It has recently been shown that miRNAs are released into the circulation, potentially for the purpose of communicating with distant tissues. This manuscript discusses miRNA alterations in cardiac muscle and the circulation during heart failure, a prevalent and costly public health issue. A potential mechanism for how skeletal muscle maladaptations during heart failure could be mediated by myocardium-derived miRNAs released to the circulation is presented. An overview …

High Resolution Time-Course Mapping Of Early Transcriptomic, Molecular And Cellular Phenotypes In Huntington's Disease Cag Knock-In Mice Across Multiple Genetic Backgrounds., Seth A Ament, Jocelynn R Pearl, Andrea Grindeland, Jason St Claire, John C Earls, Marina Kovalenko, Tammy Gillis, Jayalakshmi Mysore, James F Gusella, Jong-Min Lee, Seung Kwak, David Howland, Min Young Lee, David Baxter, Kelsey Scherler, Kai Wang, Donald Geman, Jeffrey B Carroll, Marcy E Macdonald, George Carlson, Vanessa C Wheeler, Nathan D Price, Leroy Hood

Articles, Abstracts, and Reports

Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, …

A Systematic Study Of Dysregulated Microrna In Type 2 Diabetes Mellitus., Yuqing He, Yuanlin Ding, Biyu Liang, Juanjuan Lin, Taek-Kyun Kim, Haibing Yu, Hanwei Hang, Kai Wang

Articles, Abstracts, and Reports

MicroRNAs (miRNAs) are small noncoding RNAs that modulate the cellular transcriptome at the post-transcriptional level. miRNA plays important roles in different disease manifestation, including type 2 diabetes mellitus (T2DM). Many studies have characterized the changes of miRNAs in T2DM, a complex systematic disease; however, few studies have integrated these findings and explored the functional effects of the dysregulated miRNAs identified. To investigate the involvement of miRNAs in T2DM, we obtained and analyzed all relevant studies published prior to 18 October 2016 from various literature databases. From 59 independent studies that met the inclusion criteria, we identified 158 dysregulated miRNAs in …

Predicting Disease-Related Genes Using Integrated Biomedical Networks, Jiajie Peng, Kun Bai, Xuequn Shang, Guohua Wang, Hansheng Xue, Shuilin Jin, Liang Cheng, Yadong Wang, Jin Chen

Institute for Biomedical Informatics Faculty Publications

Background: Identifying the genes associated to human diseases is crucial for disease diagnosis and drug design. Computational approaches, esp. the network-based approaches, have been recently developed to identify disease-related genes effectively from the existing biomedical networks. Meanwhile, the advance in biotechnology enables researchers to produce multi-omics data, enriching our understanding on human diseases, and revealing the complex relationships between genes and diseases. However, none of the existing computational approaches is able to integrate the huge amount of omics data into a weighted integrated network and utilize it to enhance disease related gene discovery.

Results: We propose a new network-based disease …

Association Of Body Mass Index With Dna Methylation And Gene Expression In Blood Cells And Relations To Cardiometabolic Disease: A Mendelian Randomization Approach, Michael M. Mendelson, Riccardo E. Marioni, Roby Joehanes, Chunyu Liu, Åsa K. Hedman, Stella Aslibekyan, Ellen W. Demerath, Weihua Guan, Degui Zhi, Chen Yao, Tianxiao Huan, Christine Willinger, Brian Chen, Paul Courchesne, Michael Multhaup, Marguerite R. Irvin, Ariella Cohain, Eric E. Schadt, Megan L. Grove, Jan Bressler, Kari North, Johan Sundström, Stefan Gustafsson, Sonia Shah, Allan F. Mcrae, Sarah E. Harris, Jude Gibson, Paul Redmond, Janie Corley, Lee Murphy, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background

The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.

Methods and Findings

We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs …

Inferring Condition-Specific Targets Of Human Tf-Tf Complexes Using Chip-Seq Data, Chia-Chun Yang, Min-Hsuan Chen, Sheng-Yi Lin, Erik H. Andrews, Chao Cheng, Jeremy J.W Chen

Dartmouth Scholarship

Background:

Transcription factors (TFs) often interact with one another to form TF complexes that bind DNA and regulate gene expression. Many databases are created to describe known TF complexes identified by either mammalian two-hybrid experiments or data mining. Lately, a wealth of ChIP-seq data on human TFs under different experiment conditions are available, making it possible to investigate condition-specific (cell type and/or physiologic state) TF complexes and their target genes.

Results:

Here, we developed a systematic pipeline to infer Condition-Specific Targets of human TF-TF complexes (called the CST pipeline) by integrating ChIP-seq data and TF motifs. In total, we predicted …

The Rs16906252:C>T Snp Is Not Associated With Increased Overall Survival Or Temozolomide Response In A Han-Chinese Glioma Cohort., Kuo-Chen Wei, Chia-Yuan Chen, Li-Ying Feng, Wei-Tzu Huang, Chia-Hua Chen, Peng-Wei Hsu, Kai Wang, Leroy Hood, Leslie Y Chen

Articles, Abstracts, and Reports

The methylation status of O-6-methylguanine-DNA methyltransferase (MGMT) is associated with the prognosis in gliomas and in other cancers. Recent studies showed that rs16906252, an SNP in the MGMT promoter, is associated with promoter methylation and is a predictor of the overall survival time (OST) and the response to temozolomide (TMZ) treatment. However, these findings haven't been systematically investigated in the Han-Chinese population. We analyzed the relevance between rs16906252 polymorphisms, the MGMT methylation status, and the OST in 72 Han-Chinese gliomas patients. The MGMT promoter methylation was measured by bisulfite conversion followed by pyro-sequencing, while rs16906252 was measured by restriction endonuclease …

An Indicator Cell Assay For Blood-Based Diagnostics., Samuel A Danziger, Leslie R Miller, Karanbir Singh, G Adam Whitney, Elaine R Peskind, Ge Li, Robert J Lipshutz, John D Aitchison, Jennifer J Smith

Articles, Abstracts, and Reports

We have established proof of principle for the Indicator Cell Assay Platform™ (iCAP™), a broadly applicable tool for blood-based diagnostics that uses specifically-selected, standardized cells as biosensors, relying on their innate ability to integrate and respond to diverse signals present in patients' blood. To develop an assay, indicator cells are exposed in vitro to serum from case or control subjects and their global differential response patterns are used to train reliable, disease classifiers based on a small number of features. In a feasibility study, the iCAP detected pre-symptomatic disease in a murine model of amyotrophic lateral sclerosis (ALS) with 94% …

Dna Methylation Signatures Of Chronic Low-Grade Inflammation Are Associated With Complex Diseases, Symen Ligthart, Carola Marzi, Stella Aslibekyan, Michael M. Mendelson, Karen N. Conneely, Toshiko Tanaka, Elena Colicino, Lindsay L. Waite, Roby Joehanes, Weihua Guan, Jennifer A. Brody, Cathy Elks, Riccardo Marioni, Min A. Jhun, Golareh Agha, Jan Bressler, Cavin K. Ward-Caviness, Brian H. Chen, Tianxiao Huan, Kelly Bakulski, Elias L. Salfati, Whi-Empc Investigators, Giovanni Fiorito, Charge Epigenetics Of Coronary Heart Disease, Simone Wahl, Katharina Schramm, Jin Sha, Dena G. Hernandez, Allan C. Just, Jennifer A. Smith, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10^–7) in the discovery panel …

Circnet: A Database Of Circular Rnas Derived From Transcriptome Sequencing Data, Yu-Chen Liu, Jian-Rong Li, Chuan-Hu Sun, Erik Andrews, Rou-Fang Chao, Feng-Mao Lin, Shun-Long Weng, Sheng-Da Hsu, Chieh-Chen Huang, Chao Cheng, Chun-Chi Liu, Hsien-Da Huang

Dartmouth Scholarship

Circular RNAs (circRNAs) represent a new type of regulatory noncoding RNA that only recently has been identified and cataloged. Emerging evidence indicates that circRNAs exert a new layer of post-transcriptional regulation of gene expression. In this study, we utilized transcriptome sequencing datasets to systematically identify the expression of circRNAs (including known and newly identified ones by our pipeline) in 464 RNA-seq samples, and then constructed the CircNet database (http://circnet.mbc.nctu.edu.tw/) that provides the following resources: (i) novel circRNAs, (ii) integrated miRNA-target networks, (iii) expression profiles of circRNA isoforms, (iv) genomic annotations of circRNA isoforms (e.g. 282 948 exon positions), …

Expanding The Phenotype Associated With Naa10-Related N-Terminal Acetylation Deficiency., Chloé Saunier, Svein Isungset Støve, Bernt Popp, Bénédicte Gérard, Marina Blenski, Nicholas Ahmew, +Several Additional Authors

Pediatrics Faculty Publications

N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11 females, and due to maternal germ …