Author: "Ryan P Welch" / Topic: 030304 developmental biology - Searchworks@Jio Institute Digital Library Search Results

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1. Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits

Author: Aldons J. Lusis, Karen L. Mohlke, Maren E Cannon, Mete Civelek, Michael Boehnke, Laura J. Scott, Chelsea K. Raulerson, Terrence S. Furey, Heather M. Stringham, Cassandra N. Spracklen, Anne U. Jackson, Francis S. Collins, Arthur Ko, Danyu Lin, Adam E. Locke, Michael I. Love, Päivi Pajukanta, Ying Wu, Christian Fuchsberger, John C. Kidd, Johanna Kuusisto, Markku Laakso, Kevin W Currin, Narisu Narisu, Sarah M Brotman, and Ryan P. Welch
Subjects: Male, Candidate gene, Quantitative Trait Loci, Gene Expression, Adipose tissue, Genome-wide association study, Quantitative trait locus, Biology, Article, Body Mass Index, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Genetics, medicine, Humans, Obesity, Alleles, Finland, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Waist-Hip Ratio, medicine.disease, Adipose Tissue, Diabetes Mellitus, Type 2, chemistry, Expression quantitative trait loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL
Published: 2019

2. Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences

Author: Sarah M Brotman, Chelsea K. Raulerson, Laura J. Scott, Francis S. Collins, Maren E Cannon, James P. Davis, Hannah J Perrin, Christian Fuchsberger, Karen L. Mohlke, Päivi Pajukanta, Cassandra N. Spracklen, Narisu Narisu, Johanna Kuusisto, Ying Wu, Apoorva K Iyengar, Ryan P. Welch, Kevin W Currin, Markku Laakso, Aaron T Crain, Heather M. Stringham, Yun Li, Adam E. Locke, Anne U. Jackson, Michael Boehnke, and Swarooparani Vadlamudi
Subjects: Male, Cancer Research, Heredity, Physiology, Peptide Hormones, Genome-wide association study, QH426-470, Regulatory Sequences, Nucleic Acid, Biochemistry, 0302 clinical medicine, Cell Signaling, Gene Frequency, Immune Physiology, Medicine and Health Sciences, Genetics (clinical), Genetics, Metabolic Syndrome, 0303 health sciences, Innate Immune System, Genomics, Cadherins, DNA-Binding Proteins, Genetic Mapping, Phenotype, Adipose Tissue, Cytokines, Allelic heterogeneity, Adiponectin, Genomic Signal Processing, Research Article, Signal Transduction, Immunology, DNA transcription, Quantitative Trait Loci, Locus (genetics), Quantitative trait locus, Biology, Genome Complexity, Polymorphism, Single Nucleotide, 03 medical and health sciences, Adipokines, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Alleles, 030304 developmental biology, Genetic association, Haplotype, Biology and Life Sciences, Computational Biology, Human Genetics, Cell Biology, Molecular Development, Genome Analysis, Hormones, Introns, Haplotypes, Genetic Loci, Immune System, Expression quantitative trait loci, Insulin Receptor Substrate Proteins, Gene expression, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study, Transcription Factors
Abstract: Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2, Author summary Many DNA variants affect common human traits, and distinct variants can have different effects on the function or expression level of the same gene. We identified variants associated with levels of adiponectin, a hormone involved in glucose regulation. Among these variants, we specifically studied the sets of variants located near two genes, ADIPOQ and CDH13, to determine how the variants affect gene expression or function. We focused on sets of variants that can be inherited together but are not always inherited together. Of the variants associated with adiponectin and located near ADIPOQ, one set were also associated with higher expression levels of the protein-coding ADIPOQ gene and a nearby non-coding gene, a second set of variants were associated with lower levels of the ADIPOQ-AS1 antisense gene, and additional variants changed the amino acid sequence or size of the adiponectin protein. Our examples show the benefits of identifying multiple sets of trait-associated variants in the same DNA region. These variants explain more trait variation, help identify genes that affect the trait, and guide studies of gene regulation and biological processes.
Published: 2020

3. ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition

Author: Jordana T. Bell, Tingfen Yan, Narisu Narisu, Ryan P. Welch, Päivi Pajukanta, Mario Falchi, Jaakko Tuomilehto, Karen L. Mohlke, Heikki A. Koistinen, Francis S. Collins, Amy L. Roberts, Lori L. Bonnycastle, Michael R. Erdos, Julia S. El-Sayed Moustafa, Sarah M Brotman, Laura J. Scott, Li Guan, Markku Laakso, Antonino Zito, Michael Boehnke, Sergio Villicaňa, Kerrin S. Small, Anne U. Jackson, Timo A. Lakka, Heather M. Stringham, and Stephen C. J. Parker
Subjects: medicine.medical_specialty, Cell type, Adipose tissue, Inflammation, Type 2 diabetes, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Obesity, Receptor, 030304 developmental biology, 0303 health sciences, business.industry, SARS-CoV-2, COVID-19, Cardiometabolic Risk Factors, Endothelial Cells, Heritability, medicine.disease, Phenotype, Endocrinology, Adipose Tissue, Diabetes Mellitus, Type 2, Angiotensin-Converting Enzyme 2, medicine.symptom, business
Abstract: COVID-19 severity has varied widely, with demographic and cardio-metabolic factors increasing risk of severe reactions to SARS-CoV-2 infection, but the underlying mechanisms for this remain uncertain. We investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 (ACE2), which has been shown to act as a receptor for SARS-CoV-2 cellular entry. In a meta-analysis of three independent studies including up to 1,471 participants, lower adipose tissue ACE2 expression was associated with adverse cardio-metabolic health indices including type 2 diabetes (T2D) and obesity status, higher serum fasting insulin and BMI, and lower serum HDL levels (P-4). ACE2 expression levels were also associated with estimated proportions of cell types in adipose tissue; lower ACE2 expression was associated with a lower proportion of microvascular endothelial cells (P=4.25×10-4) and higher macrophage proportion (P=2.74×10-5), suggesting a link to inflammation. Despite an estimated heritability of 32%, we did not identify any proximal or distal genetic variants (eQTLs) associated with adipose tissue ACE2 expression. Our results demonstrate that at-risk individuals have lower background ACE2 levels in this highly relevant tissue. Further studies will be required to establish how this may contribute to increased COVID-19 severity.
Published: 2020

4. LocusZoom.js: interactive and embeddable visualization of genetic association study results

Author: Daniel Taliun, Andrew P. Boughton, Gonçalo R. Abecasis, Ryan P. Welch, Michael Boehnke, Matthew Flickinger, and Peter VandeHaar
Subjects: Statistics and Probability, 0303 health sciences, Biological data, Information retrieval, AcademicSubjects/SCI01060, Computer science, 030302 biochemistry & molecular biology, Context (language use), JavaScript library, Genome Analysis, Biochemistry, Applications Notes, Computer Science Applications, Data sharing, 03 medical and health sciences, Computational Mathematics, Upload, Documentation, Computational Theory and Mathematics, Web page, MIT License, Molecular Biology, 030304 developmental biology
Abstract: Summary LocusZoom.js is a JavaScript library for creating interactive web-based visualizations of genetic association study results. It can display one or more traits in the context of relevant biological data (such as gene models and other genomic annotation), and allows interactive refinement of analysis models (by selecting linkage disequilibrium reference panels, identifying sets of likely causal variants, or comparisons to the GWAS catalog). It can be embedded in web pages to enable data sharing and exploration. Views can be customized and extended to display other data types such as phenome-wide association study (PheWAS) results, chromatin co-accessibility, or eQTL measurements. A new web upload service harmonizes datasets, adds annotations, and makes it easy to explore user-provided result sets. Availability and implementation LocusZoom.js is open-source software under a permissive MIT license. Code and documentation are available at: https://github.com/statgen/locuszoom/. Installable packages for all versions are also distributed via NPM. Additional features are provided as standalone libraries to promote reuse. Use with your own GWAS results at https://my.locuszoom.org/. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2021

5. Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle

Author: Gibran Hemani, Timo A. Lakka, Jaakko Tuomilehto, Ryan P. Welch, John P. Didion, Amy J. Swift, Markku Laakso, Michael R. Erdos, Laura J. Scott, Narisu Narisu, George Davey Smith, Francis S. Collins, Ewan Birney, Jackie Idol, Leena Kinnunen, Michael Boehnke, D. Leland Taylor, Jouko Saramies, Anne U. Jackson, Peter S. Chines, Stephen C. J. Parker, Heikki A. Koistinen, HYKS erva, Department of Public Health, HUS Internal Medicine and Rehabilitation, and Department of Medicine
Subjects: Blood Glucose, mQTL, Quantitative Trait Loci, Skeletal muscle, Gene Expression, Genome-wide association study, Biology, Quantitative trait locus, eQTL, 03 medical and health sciences, 0302 clinical medicine, MQTL, Genetic variation, Mendelian randomization, medicine, Genetics, GWAS, Humans, Insulin, Body Weights and Measures, skeletal muscle, Muscle, Skeletal, Gene, EQTL, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Multidisciplinary, DNA methylation, 1184 Genetics, developmental biology, physiology, Genomics, Biological Sciences, medicine.anatomical_structure, Diabetes Mellitus, Type 2, Expression quantitative trait loci, MENDELIAN RANDOMIZATION, Gene expression, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Significance Identifying causal relationships within a web of human genotype–phenotype correlations is a substantial challenge. Using the largest genetic study to date of comeasured expression and DNA methylation (DNAme) in skeletal muscle, we identify correlations among expression, DNAme, and physiological traits. Leveraging Mendelian randomization (MR) and mediation techniques, we identify 213 putative causal relationships between expression and DNAme. We further use MR to prioritize hundreds of genes and thousands of DNAme sites that may drive genetic associations for diseases and quantitative traits. Our study integrates genetic, diverse -omics, and physiological measurements—a challenge of increasing importance in the field of human genomics., We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height, waist, weight, waist–hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased RXRA muscle expression may decrease lean tissue mass.
Published: 2019

6. Genetic discovery and translational decision support from exome sequencing of 20,791 type 2 diabetes cases and 24,440 controls from five ancestries

Author: Humberto García-Ortiz, Loos R, Frederick E. Dewey, Farook Thameem, John C. Chambers, Mi Yeong Hwang, Nancy L. Heard-Costa, Danish Saleheen, Shuai Wang, Morris Ad, Josep M. Mercader, Noël P. Burtt, Laura J. Scott, Torben Hansen, Mark I. McCarthy, Clicerio Gonzalez, Matsuo K, Mark Seielstad, Marijana Vujkovic, Teresa Tusié-Luna, Alanna C. Morrison, Christian Gieger, Dana Dabelea, Colm O'Dushlaine, Niels Grarup, Elvia Mendoza-Caamal, Amanda F. Elliott, Ryan P. Welch, Craig L. Hanis, Kirchner Hl, Song Chen, Jennifer A. Brody, Maria L. Cortes, Asif Rasheed, Russel Tracy, Nancy J. Cox, Miriam S. Udler, Myron D. Gross, Donald W. Bowden, Oluf Pedersen, Marit E. Jørgensen, J. Tuomilehto, Yik Ying Teo, Andrew P. Morris, Zeitler P, T. M. Strom, Aris Baras, Colin N. A. Palmer, Shin Yc, Johanna Kuusisto, Lin Chen, Donna M. Lehman, Edmund Chan, Heikki A. Koistinen, Anthony Marcketta, Boehnke M, Francis S. Collins, Rayner Nw, Leslie A. Lange, Nir Barzilai, Brian E. Henderson, Jennifer Wessel, David J. Carey, Jaspal S. Kooner, Ralph A. DeFronzo, Anthony Payne, Carlos A. Aguilar-Salinas, Tien Yin Wong, Thomas Meitinger, Lyssenko, Claudia Ht Tam, Cristina Revilla-Monsalve, Daniel R. Witte, Jerome I. Rotter, Michael Preuss, Allan Linneberg, Jose C. Florez, Alisa K. Manning, Gonçalo R. Abecasis, Hyun Min Kang, van Dam Rm, Jason M. Torres, Anubha Mahajan, Claudia Schurmann, Markku Laakso, Leif Groop, Lori L. Bonnycastle, Sohee Han, Jason Flannick, Bong-Jo Kim, Lawrence M. Dolan, Brian Burke, Ma Elena Gonzalez, Kerrin S. Small, Ching-Ti Liu, Ronald C.W. Ma, Peter M. Nilsson, Eric Boerwinkle, Garay-Sevilla Me, Ravindranath Duggirala, Anne Ndungu, Cecilia Contreras-Cubas, Wendy S. Post, Tanya M. Teslovich, Brian Tomlinson, Kimberly L. Drews, Lizz Caulkins, Lee J, Philippe M. Frossard, Jianjun Liu, Hanks S, Ki-Sun Park, Tai Es, Kelsey M, S. Gabriel, Erwin P. Bottinger, Alexander P. Reiner, Tim D. Spector, Lorena Orozco, James S. Pankow, Juliana C.N. Chan, Wing-Yee So, Tiinamaija Tuomi, Malacara-Hernandez Jm, Karen L. Mohlke, S. S. Rich, de Vries Ps, Konstantin Strauch, Graeme I. Bell, Angélica Martínez-Hernández, Elizabeth J. Mayer-Davis, Thomas W. Blackwell, Heather M. Stringham, Bruce M. Psaty, Soo Heon Kwak, Catherine Pihoker, James S. Floyd, Christian Fuchsberger, Ching-Yu Cheng, Neil R. Robertson, Adolfo Correa, James G. Wilson, Ramachandran S. Vasan, Robert Sladek, James B. Meigs, Benjamin Glaser, Gil Atzmon, David Altshuler, Josée Dupuis, Xueling Sim, John Blangero, Emilio J. Cordova, C.J. O'Donnell, Maggie C.Y. Ng, Heckbert, Young-Jin Kim, Joseph B. Leader, Anne U. Jackson, Ryan Koesterer, Nicola Santoro, and Christopher A. Haiman
Subjects: Genetics, 0303 health sciences, Candidate gene, SLC30A8, Heritability, Biology, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, Sample size determination, biology.protein, Allele, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Protein-coding genetic variants that strongly affect disease risk can provide important clues into disease pathogenesis. Here we report an exome sequence analysis of 20,791 type 2 diabetes (T2D) cases and 24,440 controls from five ancestries. We identify rare (minor allele frequency30 SLC30A8 alleles, and (b) within 12 gene sets, including those corresponding to T2D drug targets (p=6.1×10−3) and candidate genes from knockout mice (p=5.2×10−3). Within our study, the strongest T2D rare variant gene-level signals explain at most 25% of the heritability of the strongest common single-variant signals, and the rare variant gene-level effect sizes we observe in established T2D drug targets will require 110K-180K sequenced cases to exceed exome-wide significance. To help prioritize genes using associations from current smaller sample sizes, we present a Bayesian framework to recalibrate association p-values as posterior probabilities of association, estimating that reaching ppwww.type2diabetesgenetics.org.
Published: 2018
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7. Imputation aware tag SNP selection to improve power for multi-ethnic association studies

Author: Carlos Bustamante, Suyash Shringarpure, Daniel Taliun, Christian Fuchsberger, Christopher S. Carlson, Alicia R. Martin, Hyun Min Kang, Christopher R. Gignoux, Ryan P. Welch, Michael Boehnke, Eimear E. Kenny, Gonçalo R. Abecasis, and Genevieve L. Wojcik
Subjects: 0303 health sciences, education.field_of_study, Linkage disequilibrium, Computer science, Population, Genomics, Tag SNP, computer.software_genre, Biobank, 03 medical and health sciences, 0302 clinical medicine, Data mining, Imputation (statistics), 1000 Genomes Project, education, computer, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology, Genetic association
Abstract: The emergence of very large cohorts in genomic research has facilitated a focus on genotype-imputation strategies to power rare variant association. Consequently, a new generation of genotyping arrays are being developed designed with tag single nucleotide polymorphisms (SNPs) to improve rare variant imputation. Selection of these tag SNPs poses several challenges as rare variants tend to be continentally-or even population-specific and reflect fine-scale linkage disequilibrium (LD) structure impacted by recent demographic events. To explore the landscape of tag-able variation and guide design considerations for large-cohort and biobank arrays, we developed a novel pipeline to select tag SNPs using the 26 population reference panel from Phase of the 1000 Genomes Project. We evaluate our approach using leave-one-out internal validation via standard imputation methods that allows the direct comparison of tag SNP performance by estimating the correlation of the imputed and real genotypes for each iteration of potential array sites. We show how this approach allows for an assessment of array design and performance that can take advantage of the development of deeper and more diverse sequenced reference panels. We quantify the impact of demography on tag SNP performance across populations and provide population-specific guidelines for tag SNP selection. We also examine array design strategies that target single populations versus multi-ethnic cohorts, and demonstrate a boost in performance for the latter can be obtained by prioritizing tag SNPs that contribute information across multiple populations simultaneously. Finally, we demonstrate the utility of improved array design to provide meaningful improvements in power, particularly in trans-ethnic studies. The unified framework presented will enable investigators to make informed decisions for the design of new arrays, and help empower the next phase of rare variant association for global health.
Published: 2017

8. Interactions between genetic variation and cellular environment in skeletal muscle gene expression

Author: Oliver Stegle, D. Leland Taylor, Michael Boehnke, Timo A. Lakka, Markku Laakso, Ewan Birney, Peter S. Chines, Jouko Sundvall, David A. Knowles, Stephen C. J. Parker, Jouko Saramies, Francesco Paolo Casale, Laura J. Scott, Francis S. Collins, Andrea H. Ramirez, Ryan P. Welch, Narisu Narisu, Leena Kinnunen, Ricardo D’Oliveira Albanus, Arushi Varshney, Heikki A. Koistinen, Michael R. Erdos, Jaakko Tuomilehto, Brooke N. Wolford, Li Guan, Clinicum, Department of Medicine, Endokrinologian yksikkö, and HUS Internal Medicine and Rehabilitation
Subjects: CHROMATIN, 0301 basic medicine, Muscle Fibers, Skeletal, Gene Expression, lcsh:Medicine, ALLELE-SPECIFIC EXPRESSION, Biochemistry, Transcriptome, 0302 clinical medicine, Endocrinology, Medicine and Health Sciences, HUMAN GENOME, Insulin, PLASTICITY, PHOSPHORYLATION, lcsh:Science, Musculoskeletal System, Genetics, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Muscles, Type 2 Diabetes, TRANSCRIPTION FACTORS, Phenotypes, Phenotype, Cellular Microenvironment, Trait, Anatomy, Research Article, Genotype, Endocrine Disorders, Quantitative Trait Loci, Single-nucleotide polymorphism, Context (language use), Computational biology, Quantitative trait locus, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, Gene mapping, Genetic variation, Diabetes Mellitus, Humans, Gene Regulation, Molecular Biology Techniques, Muscle, Skeletal, FORMINS, Molecular Biology, Genetic Association Studies, 030304 developmental biology, Diabetic Endocrinology, Evolutionary Biology, Population Biology, Gene Mapping, lcsh:R, Biology and Life Sciences, Genetic Variation, Genetic architecture, Hormones, 030104 developmental biology, Skeletal Muscles, Gene Expression Regulation, DISCOVERY, 3121 General medicine, internal medicine and other clinical medicine, Metabolic Disorders, Expression quantitative trait loci, Genetic Polymorphism, FHOD3, Human genome, Gene-Environment Interaction, lcsh:Q, 3111 Biomedicine, Energy Metabolism, 030217 neurology & neurosurgery, Population Genetics
Abstract: From whole organisms to individual cells, responses to environmental conditions are influenced by genetic makeup, where the effect of genetic variation on a trait depends on the environmental context. RNA-sequencing quantifies gene expression as a molecular trait, and is capable of capturing both genetic and environmental effects. In this study, we explore opportunities of using allele-specific expression (ASE) to discovercisacting genotype-environment interactions (GxE) - genetic effects on gene expression that depend on an environmental condition. Treating 17 common, clinical traits as approximations of the cellular environment of 267 skeletal muscle biopsies, we identify 10 candidate interaction quantitative trait loci (iQTLs) across 6 traits (12 unique gene-environment trait pairs; 10% FDR per trait) including sex, systolic blood pressure, and low-density lipoprotein cholesterol. Although using ASE is in principle a promising approach to detect GxE effects, replication of such signals can be challenging as validation requires harmonization of environmental traits across cohorts and a sufficient sampling of heterozygotes for a transcribed SNP. Comprehensive discovery and replication will require large human transcriptome datasets, or the integration of multiple transcribed SNPs, coupled with standardized clinical phenotyping.
Published: 2017
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9. Global Epigenomic Analysis of Primary Human Pancreatic Islets Provides Insights into Type 2 Diabetes Susceptibility Loci

Author: Terrence S. Furey, Stephen C. J. Parker, Praveen Sethupathy, Michael Boehnke, Ryan P. Welch, Daniel S. Pearson, Elliott H. Margulies, Francis S. Collins, Gregory E. Crawford, Peter S. Chines, Lingyun Song, Michael L. Stitzel, Alan P. Boyle, Laura J. Scott, and Michael R. Erdos
Subjects: Epigenomics, CCCTC-Binding Factor, endocrine system, endocrine system diseases, Physiology, Biology, Regulatory Sequences, Nucleic Acid, Methylation, Article, Histones, 03 medical and health sciences, Histone H3, Islets of Langerhans, 0302 clinical medicine, medicine, Deoxyribonuclease I, Humans, Enhancer, Promoter Regions, Genetic, Gene, Molecular Biology, 030304 developmental biology, Genetics, 0303 health sciences, Pancreatic islets, Lysine, Epigenome, Cell Biology, Repressor Proteins, medicine.anatomical_structure, Diabetes Mellitus, Type 2, CTCF, Regulatory sequence, Genetic Loci, 030217 neurology & neurosurgery, Genome-Wide Association Study, HeLa Cells
Abstract: SummaryIdentifying cis-regulatory elements is important to understanding how human pancreatic islets modulate gene expression in physiologic or pathophysiologic (e.g., diabetic) conditions. We conducted genome-wide analysis of DNase I hypersensitive sites, histone H3 lysine methylation modifications (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified ∼18,000 putative promoters (several hundred unannotated and islet-active). Surprisingly, active promoter modifications were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (nonpromoter) regulatory elements, 47% are islet unique and 22% are CTCF bound. In the 18 type 2 diabetes (T2D)-associated loci, we identified 118 putative regulatory elements and confirmed enhancer activity for 12 of 33 tested. Among six regulatory elements harboring T2D-associated variants, two exhibit significant allele-specific differences in activity. These findings present a global snapshot of the human islet epigenome and should provide functional context for noncoding variants emerging from genetic studies of T2D and other islet disorders.
Published: 2010
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10. Broad-Enrich: functional interpretation of large sets of broad genomic regions

Author: Ryan P. Welch, Terry E. Weymouth, Laura J. Scott, Snehal Patil, Chee Lee, Maureen A. Sartor, and Raymond G. Cavalcante
Subjects: Statistics and Probability, Chromatin Immunoprecipitation, Gene Expression, Locus (genetics), Genomics, Computational biology, ENCODE, Biochemistry, Cell Line, Histones, 03 medical and health sciences, 0302 clinical medicine, Humans, Copy-number variation, Molecular Biology, Gene, 030304 developmental biology, Genetics, 0303 health sciences, biology, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Functional interpretation, Original Papers, Computer Science Applications, Computational Mathematics, Histone, Logistic Models, Computational Theory and Mathematics, Genetic Loci, 030220 oncology & carcinogenesis, biology.protein, Eccb 2014 Proceedings Papers Committee, Chromatin immunoprecipitation, Transcription Factors
Abstract: Motivation: Functional enrichment testing facilitates the interpretation of Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) data in terms of pathways and other biological contexts. Previous methods developed and used to test for key gene sets affected in ChIP-seq experiments treat peaks as points, and are based on the number of peaks associated with a gene or a binary score for each gene. These approaches work well for transcription factors, but histone modifications often occur over broad domains, and across multiple genes. Results: To incorporate the unique properties of broad domains into functional enrichment testing, we developed Broad-Enrich, a method that uses the proportion of each gene’s locus covered by a peak. We show that our method has a well-calibrated false-positive rate, performing well with ChIP-seq data having broad domains compared with alternative approaches. We illustrate Broad-Enrich with 55 ENCODE ChIP-seq datasets using different methods to define gene loci. Broad-Enrich can also be applied to other datasets consisting of broad genomic domains such as copy number variations. Availability and implementation: http://broad-enrich.med.umich.edu for Web version and R package. Contact: sartorma@umich.edu Supplementary information: Supplementary data are available at Bioinformatics online.
Published: 2014

11. Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms

Author: Melina Claussnitzer, Simon N. Dankel, Bernward Klocke, Harald Grallert, Viktoria Glunk, Tea Berulava, Heekyoung Lee, Nikolay Oskolkov, Joao Fadista, Kerstin Ehlers, Simone Wahl, Christoph Hoffmann, Kun Qian, Tina Rönn, Helene Riess, Martina Müller-Nurasyid, Nancy Bretschneider, Timm Schroeder, Thomas Skurk, Bernhard Horsthemke, Derek Spieler, Martin Klingenspor, Martin Seifert, Michael J. Kern, Niklas Mejhert, Ingrid Dahlman, Ola Hansson, Stefanie M. Hauck, Matthias Blüher, Peter Arner, Leif Groop, Thomas Illig, Karsten Suhre, Yi-Hsiang Hsu, Gunnar Mellgren, Hans Hauner, Helmut Laumen, Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. Hofmann, Josée Dupuis, Lu Qi, Ayellet V. Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S.F. Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U. Jackson, Paul R.V. Johnson, Torben Jørgensen, Wen H.L. Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Narisu Narisu, Peter Nilsson, Katharine R. Owen, Felicity Payne, John R.B. Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N. William Rayner, Neil R. Robertson, Ghislain Rocheleau, Michael Roden, Michael J. Sampson, Richa Saxena, Beverley M. Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M. Stringham, Qi Sun, Amy J. Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M. van Dam, Timon W. van Haeften, Thijs van Herpt, Jana V. van Vliet-Ostaptchouk, G. Bragi Walters, Michael N. Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N. Bergman, Stephane Cauchi, Francis S. Collins, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, Karen L. Mohlke, Andrew D. Morris, Colin N.A. Palmer, Peter P. Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J. Wareham, Richard M. Watanabe, Goncalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, H.-Erich Wichmann, Inês Barroso, Jose C. Florez, Timothy M. Frayling, Rob Sladek, Unnur Thorsteinsdottir, James F. Wilson, Philippe Froguel, Cornelia M. van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I. McCarthy, Clinical sciences, Johnson, P, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Diabetes risk, SUSCEPTIBILITY LOCI, Medizin, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Endocrinology and Diabetes, Biology, PHOSPHOENOLPYRUVATE CARBOXYKINASE, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, 0302 clinical medicine, insulin resistance, Animals, Humans, EPIGENOMIC ANALYSIS, GENOME-WIDE ASSOCIATION, genome, Gene, Transcription factor, IN-VIVO, Cells, Cultured, Conserved Sequence, 030304 developmental biology, Genetic association, Homeodomain Proteins, Regulation of gene expression, Genetics, 0303 health sciences, Biochemistry, Genetics and Molecular Biology(all), INSULIN SENSITIVITY, Research Support, Non-U.S. Gov't, LARGE-SCALE, GENE, PPAR gamma, DNA binding site, ADIPOSE-TISSUE, Diabetes Mellitus, Type 2, Gene Expression Regulation, transcription factor binding sites, Homeobox, PPAR-GAMMA, type 2 diabetes, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors
Abstract: SummaryGenome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
Published: 2014

12. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Author: Andrew A. Hicks, Han Chen, Anders Franco-Cereceda, Vilmundur Gudnason, David M. Evans, May E. Montasser, Ulf de Faire, Jeanette S. Andrews, Rainer Rauramaa, Ching-Ti Liu, Michael Boehnke, Panos Deloukas, Naveed Sattar, Jacques S. Beckmann, Marcus E. Kleber, Hanneke Basart, Bruna Gigante, Göran Hallmans, Francis S. Collins, Toshiko Tanaka, Stella Trompet, Kathleen Stirrups, Jula Antti, Ryan P. Welch, Sirkka Keinänen-Kiukaanniemi, Jaakko Kaprio, T. Saaristo, Jeffrey R. O'Connell, Bernhard O. Boehm, Eleanor Wheeler, Kijoung Song, John Beilby, Michael A. Province, Inga Prokopenko, Ping An, Dawn M. Waterworth, Nita G. Forouhi, Nicholas J. Timpson, George Dedoussis, Fernando Rivadeneira, Winfried Maerz, Anneli Pouta, Anuj Goel, Jackie F. Price, Sarah Edkins, Markus Perola, Inês Barroso, Albertine J. Oldehinkel, Igor Rudan, Peter Vollenweider, Philippe Froguel, Richard M. Watanabe, Kari E. North, Dorret I. Boomsma, Harry Campbell, G. Kees Hovingh, Paul C. D. Johnson, Cécile Lecoeur, Vasiliki Lagou, Denis Rybin, Pierre Meneton, Soumya Raychaudhuri, Jian'an Luan, Neil Robertson, Andrew P. Morris, Veikko Salomaa, Anubha Mahajan, Beate St Pourcain, Robert A. Scott, Evelin Mihailov, Gerard R Fowkes, Nancy L. Pedersen, Susan Campbell, Sonia Shah, Veronique Vitart, Mustafa Atalay, Richard N. Bergman, Ross M. Fraser, Anders Hamsten, Benjamin F. Voight, Wolfgang Rathmann, Christian Gieger, James F. Wilson, Wieland Kiess, Marcel Bruinenberg, Serge Hercberg, Ian Ford, James B. Meigs, Tibor V. Varga, George Davey Smith, Josée Dupuis, Stefania Bandinelli, John F. Peden, Mika Kivimäki, J. Wouter Jukema, Michael Stumvoll, Caroline Hayward, Emil Rehnberg, Ozren Polasek, Letizia Marullo, Andrew D. Morris, Brenda W.J.H. Penninx, Lori L. Bonnycastle, Jouke-Jan Hottenga, Martin Farrall, Albert V. Smith, Rona J. Strawbridge, Ingrid B. Borecki, Kari Stefansson, Kirsten Ohm Kyvik, Harald Grallert, Alan James, Tim D. Spector, Paul W. Franks, Lasse Folkersen, Sara M. Willems, Stephan J. L. Bakker, Iva Miljkovic, Nigel W. Rayner, Tamara B. Harris, Momoko Horikoshi, Linda S. Adair, Christian Herder, Tõnu Esko, Thomas Illig, Alan R. Shuldiner, Ruth J. F. Loos, Serena Sanna, Massimo Mangino, Alex S. F. Doney, Hugh Watkins, Erik Ingelsson, Colin N. A. Palmer, Pau Navarro, Claudia Langenberg, Mark I. McCarthy, Johanna Kuusisto, Anne U. Jackson, Martina Müller-Nurasyid, Perttu Salo, Ying Wu, Alan F. Wright, Lars Lind, Johannes H. Smit, Gonneke Willemsen, Stefan R. Bornstein, Jennie Hui, Peter Schwarz, Anke Toenjes, Albert Hofman, Markku Laakso, Maria Dimitriou, Marjo-Riitta Järvelin, Aaron Isaacs, Hyun Min Kang, James S. Pankow, Annette Peters, André G. Uitterlinden, Loic Yengo, Beverley Balkau, Augustine Kong, Toby Johnson, Cornelia M. van Duijn, Luigi Ferrucci, Samuli Ripatti, Mulas Antonella, Aroon D. Hingorani, Meena Kumari, Nicholas J. Wareham, Sarah H. Wild, Patricia B. Munroe, Nicholas D. Hastie, Stefan Gustafsson, Kerrin S. Small, Cecilia M. Lindgren, Jennifer L. Bolton, Matti Uusitupa, Peter P. Pramstaller, Tove Fall, Patricia A. Peyser, Dmitry Shungin, Yongmei Liu, Patrik K. E. Magnusson, Jaakko Tuomilehto, Francesco Cucca, Reedik Mägi, Karen L. Mohlke, Gudmar Thorleifsson, Hanneke Jansen, Mark J. Caulfield, Tanya M. Teslovich, Timo A. Lakka, Heather M. Stringham, Bruce M. Psaty, Niek Verweij, Heikki Oksa, Wei Zhao, Andres Metspalu, Jaana Lindström, Stavroula Kanoni, Bengt Sennblad, Carlo Sidore, Eco J. C. de Geus, Ben A. Oostra, Lawrence F. Bielak, Peter Kovacs, Laura J. Rasmussen-Torvik, Tatijana Zemunik, Jose C. Florez, Antje Körner, Pim van der Harst, Ramaiah Nagaraja, Peter S. Chines, Nabila Bouatia-Naji, Addenbrooke's Hospital, Wellcome Trust Ctr Human Genet, University of Oxford [Oxford], Michigan State University [East Lansing], Michigan State University System, Wellcome Trust Sanger Inst, Partenaires INRAE, University of Maryland [College Park], University of Maryland System, University of Tartu, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], The Wellcome Trust Sanger Institute [Cambridge], Northwestern University [Evanston], Université Lille Nord de France (COMUE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Lund University [Lund], Umeå University, Consiglio Nazionale delle Ricerche (CNR), Istituto di Virologia Vegetale, Università degli studi di Torino (UNITO), Università degli Studi di Sassari, University of Glasgow, Netherlands Heart Institute, Leiden University, Queen Mary University of London (QMUL), University of Groningen, deCODE genetics [Reykjavik], Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), (IGE3 Inst Genet & Genom Geneva), University College of London [London] (UCL), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Natl Inst Hlth & Welf, University of Helsinki, University of Bristol [Bristol], North Carolina State University, Center for High Performance Simulation and Department of Chemical and Biomolecular Engineering, Wake Forest School of Medicine, Sir Charles Gairdner Hospital, University of Western Australia, PathW Lab Med WA, University of Edinburgh, Centre for Medical Systems Biology, Erasmus University Rotterdam, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Pennyslvania, Brigham and Women's Hospital, Boston University [Boston] (BU), Dept Med Genet, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire Vaudois (CHUV), National Human Genome Research Institute (NHGRI), GlaxoSmithKline, National Institute on Aging, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), National Institutes of Health [N01-AG-1-2100], National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), Althingi (the Icelandic Parliament), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Medical Research Council (MRC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Chemistry, Child and Adolescent Psychiatry / Psychology, Dermatology, Internal Medicine, Clinical Genetics, and VU University Amsterdam
Subjects: Netherlands Twin Register (NTR), Blood Glucose, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Genome-wide association study, Type 2 diabetes, Fasting/blood, Mice, 0302 clinical medicine, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, Gene Frequency, Insulin, GENETICS & HEREDITY, Genetics, 0303 health sciences, INSULIN-RESISTANCE, Metabolic Networks and Pathways/genetics, gene, glucose, glycemic, GLUCOSE-METABOLISM, 11 Medical And Health Sciences, Fasting, CARDIOVASCULAR-DISEASE, SKELETAL-MUSCLE, Female, Life Sciences & Biomedicine, Metabolic Networks and Pathways, Adult, SUSCEPTIBILITY LOCI, Quantitative Trait Loci, 030209 endocrinology & metabolism, Blood Glucose/genetics, KAPPA-B, Quantitative trait locus, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Genome-Wide Association Study/statistics & numerical data, Quantitative Trait Loci/physiology, KLOTHO GENE POLYMORPHISMS, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, Allele frequency, 030304 developmental biology, Glycemic, Science & Technology, Osmolar Concentration, 06 Biological Sciences, medicine.disease, BODY-MASS INDEX, BINDING-PROTEIN-ALPHA, Insulin/blood, Developmental Biology, Genome-Wide Association Study
Abstract: Seuls les auteurs INRA et les 100 premiers auteurs figurent sur la notice. Group Authors : DIAbet Genetics Replication traits and provide insight into the underlying biological pathways La liste complète des auteurs et de leurs affiliations des auteurs est disponible sur la publication, p. 1004-1005, à l'adresse suivante : https://www.nature.com/articles/ng.2385.pdf; International audience; Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
Published: 2012

13. Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Author: Wolfgang Lieb, Bruna Gigante, Thodur M. Vasudevan, Georg Homuth, Joseph B. Muhlestein, Mark J. Daly, Andrew P. Morris, Jacqueline de Graaf, Peter Kraft, Ann-Kristin Petersen, André G. Uitterlinden, Jaqueline C M Witteman, Valgerdur Steinthorsdottir, Jutta Palmen, Amanda L. Elliott, Cecilia M. Lindgren, Richard N. Bergman, Benjamin D. Horne, Tony R. Merriman, Robert W. Davies, Jaspal S. Kooner, Gavin Lucas, Carl G. P. Platou, Diederick E. Grobbee, Ruth J. F. Loos, Fulvio Ricceri, Karin Leander, Wen H. L. Kao, Torsten Lauritzen, Qi Sun, Narisu Narisu, Stephan B. Felix, N. William Rayner, Aaron R. Folsom, Robert D. Sayers, Ross D. Blair, John F. Carlquist, Jing Hua Zhao, L. Vicky Phillips, Gabe Crawford, Anne Johnson, Chris Wallace, Paul F. O'Reilly, Jose C. Florez, Andreas Ziegler, Salvatore Panico, Neil R. Robertson, Ruth Frikke-Schmidt, Leif Groop, Pier Mannuccio Mannucci, Stanley L. Hazen, Gerjan Navis, Peter P. Pramstaller, Laura J. Scott, Niels Grarup, Klaus Berger, Christian Gieger, Stephen E. Epstein, Cornelia Huth, Stephanie Tennstedt, Morris J. Brown, Timothy A. Barnes, Naomi Hammond, Ulf de Faire, Vilmundur Gudnason, Marcus Fischer, Nita G. Forouhi, Paolo Vineis, Thomas Quertermous, Christopher Patterson, W.H. Wilson Tang, Konstantinos A. Papadakis, Lincoln Stein, Maciej Tomaszewski, Suthesh Sivapalaratnam, M. S. Sandhu, Feng Zhang, Christa Meisinger, David R. Lewis, Norman Klopp, Roza Blagieva, Gonçalo R. Abecasis, Jeffrey L. Anderson, Lu Qi, Amy J. Swift, Albert Hofman, George Dedoussis, Robert Luben, Daniel J. Rader, Thomas Münzel, Bert Bravenboer, Christopher J. O'Donnell, Elin Org, Veikko Salomaa, Philipp S. Wild, Stephen G. Ellis, Dawn M. Waterworth, Vesela Gateva, Loukianos S. Rallidis, Joseph M. Devaney, kevin Burnand, Robert Clarke, George A. Wells, Harold Snieder, Kay-Tee Khaw, Panos Deloukas, Jaakko Tuomilehto, Louise V. Wain, Eric Boerwinkle, Inke R. König, Amanda J. Bennett, Uwe Völker, Florian Ernst, Markus M. Nöthen, Thomas Sparsø, Jean Tichet, Inga Prokopenko, Paul Johnson, Jaume Marrugat, Marju Orho-Melander, Aloysius G Lieverse, Ian Thomson, Vincent Mooser, Teresa Ferreira, Man Li, Benjamin J. Wright, Ryan P. Welch, Alessandra Allione, Stefan Blankenberg, Veryan Codd, Philippe Froguel, James C. Engert, Pekka Jousilahti, Klaus Stark, Toby Johnson, Cornelia M. van Duijn, Ivo Gut, John J.P. Kastelein, Thomas M. Morgan, Noël P. Burtt, Laura J. McCulloch, Tim D. Spector, Peter S. Chines, Timo T. Valle, Peter Shrader, Christian Dina, Diana Zelenika, Monika Stoll, Peter S. Braund, Harry Campbell, Rainer Rettig, Joep A.W. Teijink, Thomas Illig, Anne Tybjærg-Hansen, Peter Vollenweider, Guangju Zhai, Frits R. Rosendaal, Pau Navarro, James B. Meigs, Ghislain Rocheleau, Li Chen, Pilar Galan, Giuseppe Matullo, Henry Völzke, Samer S. Najjar, Christina Loley, N. Charlotte Onland-Moret, Alison H. Goodall, Riyaz S. Patel, S. Matthijs Boekholdt, Pim van der Harst, John R. B. Perry, Angela Doering, James S. Pankow, Gudmundur Thorgeirsson, Xin Yuan, Patricia B. Munroe, Abbas Dehghan, Tamara B. Smith, Valeriya Lyssenko, Mark I. McCarthy, Andrew T. Hattersley, Simon Futers, Barbara Thorand, Andre G. Uitterlinden, Simon J. Griffin, Winfried März, Nilesh J. Samani, Frank B. Hu, Valeria Romanazzi, Michael N. Weedon, Zouhair Aherrahrou, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Markus Perola, Stefania Bandinelli, Kathy Stirrups, Hilma Holm, Maja Barbalić, Kiran Musunuru, David Couper, David S. Siscovick, Guillaume Charpentier, Alexandre F.R. Stewart, Patrick Diemert, Leena Peltonen, Serge Hercberg, Robert Roberts, Michael Roden, Rhian Gwilliam, Guillaume Lettre, Eric J.G. Sijbrands, Lambertus A. Kiemeney, Martha Ganser, Silvia Polidoro, Kristin G. Ardlie, Stephen G. Ball, Kristina Bengtsson Boström, Katharine R. Owen, Paul E. de Jong, Felicity Payne, Wendy L. McArdle, Frances M K Williams, Paul Elliott, Roberto Elosua, Devin Absher, Kristian Midthjell, Jan D. Blankensteijn, Nelson B. Freimer, John C. Chambers, G. Kolovou, Karl Andersen, John Webster, Nicholas J. Wareham, Eric E. Schadt, Simon Heath, Diana Rubin, Solveig Gretarsdottir, Willem H. Ouwehand, Oluf Pedersen, Liming Qu, Sandra Eifert, Mary Susan Burnett, Paul Burton, Frank M. van Bockxmeer, Eleftheria Zeggini, Stephen M. Schwartz, Simon C. Potter, Tiinamaija Tuomi, Jeffrey R. Gulcher, David Altshuler, Harald Grallert, Hooman Allayee, Kari Stefansson, Anne H. Child, Sekar Kathiresan, Torben Hansen, Unnur Thorsteinsdottir, Isaac Subirana, Serena Sanna, Muredach P. Reilly, J. Wouter Jukema, H.-Erich Wichmann, François Cambien, Pier Angelica Merlini, Wiek H. van Gilst, Caroline S. Fox, Andrew Smith, Oliviero Olivieri, S Sohrabi, James F. Wilson, Gillian W. Cockerill, Guanming Wu, Andrew D. Morris, Carlos Iribarren, Joshua W. Knowles, Angelo Scuteri, Göran Berglund, Marilyn C. Cornelis, Pascal P. McKeown, Thorsten Reffelmann, Gérard Waeber, Les McNoe, Maris Laan, Dilip K. Naik, Karen L. Mohlke, Matthew Waltham, Rachel E. Clough, Claudia Langenberg, Seamus C. Harrison, Hany Hafez, Timon W. van Haeften, Carlotta Sacerdote, Robert Sladek, Nicola Martinelli, Declan Bradley, Cristen J. Willer, Sarah E. Hunt, Sven Cichon, Udo Seedorf, Winston Hide, Arne Schillert, Cuno S.P.M. Uiterwaal, Steve E. Humphries, Andre A van Rij, Stéphane Cauchi, Michael Boehnke, Beverley M. Shields, Suzannah Bumpstead, Diane M. Becker, Ron Do, Heribert Schunkert, Jacques S. Beckmann, Alistair S. Hall, Mike Sampson, Christine Proença, Lachlan J. M. Coin, Rob M. van Dam, Mohan U. Sivananthan, Martin Farrall, B. Gerry Hill, Simonetta Guarrera, Thijs T. W. van Herpt, Sonia S. Anand, Peter M. Nilsson, Arne Pfeufer, Rafn Benediktsson, Candace Guiducci, Lee M. Kaplan, Michel Marre, Thomas Meitinger, Annette F. Baas, Graham A. Hitman, Roberto Lorbeer, Flora Peyvandi, David J. Hunter, Seraya Maouche, G. Mark Lathrop, Michael R. Erdos, Thomas W. Mühleisen, L. Adrienne Cupples, Anne E. Hughes, Ayellet V. Segrè, Igor Rudan, Kijoung Song, Reijo Laaksonen, G. Bragi Walters, Christopher P. Nelson, Christopher S. Franklin, Richard M. Watanabe, Mattijs E. Numans, Christina Willenborg, Jeanette Erdmann, Alessandra Di Gregorio, John M. C. Connell, Soumya Raychaudhuri, Jian'an Luan, Anthony J. Balmforth, Yurii S. Aulchenko, Arne Schäfer, Catherine M. Rice, Tanja Zeller, Grace Yu, Augustine Kong, Matthew M Thompson, Diego Ardissino, Oliver Hofmann, John R. Thompson, J.B. Wild, Alexander Teumer, Ulf Gyllensten, David P. Strachan, Martin D. Tobin, Michael A. Kaiser, Steve McCarroll, Beverley Balkau, Stephen J. Newhouse, Michael Preuss, John A. Spertus, Janja Nahrstaedt, Neelam Hassanali, Gunnar Sigurdsson, Jaapjan D. Snoep, Angela Döring, Todd Green, D. Julian A. Scott, Christian Herder, Bo Isomaa, Anne U. Jackson, David Hadley, Domenico Girelli, Jes S. Lindholt, Toshiko Tanaka, Ruth Topless, Bernhard O. Boehm, Jana V. van Vliet-Ostaptchouk, Anna-Liisa Hartikainen, Anneli Pouta, Anuj Goel, Stefan Schreiber, Kristian Hveem, Gabriel Crawford, Pierre Meneton, Jürgen Schrezenmeir, Andre M. van Rij, Markku Laakso, Richa Saxena, Joshua C. Bis, Samy Hadjadj, Anders Franco-Cereceda, Noha Lim, Christopher J. Groves, Klaus Strassburger, Stefan E Matthiasson, M. Lourdes Sampietro, Josée Dupuis, Morris J. Bown, Cisca Wijmenga, Shu Ye, Jennifer Freyer, Anders Hamsten, Christian Hengstenberg, Olle Melander, Sarah Edkins, Alberto Smith, Luigi Ferrucci, Murielle Bochud, Lori L. Bonnycastle, Gregory T. Jones, Manuela Uda, Lasse Folkersen, Timothy M. Frayling, Giovanni Tognoni, Torben Jørgensen, Anna F. Dominiczak, Michiel L. Bots, Mario A. Morken, Ian Buysschaert, Colin N. A. Palmer, Andrew Hill, Mark J. Caulfield, Nicolas Sylvius, Nicole Soranzo, Susana Eyheramendy, Christopher Newton-Cheh, Eran Halperin, Mandy van Hoek, Stephen A. Badger, Paul Scheet, Gudmar Thorleifsson, Themistocles L. Assimes, Inês Barroso, Sheila Bingham, Nour Eddine El Mokhtari, Yvonne T. van der Schouw, Andrew J. Lotery, Heather M. Stringham, Marcus Dörr, Per Eriksson, Mark Walker, Mette Refstrup, Anna L. Gloyn, Ann-Christine Syvänen, John F. Peden, Diether Lambrechts, Arshed A. Quyyumi, Katherine S. Elliott, Jonathan Golledge, Edward G. Lakatta, Serkalem Demissie, Lewis C. Becker, Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Paul Norman, Marjo-Riitta Järvelin, Annette Peters, David Schlessinger, Janet T. Powell, Surgery, ICaR - Ischemia and repair, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Male, VASCULAR WALL, Genome-wide association study, 030204 cardiovascular system & hematology, Bioinformatics, Aortic aneurysm, 0302 clinical medicine, Risk Factors, Odds Ratio, Genetics(clinical), Genetics (clinical), Aorta, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Homozygote, Abdominal aortic aneurysm, Organ Specificity, Data Interpretation, Statistical, CORONARY-ARTERY-DISEASE, Female, METALLOPROTEINASE, Sterol Regulatory Element Binding Protein 1, Low Density Lipoprotein Receptor-Related Protein-1, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Locus (genetics), Biology, Polymorphism, Single Nucleotide, DISSECTIONS, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genome-wide associaton, Coronary-artery-disease, Susceptibility loci, Sequence variant, Vascular wall, Metalloproteinase, Atherosclerosis, Identification, Metaanalysis, Dissections, medicine.artery, Internal medicine, Cell Line, Tumor, medicine, Genetics, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Genetic association, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Aged, IDENTIFICATION, Case-control study, Odds ratio, medicine.disease, Endocrinology, ATHEROSCLEROSIS, SEQUENCE VARIANT, Genetic Loci, Case-Control Studies, Aortic Aneurysm, Abdominal, Follow-Up Studies, Genome-Wide Association Study
Abstract: Contains fulltext : 97601.pdf (Publisher’s version ) (Closed access) Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 x 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 x 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression. 9 p.
Published: 2011

14. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Author: Fredrik Karpe, Ivonne Jarick, Julius S. Ngwa, Alan F. Wright, Robert Luben, Aaron R. Folsom, Sailaja Vedantam, Veikko Salomaa, Markku J. Savolainen, Robert Clarke, Shah Ebrahim, Thomas A. Buchanan, Mao Fu, Albert Hofman, Philippe Goyette, Camilla H. Sandholt, Fabio Macciardi, Elizabeth K. Speliotes, Barbara McKnight, Anne McCarthy, Mika Kaehoenen, Christian Gieger, Jorma S. A. Viikari, Nicholas J. Timpson, Kirsti Kvaløy, Douglas F. Levinson, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Andrew A. Hicks, Niina Pellikka, Charles C. White, Leena Peltonen, Reedik Maegi, John-Olov Jansson, Qunyuan Zhang, Claudia Lamina, Robert C. Kaplan, Peter M. Visscher, Laura J. Scott, Claes Ohlsson, Brian Thomson, Jubao Duan, Heikki V. Huikuri, Stephen O'Rahilly, Anette P. Gjesing, David P. Strachan, Caroline S. Fox, Sekar Kathiresan, Anna-Liisa Hartikainen, Johannes Kettunen, Maris Teder-Laving, Erik Ingelsson, Mario A. Morken, Peter Kovacs, Elisabeth Widen, Caroline Hayward, Eleanor Wheeler, Jing Hua Zhao, Vilmundur Gudnason, Panos Deloukas, Jacqueline C. M. Witteman, Gert-Jan B. van Ommen, Eric Boerwinkle, Martin Wabitsch, Christian Hengstenberg, Beverley Balkau, Thor Aspelund, Neelam Hassanali, Paul M. Ridker, Nicole L. Glazer, Joyce B. J. van Meurs, Michel Marre, Alan James, Ben A. Oostra, David Meyre, Ida Surakka, Stefan Schreiber, Nigel W. Rayner, Heribert Schunkert, Thomas Quertermous, Stefan Gustafsson, Peter Kraft, Benjamin F. Voight, Irene Pichler, Olle Melander, Ozren Polasek, Antti Jula, Alan R. Sanders, Andrew R. Wood, Yoav Ben-Shlomo, Thomas Illig, Jianjun Liu, Gerard Waeber, André G. Uitterlinden, Torben Hansen, Helene Alavere, André Scherag, Paolo Manunta, Johannes Hebebrand, Themistocles L. Assimes, Stefan R. Bornstein, Jaakko Tuomilehto, Morris Brown, Jianfeng Xu, Yii-Der Ida Chen, Nancy L. Heard-Costa, Cristen J. Willer, Henrik Greonberg, Guillaume Lettre, John R. Thompson, Inês Barroso, John R. B. Perry, Andreas Ziegler, James F. Wilson, Christopher J. O'Donnell, Maurizio F. Facheris, Robert Lawrence, Jan Smit, Lyle J. Palmer, Ulf Gyllensten, Richard B. Hayes, Shengxu Li, Barbara Ludwig, Larry D. Atwood, Valgerdur Steinthorsdottir, Sabine Schipf, Jouko Saramies, Tanja Boes, Martin Ridderstråle, Jennie Hui, Lina Zgaga, Susann Scherag, Alexandra I. F. Blakemore, Marjolein Peters, Timo T. Valle, Nelson B. Freimer, Kay-Tee Khaw, Amy J. Swift, Michael Stumvoll, Miriam F. Moffatt, Cecilia M. Lindgren, Ayellet V. Segrè, Neil Robertson, Richard N. Bergman, Francis S. Collins, Ryan P. Welch, Mari-Liis Tammesoo, Devin Absher, Tamara B. Harris, Kari E. North, Manuela Uda, Karen L. Mohlke, Inga Prokopenko, Per Hall, Gudmar Thorleifsson, Marjo-Riitta Järvelin, Guillaume Paré, Stefan Gaget, G. Bragi Walters, Michael N. Weedon, Jean-Claude Tardif, Mary F. Feitosa, Anke Toenjes, Ken K. Ong, Cécile Lecoeur, Paavo Zitting, David S. Siscovick, Chih-Mei Chen, Peter Almgren, Anneli Pouta, Philippe Froguel, Pekka Jousilahti, Jaakko Kaprio, Maria Teresa Sciarrone Alibrandi, Sophie van Wingerden, Steven A. McCarroll, Oluf Pedersen, Shaun Purcell, Veronique Vitart, Leena Kinnunen, Markus Perola, Jacques S. Beckmann, Vincent Vatin, Christopher J. Groves, Zoltán Kutalik, Lu Qi, Volker Hoesel, Seppo Koskinen, Suzanne Rafelt, Anke Hinney, Annette Peters, David Schlessinger, Eero Kajantie, Jian Yang, Nicholas G. Martin, Joshua W. Knowles, Kristian Midthjell, Olivier Lantieri, Dorret I. Boomsma, Harry Campbell, Ulrich John, Kirsi H. Pietilaeinen, George Davey Smith, Carl G. P. Platou, Sarah H. Wild, Patricia B. Munroe, Iris M. Heid, Diana Marek, Michael Boehnke, Andres Metspalu, Hana Lango Allen, Peter Rzehak, Christine Cavalcanti-Proença, M. Carola Zillikens, Åsa Johansson, Anuj Goel, Andrew T. Hattersley, Massimo Mangino, Michael E. Goddard, Tim D. Spector, Winfried Rief, Jonathan Tyrer, Lachlan J. M. Coin, Peter P. Pramstaller, Narisu Narisu, John Beilby, Jonathan Stephens, Christina Barlassina, Pamela Fischer-Posovszky, Brenda W.J.H. Penninx, Kaisa Silander, Richard H. Myers, Jouke-Jan Hottenga, Eric E. Schadt, Francesco P. Cappuccio, Martin den Heijer, Fernando Rivadeneira, Lindsay L. Waite, Wilmar Igl, Igor Rudan, Manjinder S. Sandhu, Debbie A Lawlor, Kristian Hveem, Susanna Wiegand, Mari Nelis, Thomas Reinehr, Elisabeth Thiering, Inke R. Koenig, Stephan B. Felix, Fredrik Wiklund, Ian N. M. Day, Willem H. Ouwehand, Peter Schwarz, Richard M. Watanabe, Keri L. Monda, Kari Stefansson, Gudny Eiriksdottir, H-Erich Wichmann, Jianxin Shi, Najaf Amin, Carlos Iribarren, Heiko Krude, Dale R. Nyholt, Lenore J. Launer, Stephen J. Chanock, Harald Grallert, Hugh Watkins, Juergen Graessler, Tsegaselassie Workalemahu, Jeanette Erdmann, Mattias Lorentzon, Leif Groop, Teresa Ferreira, Chiara Lanzani, Johanna Kuusisto, Johan G. Eriksson, Tõnu Esko, Torben Jørgensen, Robert J. Weyant, Michael Preuss, Lambertus A. Kiemeney, Daniel I. Chasman, Daniel R. Witte, Kevin B. Jacobs, Nicole Soranzo, John M. C. Connell, Soumya Raychaudhuri, Jian'an Luan, Joshua C. Randall, Joachim Heinrich, Anthony J. Balmforth, Eva Fisher, Elizabeth S. Jewell, Alice M. Arnold, Nele Friedrich, Olli T. Raitakari, Henri Wallaschofski, Jeffrey R. O'Connell, Terho Lehtimaeki, Marika Kaakinen, Heather M. Stringham, Bo Isomaa, I. Sadaf Farooqi, Anna L. Dixon, Anne U. Jackson, Mark I. McCarthy, Lori L. Bonnycastle, Aila Rissanen, Joel N. Hirschhorn, Nilesh J. Samani, Aimo Ruokonen, Frank B. Hu, L. Adrienne Cupples, Amanda J. Bennett, Shamika Ketkar, Ruth J. F. Loos, Nicholas J. Wareham, Tiinamaija Tuomi, Timothy M. Frayling, Ulla Sovio, Georg Homuth, Liming Liang, Heiner Boeing, Unnur Thorsteinsdottir, Ingrid B. Borecki, Danielle M. Greenawalt, Rosanda Mulić, Ivana Kolcic, Talin Haritunians, Mark J. Caulfield, Marja-Liisa Lokki, Tanya M. Teslovich, Paul Elliott, Matt Neville, Nilanjan Chatterjee, Albert V. Smith, Andrew P. Morris, Fabio Busonero, Gonçalo R. Abecasis, Jaana Laitinen, Michael R. Erdos, Candace Guiducci, Lee M. Kaplan, Aki S. Havulinna, Pablo V. Gejman, Alan R. Shuldiner, Serena Sanna, David J. Hunter, Sonja I. Berndt, Carla I. G. Vogel, Alistair S. Hall, Karol Estrada, Sven Bergmann, Thomas Meitinger, Gonneke Willemsen, Andrew C. Heath, Katja K.H. Aben, Markku Laakso, Juha Sinisalo, Tuomas O. Kilpelaenen, Mark E. Cooper, Heike Biebermann, Eco J. C. de Geus, Grant W. Montgomery, Sophie Visvikis-Siest, Thomas W. Winkler, Ju-Hyun Park, Alex N. Parker, Peter S. Chines, James Nemesh, Nabila Bouatia-Naji, Wendy L. McArdle, Roberto Elosua, Markku S. Nieminen, Psychiatry, NCA - Anxiety & Depression, EMGO - Mental health, Epidemiology, Internal Medicine, Clinical Genetics, Radiology & Nuclear Medicine, Erasmus MC other, Public Health, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, MAGIC, Procardis Consortium, Medical Research Council (MRC), Speliotes, Ek, Willer, Cj, Berndt, Si, Monda, Kl, Thorleifsson, G, Jackson, Au, Allen, Hl, Lindgren, Cm, Luan, J, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Qi, L, Workalemahu, T, Heid, Im, Steinthorsdottir, V, Stringham, Hm, Weedon, Mn, Wheeler, E, Wood, Ar, Ferreira, T, Weyant, Rj, Segrè, Av, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Gustafsson, S, Kilpeläinen, To, Yang, J, BOUATIA NAJI, N, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Raychaudhuri, S, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Amin, N, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, HEARD COSTA, Nl, Hoesel, V, Hottenga, Jj, Johansson, A, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Narisu, N, Perry, Jr, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Scott, Lj, Timpson, Nj, Tyrer, Jp, VAN WINGERDEN, S, Watanabe, Rm, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Prokopenko, I, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Almgren, P, Arnold, Am, Aspelund, T, Atwood, Ld, Balkau, B, Balmforth, Aj, Bennett, Aj, BEN SHLOMO, Y, Bergman, Rn, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bonnycastle, Ll, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Campbell, H, Cappuccio, Fp, CAVALCANTI PROENÇA, C, Chen, Yd, Chen, Cm, Chines, P, Clarke, R, Coin, L, Connell, J, Day, In, DEN HEIJER, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Erdos, Mr, Eriksson, Jg, Facheris, Mf, Felix, Sb, FISCHER POSOVSZKY, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gieger, C, Gjesing, Ap, Goel, A, Goyette, P, Grallert, H, Grässler, J, Greenawalt, Dm, Groves, Cj, Gudnason, V, Guiducci, C, Hartikainen, Al, Hassanali, N, Hall, A, Havulinna, A, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Hofman, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Isomaa, B, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kajantie, E, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kuusisto, J, Kraft, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Lehtimäki, T, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, Paolo, Marek, D, Marre, M, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Meitinger, T, Melander, O, Meyre, D, Midthjell, K, Montgomery, Gw, Morken, Ma, Morris, Ap, Mulic, R, Ngwa, J, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Robertson, Nr, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, M, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, D, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Swift, Aj, Tammesoo, Ml, Tardif, Jc, TEDER LAVING, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, Tuomi, T, VAN MEURS, Jb, VAN OMMEN, Gj, Vatin, V, Viikari, J, VISVIKIS SIEST, S, Vitart, V, Vogel, Ci, Voight, Bf, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, I, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, M, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, J, Boeing, H, Boerwinkle, E, Boomsma, Di, Caulfield, Mj, Chanock, Sj, Collins, F, Cupples, La, Smith, Gd, Erdmann, J, Froguel, P, Grönberg, H, Gyllensten, U, Hall, P, Hansen, T, Harris, Tb, Hattersley, At, Hayes, Rb, Heinrich, J, Hu, Fb, Hveem, K, Illig, T, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Laakso, M, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Pedersen, O, Penninx, Bw, Peters, A, Pramstaller, Pp, Quertermous, T, Reinehr, T, Rissanen, A, Rudan, I, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Tuomilehto, J, Uda, M, Uitterlinden, A, Valle, Tt, Wabitsch, M, Waeber, G, Wareham, Nj, Watkins, H, Procardis, Consortium, Wilson, Jf, Wright, Af, Zillikens, Mc, Chatterjee, N, Mccarroll, Sa, Purcell, S, Schadt, Ee, Visscher, Pm, Assimes, Tl, Borecki, Ib, Deloukas, P, Fox, C, Groop, Lc, Haritunians, T, Hunter, Dj, Kaplan, Rc, Mohlke, Kl, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, VAN DUIJN, Cm, Wichmann, He, Frayling, Tm, Thorsteinsdottir, U, Abecasis, Gr, Barroso, I, Boehnke, M, Stefansson, K, North, Ke, Mccarthy, Mi, Hirschhorn, Jn, Ingelsson, E, and Loos, Rj
Subjects: Netherlands Twin Register (NTR), Medizin, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], FTO gene, Body Mass Index, 0302 clinical medicine, SH2B1, GASTRIC-INHIBITORY POLYPEPTIDE, ADULT OBESITY, Glucose homeostasis, Body Size, GENETICS & HEREDITY, 2. Zero hunger, Genetics, Genetics & Heredity, RISK, 0303 health sciences, Neuronal growth regulator 1, Genetics of obesity, COMMON VARIANTS, Chromosome Mapping, 11 Medical And Health Sciences, Body Height/genetics, Body Size/genetics, Body Weight/genetics, European Continental Ancestry Group/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Humans, Obesity/genetics, Polymorphism, Single Nucleotide, FAT MASS, Body Height/*genetics *Body Mass Index Body Size/genetics Body Weight/*genetics *Chromosome Mapping European Continental Ancestry Group/genetics Genetic Predisposition to Disease/genetics Genome-Wide Association Study Humans Obesity/genetics Polymorphism, Single Nucleotide, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, MELANOCORTIN-4 RECEPTOR GENE, Life Sciences & Biomedicine, European Continental Ancestry Group, EARLY-ONSET, 030209 endocrinology & metabolism, Locus (genetics), Biology, Article, White People, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, body mass index, genome-wide association, meta-analysis, Genetic Predisposition to Disease, Obesity, GENOME-WIDE ASSOCIATION, FTO GENE, 030304 developmental biology, Science & Technology, genome-wide association gastric-inhibitory polypeptide melanocortin-4 receptor gene glucose-homeostasis common variants adult obesity early-onset fat mass risk metaanalysis, Body Weight, 06 Biological Sciences, MAGIC, Body Height, GLUCOSE-HOMEOSTASIS, Procardis Consortium, Body mass index, Developmental Biology
Abstract: Obesity is globaLy prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined aSociations betwEn body maS index and ĝ̂1/42.8 miLion SNPs in up to 123,865 individuals with targeted foLow up of 42 SNPs in up to 125,931 aDitional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci aSociated with body maS index (P < 5-10-8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly aSociated loci may provide new insights into human body weight regulation. © 2010 Nature America, Inc. All rights reserved.
Published: 2010

15. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Author: Unnur Thorsteinsdottir, Carl G. P. Platou, Albert Hofman, Qi Sun, Narisu Narisu, Oliver Hofmann, Jean Tichet, Lu Qi, Jose C. Florez, H-Erich Wichmann, Peter Kraft, Leif Groop, Benjamin F. Voight, Wolfgang Rathmann, Francis S. Collins, Wen H. L. Kao, André G. Uitterlinden, Torben Hansen, James F. Wilson, Guanming Wu, Valgerdur Steinthorsdottir, Robert Sladek, Cornelia M. van Duijn, James B. Meigs, Philippe Froguel, Cristen J. Willer, Andrew D. Morris, Harry Campbell, Cecilia M. Lindgren, Igor Rudan, Josée Dupuis, Richard N. Bergman, Andrew T. Hattersley, Suzannah Bumpstead, Kristian Midthjell, Richard M. Watanabe, Kristina Bengtsson Boström, Eric J.G. Sijbrands, Mike Sampson, Thomas Meitinger, Graham A. Hitman, Amanda J. Bennett, Anna L. Gloyn, Ayellet V. Segrè, Mark I. McCarthy, Simon J. Griffin, Frank B. Hu, Kari Stefansson, Soumya Raychaudhuri, G. Bragi Walters, David Altshuler, Karen L. Mohlke, Michel Marre, Harald Grallert, Yurii S. Aulchenko, Bernhard O. Boehm, Aloysius G Lieverse, Christian Gieger, Samy Hadjadj, Kristin Ardlie, Man Li, Winston Hide, Caroline S. Fox, N P Burtt, Gonçalo R. Abecasis, Katharine R. Owen, Inês Barroso, Neil R. Robertson, Beverley M. Shields, Ulf Gyllensten, Torsten Lauritzen, Gabe Crawford, Claudia Langenberg, Martha Ganser, Bo Isomaa, Anne U. Jackson, Eleftheria Zeggini, Timon W. van Haeften, Jana V. van Vliet-Ostaptchouk, Rob M. van Dam, Richa Saxena, Ghislain Rocheleau, Mandy van Hoek, Niels Grarup, Cornelia Huth, Roza Blagieva, Christian Dina, Katherine S. Elliott, Rafn Benediktsson, Candace Guiducci, Barbara Thorand, Alex S. F. Doney, Najaf Amin, Christopher J. Groves, Gudmar Thorleifsson, Todd Green, Amy J. Swift, Klaus Strassburger, Paul Johnson, Johanna Kuusisto, Mark J. Daly, Jaakko Tuomilehto, Andrew P. Morris, David J. Hunter, Thomas Sparsø, N. William Rayner, Ann-Kristin Petersen, Pau Navarro, Norman Klopp, Jacqueline C. M. Witteman, Torben Jørgensen, Mark Walker, Eric Boerwinkle, Inga Prokopenko, Teresa Ferreira, Kristian Hveem, John R. B. Perry, Peter P. Pramstaller, James S. Pankow, Valeriya Lyssenko, Cisca Wijmenga, Lori L. Bonnycastle, Michael Roden, Felicity Payne, Timothy M. Frayling, Nicholas J. Wareham, Tiinamaija Tuomi, Heather M. Stringham, Mario A. Morken, Colin N. A. Palmer, Laura J. Scott, Thomas Illig, Guillaume Charpentier, Christian Herder, Lincoln Stein, Michael N. Weedon, Markku Laakso, Michael R. Erdos, Beverley Balkau, Augustine Kong, Neelam Hassanali, Steve McCarroll, Stéphane Cauchi, Michael Boehnke, David Couper, Peter M. Nilsson, Christopher S. Franklin, Marilyn C. Cornelis, Peter Shrader, Laura J. McCulloch, Oluf Pedersen, Peter S. Chines, Christine Proença, Thijs T. W. van Herpt, Amanda F. Elliott, Gunnar Sigurdsson, Bert Bravenboer, Ryan P. Welch, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Epidemiology, Internal Medicine, Dermatology, Erasmus MC other, and Ophthalmology
Subjects: Blood Glucose, QT INTERVAL DURATION, COMPLEX DISEASES, endocrine system diseases, Gene Dosage, Locus (genetics), KLF14, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Article, HNF1-ALPHA GENE, 03 medical and health sciences, Genetic Heterogeneity, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, genome wide association study, glucose, diabetes type 2, Genetics, medicine, Humans, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-alpha, GENOME-WIDE ASSOCIATION, CDKAL1, 030304 developmental biology, Genetic association, GENE-EXPRESSION, 0303 health sciences, INSULIN-RESISTANCE, Genetic heterogeneity, Genome, Human, Gene Expression Profiling, COMMON VARIANTS, nutritional and metabolic diseases, Fasting, medicine.disease, C-REACTIVE PROTEIN, CROHNS-DISEASE, HNF1A, FASTING PLASMA-GLUCOSE, Diabetes Mellitus, Type 2, KCNQ1 Potassium Channel, Dual-Specificity Phosphatases, Mitogen-Activated Protein Kinase Phosphatases, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. © 2010 Nature America, Inc. All rights reserved.
Published: 2010

16. LocusZoom: regional visualization of genome-wide association scan results

Author: Gonçalo R. Abecasis, Cristen J. Willer, Serena Sanna, Michael Boehnke, Tanya M. Teslovich, Randall Pruim, Ryan P. Welch, Terry P. Gliedt, and Peter S. Chines
Subjects: Statistics and Probability, Linkage disequilibrium, Genome-wide association study, Computational biology, Biology, Biochemistry, Genome, Genome Wide Association Scan, 03 medical and health sciences, 0302 clinical medicine, Computer Graphics, Humans, Molecular Biology, 030304 developmental biology, Genetic association, Genetics, Internet, 0303 health sciences, Extramural, Genome Analysis, Computer Science Applications, Visualization, Applications Note, Computational Mathematics, Computational Theory and Mathematics, Software, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Summary: Genome-wide association studies (GWAS) have revealed hundreds of loci associated with common human genetic diseases and traits. We have developed a web-based plotting tool that provides fast visual display of GWAS results in a publication-ready format. LocusZoom visually displays regional information such as the strength and extent of the association signal relative to genomic position, local linkage disequilibrium (LD) and recombination patterns and the positions of genes in the region. Availability: LocusZoom can be accessed from a web interface at http://csg.sph.umich.edu/locuszoom. Users may generate a single plot using a web form, or many plots using batch mode. The software utilizes LD information from HapMap Phase II (CEU, YRI and JPT+CHB) or 1000 Genomes (CEU) and gene information from the UCSC browser, and will accept SNP identifiers in dbSNP or 1000 Genomes format. Single plots are generated in ∼20 s. Source code and associated databases are available for download and local installation, and full documentation is available online. Contact: cristen@umich.edu
Published: 2010

17. Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Author: Seppo Koskinen, Christian Herder, Daniel I. Chasman, Andrew R. Wood, Jonna L. Grimsby, J.F. Wilson, Day Inm., Massimo Mangino, Gonneke Willemsen, Robert W. Mahley, Cristian Pattaro, Nicole L. Glazer, T.B. Harris, Irene Pichler, M S Sandhu, D. van Heemst, Christine Proença, Martha Ganser, Robert A. Hegele, Richa Saxena, Eleftheria Zeggini, Markku Laakso, Peter Kraft, Judith B. Borja, Karen L. Mohlke, J B Richards, de Geus Ejc., Robert Sladek, Cristen J. Willer, Samy Hadjadj, S.M. Boekholdt, Gina M. Peloso, Kijoung Song, Sutapa Mukherjee, Gudmar Thorleifsson, Winston Hide, Mark I. McCarthy, Ruth E. Pakyz, Marian Beekman, Ayellet V. Segrè, Inga Prokopenko, Ping An, George Dedoussis, Danielle Posthuma, Jeanette Erdmann, Simon J. Griffin, Nilesh J. Samani, Inke R. König, Frank B. Hu, Lokki M-L., David M. Evans, Xiaohui Li, Valgerdur Steinthorsdottir, Aimo Ruokonen, A Pouta, Kerrin S. Small, Cecilia M. Lindgren, O Le Bacquer, Xijing Han, Florian Kronenberg, E Katsareli, Christian Dina, S. Gabriel, Jochen Spranger, James S. Pankow, M. Kloppenburg, Penninx Bwjh., Torben Hansen, Josh Smith, Jennie Hui, Gordon H. Williams, Mark Seielstad, Ingrid B. Borecki, Weihua Zhang, Peter P. Pramstaller, Stephen J. Sharp, Neil R. Robertson, Zee Ryl., Mike Sampson, Angela Silveira, C.M. van Duijn, Anders Hamsten, Peter Shrader, Denis Rybin, Chen Y-Di., Gunnar Sigurdsson, Michael Stumvoll, Russel Tracy, Mark O. Goodarzi, Göran Hallmans, Michael R. Erdos, Valeriya Lyssenko, Juha Saharinen, Sven Bergmann, Jeffrey R. O'Connell, Debbie A Lawlor, Thomas Meitinger, Yvonne Böttcher, Jérôme Delplanque, Sarah G. Buxbaum, Silvia Naitza, Shah Ebrahim, Graham A. Hitman, Angelo Scuteri, Aroon D. Hingorani, Heribert Schunkert, François Pattou, Claudia Lamina, A L Elliott, Sekar Kathiresan, Dawn M. Waterworth, Jennifer A. Brody, Thomas Quertermous, Leena Peltonen, Josephine M. Egan, Daniel J. Rader, J F Peden, Yarnell Jwg., Daniel S. Pearson, Pfeiffer Afh., P S Chines, N Vogelzangs, Susan Redline, Alka M. Kanaya, T B Harris, J. V. van Vliet-Ostaptchouk, Ghislain Rocheleau, Rune R. Frants, Olga D. Carlson, James G. Wilson, Melissa Garcia, Ong Rt-H., Mark J. Caulfield, Tanya M. Teslovich, Loo B-M., Beatrice Knight, Andreas Ziegler, Claudia Langenberg, Yoon Shin Cho, Paul M. Ridker, Mark J. Rieder, Praveen Sethupathy, Bert Bravenboer, J. Viikari, Matt Neville, Ioannis M. Stylianou, Andrew Walley, Jarvelin M-R., Jarred B. McAteer, Ronald M. Krauss, Augustine Kong, Oluf Pedersen, Mark J. Daly, Andrew P. Morris, Anna F. Dominiczak, Stéphane Cauchi, Michael Boehnke, Christopher J. O'Donnell, Barbara Thorand, Peter M. Nilsson, Aaron Isaacs, Deborah A. Nickerson, Roza Blagieva, Mary F. Feitosa, Nicholas J. Wareham, Robert Roberts, J S Kooner, K W van Dijk, Tiinamaija Tuomi, Paul Scheet, Lynda M. Rose, Albert V. Smith, Rafn Benediktsson, Chiara Sabatti, Candace Guiducci, Lee M. Kaplan, Aki S. Havulinna, Toby Johnson, Samuli Ripatti, Erik Ingelsson, Mario A. Morken, Carl G. P. Platou, Anke Tönjes, Qi Sun, Narisu Narisu, S J Bumpstead, Jose M. Ordovas, Alan B. Feranil, L Groop, P Chines, Sara M. Willems, Perry Jrb., Matthew A. Allison, Jan Scott, Cécile Lecoeur, Kastelein Jjp., Herman A. Taylor, Anyuan Cao, Christopher J. Groves, Lincoln D. Stein, Laura J. Scott, John Beilby, Kristin G. Ardlie, Christopher S. Franklin, Yoav Ben-Shlomo, B M Shields, N J Timpson, Marco Orrù, Amélie Bonnefond, Kiran Musunuru, Murielle Bochud, Udo Seedorf, Yongmei Liu, Guillaume Lettre, Lee J-Y., Alan R. Shuldiner, Ryan P. Welch, David J. Hunter, John Whitfield, Klaus Strassburger, Khaw K-T., Hartikainen A-L., Gunnar Sigurðsson, Lu Qi, Richard N. Bergman, G M Lathrop, Sigrid W. Fouchier, T van Herpt, David S. Siscovick, Igor Rudan, Richard M. Watanabe, Themistocles L. Assimes, Nicholas G. Martin, Ozren Polasek, Dhiraj Varma, K Kim, Oliver Hofmann, Nicholas D. Hastie, S Bumpstead, Jose C. Florez, Fernando Rivadeneira, Katharine R. Owen, Braxton D. Mitchell, Alisa K. Manning, Abbas Dehghan, Bruce Bartholow Duncan, Cisca Wijmenga, Timo T. Valle, Jaakko Kaprio, Mika Kivimäki, B Shields, Laila Simpson, Tim D. Spector, Paul W. Franks, Guangju Zhai, María Teresa Martínez-Larrad, Janssens Acjw., Kim L. Ward, Inês Barroso, Xiuqing Guo, Rosa Maria Roccasecca, Zari Dastani, Reijo Laaksonen, Wilmar Igl, Vincent Mooser, Niels Grarup, Cornelia Huth, Christian Gieger, Fabio Marroni, Jaakko Tuomilehto, Doney Asf., Andrew C. Edmondson, Christian Fuchsberger, Meena Kumari, David M. Nathan, Reedik Mägi, Solomon K. Musani, U de Faire, Knut Borch-Johnsen, Masahiro Koseki, Giuseppe Paolisso, Norman Klopp, Caroline S. Fox, Nelson B. Freimer, Mika Kähönen, Peter Henneman, Diana Zelenika, K Willems-Vandijk, Steven A. McCarroll, Paul Elliott, Wichmann H-E., J. C. Bis, Nita G. Forouhi, Antti Jula, Witteman Jcm., Fredrik Karpe, Joseph Hung, Antje Fischer-Rosinsky, Eric J. Brunner, Elena Gonzalez, Soumya Raychaudhuri, Jian'an Luan, Josée Dupuis, Joshua C. Randall, Taesung Park, Francis S. Collins, Lori L. Bonnycastle, Andrew A. Hicks, Peter Kovacs, Thomas Illig, Maja Barbalić, David Couper, Jaspal S. Kooner, Damien C. Croteau-Chonka, Gavin Lucas, P J Wagner, Young-Jin Kim, Yurii S. Aulchenko, Aurelian Bidulescu, Ingrid Meulenbelt, Pilar Galan, Iris M. Heid, Michael N. Weedon, Serena Sanna, Sarah H. Wild, Hivert M-F., Patricia B. Munroe, Johan G. Eriksson, Teresa Ferreira, Robert A. Scott, A. Sandbaek, Kenneth Rice, Veronique Vitart, Xin Yuan, Leslie A. Lange, Hilma Holm, Jorge R. Kizer, Timothy M. Frayling, Marika Kaakinen, Liu C-T., Petersen A-K., Peter Schwarz, G B Walters, Palmer Cna., Jean Tichet, Bernhard Paulweber, Ying Wu, Alyson Hall, Christopher T. Johansen, David Masson, Martin Ladouceur, Christie M. Ballantyne, Tai E-S., Robert Luben, Guillaume Charpentier, Angela Döring, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Mark Walker, Markus Perola, M. A. Province, Veikko Salomaa, James B. Meigs, George Davey Smith, Robert Clarke, Gerard Waeber, Stefania Bandinelli, Sally L. Ricketts, Kaisa Silander, Loos Rjf., Amanda J. Bennett, John C. Chambers, Marilyn C. Cornelis, L A Cupples, Andrew T. Hattersley, M Sandhu, Marju Orho-Melander, C M van Duijn, Olli T. Raitakari, David Meyre, Ida Surakka, Jouke-Jan Hottenga, Uh H-W., Kari Stefansson, David Melzer, P E Slagboom, Kristian Midthjell, Robert K. Semple, James P. Pirruccello, Aloysius G Lieverse, Åsa Johansson, Michael Roden, Felicity Payne, Eric J.G. Sijbrands, N P Burtt, David R. Hillman, Michael Marmot, Todd Green, Eric E. Schadt, Sijbrands Ejg., Tien Yin Wong, Coin Ljm., K B Boström, Olov Rolandsson, A D Morris, David Altshuler, Harald Grallert, L C Groop, Alan F. Wright, Karen Kapur, Xueling Sim, Philippe Froguel, K O Kyvik, T. Lauritzen, Linda S. Adair, Yavuz Ariyurek, Talin Haritunians, Toshiko Tanaka, Albert Hofman, MariaGrazia Franzosi, Nicholas L. Smith, Laura Crisponi, Andrew B. Singleton, A Uitterlinden, Bo Isomaa, Y A Kesaniemi, Anne U. Jackson, Christa Meisinger, Holly E. Syddall, Dorret I. Boomsma, Harry Campbell, Gonçalo R. Abecasis, Lyudmyla Kedenko, Christine Cavalcanti-Proença, G Crawford, Scott M. Grundy, Johnson Prv., Nuotio M-L., I Chen, J.H. Smit, Anuj Goel, M Li, David P. Strachan, Kenechi Ejebe, Beverley Balkau, Neelam Hassanali, Kristian Hveem, Pierre Meneton, R. Gwilliam, A J Swift, Caroline Hayward, J. Graessler, Carina Zabena, B. St Pourcain, Michel Marre, Margot Haun, Lyytikäinen L-P., Ben A. Oostra, Stefan Coassin, M. van Hoek, Nigel W. Rayner, John R. Thompson, Kurt Lohman, Ulla Sovio, Unnur Thorsteinsdottir, Naveed Sattar, Lyle J. Palmer, Ulf Gyllensten, A Elliott, Muredach P. Reilly, A Swift, Luigi Ferrucci, Syvänen A-C., Simon C. Potter, T.W. van Haeften, G Wu, Stefan Böhringer, Grant W. Montgomery, Edward G. Lakatta, Serkalem Demissie, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Lars Lind, Stefan R. Bornstein, Laura J. Rasmussen-Torvik, Terho Lehtimäki, Guillaume Paré, Sophie Visvikis-Siest, S C Heath, David Schlessinger, Juha Sinisalo, Kao Whl., Mark E. Cooper, Kati Kristiansson, Thomas W. Winkler, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Alex N. Parker, Nabila Bouatia-Naji, Markku S. Nieminen, Peter Vollenweider, Wendy L. McArdle, G K Hovingh, Thomas A. Buchanan, Avan Aihie Sayer, M C Zillikens, Jing Hua Zhao, Naomi Hammond, Vilmundur Gudnason, Björn Zethelius, Panos Deloukas, Jacqueline C. M. Witteman, Eric Boerwinkle, Manuel Serrano-Ríos, Anna L. Gloyn, Katherine S. Elliott, A C Fedson, Torben Jørgensen, Nicole Soranzo, Heather M. Stringham, Bruce M. Psaty, A G Uitterlinden, Stavroula Kanoni, Christian Hengstenberg, Yun Li, Olle Melander, Alan R. Tall, Manuela Uda, Magnusson Pke., Christopher W. Kuzawa, V Mooser, R. M. van Dam, Jerome I. Rotter, Greenwood Cmt., Cyrus Cooper, Pau Navarro, Min Jin Go, Nancy L. Pedersen, Serge Hercberg, Bernhard O. Boehm, Eleanor Wheeler, Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Genetics, Dastani, Z, Hivert, Mf, Timpson, N, Perry, Jr, Yuan, X, Scott, Ra, Henneman, P, Heid, Im, Kizer, Jr, Lyytikäinen, Lp, Fuchsberger, C, Tanaka, T, Morris, Ap, Small, K, Isaacs, A, Beekman, M, Coassin, S, Lohman, K, Qi, L, Kanoni, S, Pankow, J, Uh, Hw, Wu, Y, Bidulescu, A, Rasmussen Torvik, Lj, Greenwood, Cm, Ladouceur, M, Grimsby, J, Manning, Ak, Liu, Ct, Kooner, J, Mooser, Ve, Vollenweider, P, Kapur, Ka, Chambers, J, Wareham, Nj, Langenberg, C, Frants, R, Willems Vandijk, K, Oostra, Ba, Willems, Sm, Lamina, C, Winkler, Tw, Psaty, Bm, Tracy, Rp, Brody, J, Chen, I, Viikari, J, Kähönen, M, Pramstaller, Pp, Evans, Dm, St Pourcain, B, Sattar, N, Wood, Ar, Bandinelli, S, Carlson, Od, Egan, Jm, Böhringer, S, van Heemst, D, Kedenko, L, Kristiansson, K, Nuotio, Ml, Loo, Bm, Harris, T, Garcia, M, Kanaya, A, Haun, M, Klopp, N, Wichmann, He, Deloukas, P, Katsareli, E, Couper, Dj, Duncan, Bb, Kloppenburg, M, Adair, L, Borja, Jb, DIAGRAM+, Consortium, Magic, Consortium, Glgc, Investigator, Muther, Consortium, Wilson, Jg, Musani, S, Guo, X, Johnson, T, Semple, R, Teslovich, Tm, Allison, Ma, Redline, S, Buxbaum, Sg, Mohlke, Kl, Meulenbelt, I, Ballantyne, Cm, Dedoussis, Gv, Hu, Fb, Liu, Y, Paulweber, B, Spector, Td, Slagboom, Pe, Ferrucci, L, Jula, A, Perola, M, Raitakari, O, Florez, Jc, Salomaa, V, Eriksson, Jg, Frayling, Tm, Hicks, Aa, Lehtimäki, T, Smith, Gd, Siscovick, D, Kronenberg, F, van Duijn, C, Loos, Rj, Waterworth, Dm, Meigs, Jb, Dupuis, J, Richards, Jb, Voight, Bf, Scott, Lj, Steinthorsdottir, V, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Morris, Ad, Palmer, Cn, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Pedersen, O, Barroso, I, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Elliott, P, Rybin, D, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Lajunen, T, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sigurðsson, G, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Diagram, Consortium, Giant, Consortium, Global B., Pgen Consortium, Borecki, Ib, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Serrano Ríos, M, Lind, L, Palmer, Lj, Hu FB, 1st, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Procardis, Consortium, Buchanan, Ta, Valle, Tt, Rotter, Ji, Penninx, Bw, Boomsma, Di, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Peltonen, L, Mooser, V, Magic, Investigator, Glgc, Consortium, Musunuru, K, Smith, Av, Edmondson, Ac, Stylianou, Im, Koseki, M, Pirruccello, Jp, Chasman, Di, Johansen, Ct, Fouchier, Sw, Peloso, Gm, Barbalic, M, Ricketts, Sl, Bis, Jc, Feitosa, Mf, Orho Melander, M, Melander, O, Li, X, Cho, Y, Go, Mj, Kim, Yj, Lee, Jy, Park, T, Kim, K, Sim, X, Ong, Rt, Croteau Chonka, Dc, Lange, La, Smith, Jd, Ziegler, A, Zhang, W, Zee, Ry, Whitfield, Jb, Thompson, Jr, Surakka, I, Smit, Jh, Sinisalo, J, Scott, J, Saharinen, J, Sabatti, C, Rose, Lm, Roberts, R, Rieder, M, Parker, An, Pare, G, O'Donnell, Cj, Nieminen, M, Nickerson, Da, Montgomery, Gw, Mcardle, W, Masson, D, Martin, Ng, Marroni, F, Lucas, G, Luben, R, Lokki, Ml, Lettre, G, Launer, Lj, Lakatta, Eg, Laaksonen, R, König, Ir, Khaw, Kt, Kaplan, Lm, Johansson, Å, Janssens, Ac, Igl, W, Hovingh, Gk, Hengstenberg, C, Havulinna, A, Hastie, Nd, Harris, Tb, Haritunians, T, Hall, A, Groop, Lc, Gonzalez, E, Freimer, Nb, Erdmann, J, Ejebe, Kg, Döring, A, Dominiczak, Af, Demissie, S, de Faire, U, Caulfield, Mj, Boekholdt, Sm, Assimes, Tl, Quertermous, T, Seielstad, M, Wong, Ty, Tai, E, Feranil, Ab, Kuzawa, Cw, Taylor HA, Jr, Gabriel, Sb, Holm, H, Gudnason, V, Krauss, Rm, Ordovas, Jm, Munroe, Pb, Tall, Ar, Hegele, Ra, Kastelein, Jj, Schadt, Ee, Strachan, Dp, Reilly, Mp, Samani, Nj, Schunkert, H, Cupples, La, Ridker, Pm, Rader, Dj, Kathiresan, S., Medical Research Council (MRC), Perry, John [0000-0001-6483-3771], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Semple, Robert [0000-0001-6539-3069], Griffin, Simon [0000-0002-2157-4797], Barroso, Ines [0000-0001-5800-4520], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Zhao, Jing Hua [0000-0003-4930-3582], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Sandhu, Manjinder [0000-0002-2725-142X], Apollo - University of Cambridge Repository, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Other departments, Experimental Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Lääketieteen yksikkö - School of Medicine, University of Tampere, Institute for Molecular Medicine Finland, Hjelt Institute (-2014), Clinicum, Department of General Practice and Primary Health Care, Department of Public Health, Haartman Institute (-2014), Transplantation Laboratory, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., and O'Leary, DH.
Subjects: Netherlands Twin Register (NTR), Male, Insulin Resistance/genetics, VARIANTS, 0302 clinical medicine, POPULATION, African Americans, blood/genetics, 0303 health sciences, education.field_of_study, Adiponectin/blood, Adiponectin/genetics, Asian Continental Ancestry Group, Cholesterol, HDL/genetics, Diabetes Mellitus, Type 2/genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Global B Pgen Consortium, MAGIC investigators, 3. Good health, Cholesterol, Medicine, Adiponectin, Type 2, medicine.medical_specialty, HDL, Biolääketieteet - Biomedicine, Single-nucleotide polymorphism, DIAGRAM Consortium, White People, Molecular Genetics, GLGC Consortium, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, GIANT Consortium, Diabetes Mellitus, Genetics, DIAGRAM+ Consortium, GENOME-WIDE ASSOCIATION, Polymorphism, education, Biology, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Science & Technology, GLGC Investigators, nutritional and metabolic diseases, ta3121, medicine.disease, Obesity, Black or African American, blood/genetics, African Americans, Asian Continental Ancestry Group, Cholesterol, genetics, Diabetes Mellitus, genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, genetics, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Endocrinology, Diabetes Mellitus, Type 2, Developmental Biology, Type 2/genetics, Cancer Research, Type 2 diabetes, QH426-470, 030204 cardiovascular system & hematology, LIPID CONCENTRATIONS, GENETICS & HEREDITY, Genetics (clinical), RISK, 2. Zero hunger, INSULIN-RESISTANCE, Glucose tolerance test, medicine.diagnostic_test, MAGIC Consortium, Single Nucleotide, ADIPOSE-TISSUE, CORONARY-ARTERY-DISEASE, Life Sciences & Biomedicine, Research Article, Clinical Research Design, GENETIC-BASIS, Population, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, ddc:610, 030304 developmental biology, RECEPTOR, Cholesterol, HDL, Human Genetics, HDL/genetics, 3121 General medicine, internal medicine and other clinical medicine, MuTHER Consortium, 3111 Biomedicine, Procardis Consortium, Insulin Resistance
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p, Author Summary Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.
Published: 2012

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17 results on '"Ryan P Welch"'

1. Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits

2. Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences

3. ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition

4. LocusZoom.js: interactive and embeddable visualization of genetic association study results

5. Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle

6. Genetic discovery and translational decision support from exome sequencing of 20,791 type 2 diabetes cases and 24,440 controls from five ancestries

7. Imputation aware tag SNP selection to improve power for multi-ethnic association studies

8. Interactions between genetic variation and cellular environment in skeletal muscle gene expression

9. Global Epigenomic Analysis of Primary Human Pancreatic Islets Provides Insights into Type 2 Diabetes Susceptibility Loci

10. Broad-Enrich: functional interpretation of large sets of broad genomic regions

11. Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms

12. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

13. Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

14. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

15. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

16. LocusZoom: regional visualization of genome-wide association scan results

17. Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

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