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36 results on '"Ayellet V Segrè"'

1. Deep Learning of the Retina Enables Phenome- and Genome-Wide Analyses of the Microvasculature

Author

Sarah Urbut, Ron A. Adelman, Pradeep Natarajan, Tobias Elze, Seyedeh M. Zekavat, Janey L. Wiggs, Declan P. O'Regan, Vineet K. Raghu, Mark Trinder, Yixuan Ye, Hongyu Zhao, Zhi Yu, Michael C. Honigberg, Ayellet V. Segrè, Sara Haidermota, Nazlee Zebardast, James F. Martone, Jay C. Wang, Akhil Pampana, Patrick T. Ellinor, Satoshi Koyama, Lucian V. Del Priore, Imperial College Healthcare NHS Trust- BRC Funding, and British Heart Foundation

Subjects
Male, retina, microvessels, Phenome, Fundus (eye), Genome, 1117 Public Health and Health Services, chemistry.chemical_compound, Original Research Articles, Physiology (medical), medicine, Humans, 1102 Cardiorespiratory Medicine and Haematology, Retina, business.industry, deep learning, 1103 Clinical Sciences, Retinal, Genomics, Mendelian Randomization Analysis, Middle Aged, medicine.anatomical_structure, Cardiovascular System & Hematology, chemistry, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, epidemiology, Cardiology and Cardiovascular Medicine, business, Neuroscience, Genome-Wide Association Study
Abstract

Supplemental Digital Content is available in the text., Background: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health and tumorigenesis. The retinal fundus is a window for human in vivo noninvasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. Methods: We used 97 895 retinal fundus images from 54 813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated vascular density and fractal dimension as a measure of vascular branching complexity. We associated these indices with 1866 incident International Classification of Diseases–based conditions (median 10-year follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. Results: Low retinal vascular fractal dimension and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular fractal dimension and density identified 7 and 13 novel loci, respectively, that were enriched for pathways linked to angiogenesis (eg, vascular endothelial growth factor, platelet-derived growth factor receptor, angiopoietin, and WNT signaling pathways) and inflammation (eg, interleukin, cytokine signaling). Conclusions: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights into genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health record, biomarker, and genetic data to inform risk prediction and risk modification.

Published
2022

2. Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy

Author

Jie Jin Wang, Robert P. Igo, Barry I. Freedman, Jerome I. Rotter, Kathyrn P. Burdon, Alan D. Penman, Albert V. Smith, Xiaohui Li, Jamie E. Craig, Paul Mitchell, Brian L. Yaspan, Mary Frances Cotch, John M. Rouhana, Ayellet V. Segrè, Barbara E.K. Klein, Ashley Li, Richard A. Jensen, Gayatri Susarla, Lynn K. Stanwyck, Sudha K. Iyengar, Maggie C.Y. Ng, Ching J. Chen, Kent D. Taylor, Donald W. Bowden, Lucia Sobrin, Tien Yin Wong, Emily Y. Chew, Sharon G. Adler, Samuela Pollack, and Jane Z. Kuo

Subjects
Lipid catabolic process, Clinical Sciences, Genome-wide association study, Type 2 diabetes, Biology, Ophthalmology & Optometry, Polymorphism, Single Nucleotide, Article, Opthalmology and Optometry, Risk Factors, Diabetes Mellitus, Genetics, medicine, 2.1 Biological and endogenous factors, Humans, Interferon gamma, Polymorphism, Aetiology, Eye Disease and Disorders of Vision, Gene, Metabolic and endocrine, Lipid Transport, Diabetic Retinopathy, Catabolism, Diabetes, Human Genome, Single Nucleotide, medicine.disease, Ophthalmology, Diabetes Mellitus, Type 2, Public Health and Health Services, Lipid digestion, Type 2, Biotechnology, Genome-Wide Association Study, medicine.drug
Abstract

To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses.MethodsWe analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Americans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in 4 pathway and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was

Published
2022

3. Interaction of background genetic risk, psychotropic medications, and primary angle closure glaucoma in the UK Biobank

Author

Sayuri Sekimitsu, Jiali Wang, Tobias Elze, Ayellet V. Segrè, Janey L. Wiggs, and Nazlee Zebardast

Subjects
Psychotropic Drugs, Multidisciplinary, Risk Factors, Humans, Prospective Studies, Glaucoma, Angle-Closure, United Kingdom, Biological Specimen Banks, Genome-Wide Association Study
Abstract

Background/Aims Psychotropic medications have been reported as a risk factor for angle closure disease. However, the interaction between background genetic risk for primary angle closure glaucoma (PACG) and susceptibility to angle closure disease among psychotropic medication users has not been investigated. Here we demonstrate the utility of a genome-wide polygenic risk score (PRS) in identifying and risk-stratifying subjects with PACG and investigate the association between PACG genetic burden and exposure to psychotropic medications on prevalent angle closure. Methods This analysis used the UK Biobank dataset, a prospective cohort study of 502,506 UK residents. We constructed a PACG PRS for participants using genome-wide association study summary statistics from a multiethnic meta-analysis using the Lassosum method. Results Among the 441,054 participants, 959 (0.22%) were identified as PACG cases. Individuals with PACG had higher PRS compared to those without PACG (0.24±1.03 SD vs. 0.00±1.00 SD, p Conclusion We demonstrate the utility of a PRS for identifying individuals at higher risk of PACG. Additionally, we demonstrate an important relationship where the association between psychotropic medications use and PACG diagnosis varies across the polygenic risk spectrum.

Published
2022

4. The impact of sex on gene expression across human tissues

Author

Tuuli Lappalainen, Andrew D. Skol, Valentin Wucher, Ekaterina A. Khramtsova, Diego Garrido-Martín, Stephane E. Castel, Stephen B. Montgomery, Emmanouil T. Dermitzakis, Anthony Payne, Barbara E. Stranger, José Manuel Soria, Ferran Reverter, Hae Kyung Im, Daniel J. Cotter, Rodrigo Bonazzola, Brunilda Balliu, Brandon L. Pierce, Eric R. Gamazon, Alexis Battle, Pejman Mohammadi, Andrew R Hamel, Roderic Guigó, Ariel D. H. Gewirtz, Manuel Muñoz-Aguirre, Kristin G. Ardlie, Patrick Evans, Alvaro N. Barbeira, Yuxin Zou, Andrew A. Brown, Silva Kasela, Matthew Stephens, Barbara E. Engelhardt, Sarah Kim-Hellmuth, Angel Martinez-Perez, Ana Viñuela, Meritxell Oliva, Eleazar Eskin, Ayellet V. Segrè, Princy Parsana, and François Aguet

Subjects
Male, Single sex, Quantitative Trait Loci, Gene Expression, Genome-wide association study, Quantitative trait locus, Biology, Genoma humà, Article, Epigenesis, Genetic, Transcriptome, Cellular origin, Sex Factors, Gene expression, Genetic variation, Humans, Disease, Precision Medicine, Promoter Regions, Genetic, Gene, Genetics, Regulation of gene expression, Chromosomes, Human, X, Sex Characteristics, Multidisciplinary, Human genome, Cromosomes sexuals, Genetic Variation, Sex chromosomes, Phenotype, Expressió gènica, Gene Expression Regulation, Organ Specificity, Expression quantitative trait loci, Female, Genome-Wide Association Study
Abstract

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation. INTRODUCTION: Many complex human pheno-types, including diseases, exhibit sex-differentiated characteristics. These sex differences have been variously attributed to hormones, sex chromosomes, genotype × sex effects, differences in behavior, and differences in environmental exposures; however, their mechanisms and underlying biology remain largely unknown. The Genotype-Tissue Expression (GTEx) project provides an opportunity to investigate the prevalence and genetic mechanisms of sex differences in the human transcriptome by surveying many tissues that have not previously been characterized in this manner. RATIONALE: To characterize sex differences in the human transcriptome and its regulation, and to discover how sex and genetics interact to influence complex traits and disease, we generated a catalog of sex differences in gene expression and its genetic regulation across 44 human tissue sources surveyed by the GTEx project (v8 data release), analyzing 16,245 RNA-sequencing samples and genotypes of 838 adult individuals. We report sex differences in gene expression levels, tissue cell type composition, and cis expression quantitative trait loci (cis-eQTLs). To assess their impact, we integrated these results with gene function, transcription factor binding annotation, and genome-wide association study (GWAS) summary statistics of 87 GWASs. RESULTS: Sex effects on gene expression are ubiquitous (13,294 sex-biased genes across all tissues). However, these effects are small and largely tissue-specific. Genes with sex-differentiated expression are not primarily driven by tissue-specific gene expression and are involved in a diverse set of biological functions, such as drug and hormone response, embryonic development and tissue morphogenesis, fertilization, sexual reproduction and spermatogenesis, fat metabolism, cancer, and immune response. Whereas X-linked genes with higher expression in females suggest candidates for escape from X-chromosome inactivation, sex-biased expression of autosomal genes suggests hormone-related transcription factor regulation and a role for additional transcription factors, as well as sex-differentiated distribution of epigenetic marks, particularly histone H3 Lys(27) trimethylation (H3K27me3). Sex differences in the genetic regulation of gene expression are much less common (369 sex-biased eQTLs across all tissues) and are highly tissue-specific. We identified 58 gene-trait associations driven by genetic regulation of gene expression in a single sex. These include loci where sex-differentiated cell type abundances mediate genotype-phenotype associations, as well as loci where sex may play a more direct role in the underlying molecular mechanism of the association. For example, we identified a female-specific eQTL in liver for the hexokinase HKDC1 that influences glucose metabolism in pregnant females, which is subsequently reflected in the birth weight of the offspring. CONCLUSION: By integrating sex-aware analyses of GTEx data with gene function and transcription factor binding annotations, we describe tissue-specific and tissue-shared drivers and mechanisms contributing to sex differences in the human transcriptome and eQTLs. We discovered multiple sex-differentiated genetic effects on gene expression that colocalize with complex trait genetic associations, thereby facilitating the mechanistic interpretation of GWAS signals. Because the causative tissue is unknown for many phenotypes, analysis of the diverse GTEx tissue collection can serve as a powerful resource for investigations into the basis of sex-biased traits. This work provides an extensive characterization of sex differences in the human transcriptome and its genetic regulation. ■

Published
2020

5. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author

Eric Jorgenson, Mark James Simcoe, Alex W. Hewitt, Omar A. Mahroo, Anthony P Khawaja, Pirro G. Hysi, Paul J. Foster, Virginie J. M. Verhoeven, UK Eye, Jie Yin, David A. Mackey, Ayellet V. Segrè, Christopher J Hammond, Milly S. Tedja, Peng T. Khaw, Richard A. Stone, Jugnoo S Rahi, Hélène Choquet, Jeremy A. Guggenheim, Karina Patasova, Phillippa M. Cumberland, Khanh K. Thai, Caroline C W Klaver, Ronald B. Melles, Robert Wojciechowski, Nicholas J. Wareham, Myopia, Veronique Vitart, Stuart MacGregor, Ophthalmology, Epidemiology, and Clinical Genetics

Subjects
Adult, Male, Refractive error, genetic structures, Genome-wide association study, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, White People, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Myopia, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Aged, 030304 developmental biology, Genetic association, 0303 health sciences, Genetic heterogeneity, Middle Aged, Heritability, Refractive Errors, medicine.disease, eye diseases, 3. Good health, Abnormal eye, Meta-analysis, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability world-wide. Genetic investigation can improve understanding of the molecular mechanisms underlying abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies involving 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (AUC=0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes participating in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may make possible predicting refractive error and the development of personalized myopia prevention strategies in the future., Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Published
2020

6. A vast resource of allelic expression data spanning human tissues

Author

Nancy J. Cox, Sayantan Das, Abhi Rao, Pejman Mohammadi, Alan Kwong, Brandon L. Pierce, Yanyu Liang, Yuxin Zou, Anna M. Smith, Matthew Stephens, Chiara Sabatti, Yuan He, Kasper D. Hansen, Lei Hou, Meritxell Oliva, W. James Kent, Stacey Gabriel, Andrew R. Hame, Tanya Krubit, Gary Walters, Lori E. Brigham, Gao Wang, Kevin S. Smith, Michael J. Gloudemans, Barbara E. Engelhardt, Yongjin Park, Nicole A. Teran, David A. Davis, Thomas Juettemann, Kimberley Ramsey, Fred A. Wright, Lin Chen, Valentin Wucher, Benjamin J. Strober, Duyen T. Nguyen, Eleazar Eskin, Kane Hadley, Deborah C. Mash, Michael Snyder, Sarah Kim-Hellmuth, Laura A. Siminoff, Maghboeba Mosavel, Shin Lin, Richard Hasz, Daniel C. Rohrer, Latarsha J. Carithers, Kevin Myer, Rajinder Kaul, Andrew D. Skol, Bryan Gillard, Dana R. Valley, Philip A. Branton, Stephane E. Castel, Robert E. Handsaker, Debra Bradbury, Meng Wang, Mary Barcus, Xiaoquan Wen, Hua Tang, Daniel J. Cotter, Lihua Jiang, Jason Bridge, Ashis Saha, Gen Li, Susan E. Koester, Qin Li, Mark H. Johnson, Barbara E. Stranger, Jimmie B. Vaught, Hae Kyung Im, Paul Flicek, Marcus Hunter, François Aguet, Elise D. Flynn, Sandra Linder, Nancy Roche, Daniel R. Zerbino, Xiao Li, Barbara A. Foster, Stephen B. Montgomery, Daniel Nachun, Serghei Mangul, Emmanouil T. Dermitzakis, Brian Jo, Simona Volpi, Farzana Jasmine, Scott D. Jewell, Jonah Einson, Tuuli Lappalainen, Farhad Hormozdiari, John M. Rouhana, Ana Viñuela, Daniel G. MacArthur, William F. Leinweber, Gad Getz, Peter Hickey, Eric R. Gamazon, Brunilda Balliu, Jennifer A. Doherty, Christopher D. Brown, Roderic Guigó, Gene Kopen, Rodrigo Bonazzola, Pedro G. Ferreira, Andrew P. Feinberg, Shankara Anand, Helen M. Moore, Paul J. Hoffman, Heather M. Gardiner, Ping Guan, Ferran Reverter, Jin Billy Li, Tiffany Eulalio, Joseph Wheeler, Alvaro N. Barbeira, Jared L. Nedzel, Seva Kashin, Laure Fresard, Lindsay F. Rizzardi, Abhiram Rao, Muhammad G. Kibriya, David Tabor, Leslie H. Sobin, A. Roger Little, Stephen J. Trevanion, Nicole M. Ferraro, Kate R. Rosenbloom, John A. Stamatoyannopoulos, Liqun Qi, Princy Parsana, Ayellet V. Segrè, Dan Sheppard, Nathan S. Abell, Kathryn Demanelis, Manolis Kellis, Silva Kasela, Xin Li, Conner C. Powell, YoSon Park, Michael Washington, Magali Ruffier, Saboor Shad, Christopher Johns, Jeffrey A. Thomas, Andrew Brown, Alisa McDonald, Karna Robinson, Esti Yeger-Lotem, Manuel Muñoz-Aguirre, Kieron Taylor, Marta Melé, Diego Garrido-Martín, Brian Roe, Michael T. Moser, Andrew B. Nobel, Alexis Battle, Maximilian Haeussler, Concepcion R. Nierras, Ellen Karasik, Sam Meier, Anita H. Undale, Ellen Todres, Aaron Graubert, Joshua M. Akey, Jeffrey McLean, Donald F. Conrad, Olivia M. De Goede, Katherine H. Huang, Laura Barker, Kristin G. Ardlie, and Christopher Lee

Subjects
animal structures, Future studies, lcsh:QH426-470, Short Report, Gene Expression, Genomics, Computational biology, Biology, eQTL, Polymorphism, Single Nucleotide, ASE, Regulatory variation, 03 medical and health sciences, 0302 clinical medicine, Resource (project management), Humans, SNP, Allele, lcsh:QH301-705.5, Alleles, Allele specific, 030304 developmental biology, 0303 health sciences, Allelic expression, Genome, Human, Sequence Analysis, RNA, Haplotype, Functional genomics, Human genetics, lcsh:Genetics, Haplotypes, lcsh:Biology (General), Expression data, Expression quantitative trait loci, GTEx, 030217 neurology & neurosurgery
Abstract

Allele expression (AE) analysis robustly measures cis-regulatory effects. Here, we present and demonstrate the utility of a vast AE resource generated from the GTEx v8 release, containing 15,253 samples spanning 54 human tissues for a total of 431 million measurements of AE at the SNP level and 153 million measurements at the haplotype level. In addition, we develop an extension of our tool phASER that allows effect sizes of cis-regulatory variants to be estimated using haplotype-level AE data. This AE resource is the largest to date, and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.

Published
2020

7. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Author

Mark I. McCarthy, Weihua Meng, Brian L. Yaspan, M Imamura, Mark W. Christiansen, Niina Sandholm, Yii-Der Ida Chen, Sharon G. Adler, Lucia Sobrin, Craig L. Hanis, Valeriya Lyssenko, Shiro Maeda, Yang Hai, Paul Mitchell, Roberta McKean-Cowdin, Xiuqing Guo, John R. Sedor, David S. Siscovick, Sudha K. Iyengar, Heather Hancock, Jane Z. Kuo, Barbara E.K. Klein, David-Alexandre Tregouet, Elisabet Agardh, Kent D. Taylor, Andrew D. Morris, S. Mohsen Hosseini, Andrew D. Paterson, I-Te Lee, Wayne Huey-Herng Sheu, Emma Ahlqvist, Kathryn P. Burdon, Leif Groop, Ayellet V. Segrè, Samy Hadjadj, Samaneh Davoudi, Lynn K. Stanwyck, Emily Y. Chew, Xiaohui Li, Michael A. Grassi, Jie Jin Wang, Samuela Pollack, Albert V. Smith, Kyu Hyung Park, Michiaki Kubo, Mary Frances Cotch, Yucheng Jia, Ching J. Chen, Colin N. A. Palmer, Helen M. Colhoun, Alan D. Penman, R. Varma, Per-Henrik Groop, Tien Yin Wong, Barry I. Freedman, Eli Ipp, Alex S. F. Doney, Gavin Tan, Ronald Klein, Kaanan P. Shah, Jamie E Craig, Donald W. Bowden, Jerome I. Rotter, Robert P. Igo, Darryl Nousome, Ching-Yu Cheng, Michel Marre, Maggie C.Y. Ng, Latchezar Dimitrov, Jeeyun Ahn, Atsushi Takahashi, Richard A. Jensen, Aaron Leong, Jihye Kim, Iiro Toppila, Elizabeth J. Rossin, Alkes L. Price, Diabetes and Obesity Research Program, University of Helsinki, Department of Medicine, Nefrologian yksikkö, Research Programs Unit, Clinicum, HUS Abdominal Center, and Per Henrik Groop / Principal Investigator

Subjects
Blood Glucose, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Endocrinology, Diabetes and Metabolism, LOCI, 030209 endocrinology & metabolism, Genome-wide association study, VARIANTS, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, RESOURCE, Internal medicine, Diabetes mellitus, REVEALS, Genetic variation, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, CHINESE PATIENTS, Allele, METAANALYSIS, POLYMORPHISMS, Glycemic, Glycated Hemoglobin, Diabetic Retinopathy, business.industry, Diabetic retinopathy, medicine.disease, PREVALENCE, 3. Good health, SEVERITY, 030104 developmental biology, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, Multiple comparisons problem, RISK-FACTORS, Medical genetics, Erratum, business, Genome-Wide Association Study, Protein Binding
Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value

Published
2018

8. Exploiting the GTEx resources to decipher the mechanisms at GWAS loci

Author

Christopher D. Brown, Gao Wang, Lisa Bastarache, Boxiang Liu, Tuuli Lappalainen, Marie Verbanck, Xiaoquan Wen, Zhuoxun Jiang, Farhad Hormozdiari, Eric R. Gamazon, Mark I. McCarthy, Sarah Kim-Hellmuth, Rodrigo Bonazzola, Milton Pividori, Alvaro N. Barbeira, Kristin G. Ardlie, Abhiram Rao, Daniel M. Jordan, Yanyu Liang, Andrew R. Hamel, Dan Zhou, YoSon Park, Stephen B. Montgomery, Matthew Stephens, Hae Kyung Im, François Aguet, Ron Do, Ayellet V. Segrè, Im, Hae Kyung [0000-0003-0333-5685], and Apollo - University of Cambridge Repository

Subjects
Multifactorial Inheritance, Genotype, lcsh:QH426-470, Research, Gene Expression, Genome-wide association study, Computational biology, Biology, Phenotype, Human genetics, Transcriptome, lcsh:Genetics, Rna expression, Genes, lcsh:Biology (General), RNA splicing, Humans, DECIPHER, Genetic Predisposition to Disease, Allelic heterogeneity, lcsh:QH301-705.5, Gene, Genome-Wide Association Study, Genetic association
Abstract

The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2,519 out of 5,385) of the GWAS loci examined. Our results demonstrate the translational relevance of the GTEx resources and highlight the need to increase their resolution and breadth to further our understanding of the genotype-phenotype link.

Published
2019

9. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

Author

Jonna Grimsby, Nicholas J. Haradhvala, Julian M. Hess, Hailei Zhang, Eila Arich-Landkof, Paz Polak, Chip Stewart, Philip A. Branton, Gad Getz, Noam Shoresh, Ruslana Frazer, Kristin G. Ardlie, Jaegil Kim, Keren Yizhak, Dimitri Livitz, Daniel Rosebrock, K Kübler, François Aguet, Ayellet V. Segrè, and Xiao Li

Subjects
Male, Genetics, Mutation, Multidisciplinary, Sequence Analysis, RNA, Somatic cell, Sequence analysis, DNA Mutational Analysis, Cell, Normal tissue, RNA, Disease, Biology, medicine.disease_cause, Clone Cells, medicine.anatomical_structure, Organ Specificity, Neoplasms, RNA Sequence, medicine, Humans, Female
Abstract

Somatic mosaicism in normal tissues Somatic cells can accumulate mutations over the course of an individual's lifetime. This generates cells that differ genetically at specific loci within the genome. To explore how this genetic diversity in individuals contributes to disease, Yizhak et al. developed a method to detect mutations from RNA sequencing data (see the Perspective by Tomasetti). Applying this method to Cancer Genome Atlas samples and normal samples from the Genotype-Tissue Expression (GTEx) project generated a tissue-specific study of mutation accumulation. Somatic mutations were detected in nearly all individuals and across many normal human tissues in genomic regions called cancer hotspots and in genes that play a role in cancer. Interestingly, the skin, lung, and esophagus exhibited the most mutations, suggesting that the environment generates many human mutations. Science , this issue p. eaaw0726 ; see also p. 938

Published
2019

10. Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease

Author

Olivia M. de Goede, Daniel C. Nachun, Nicole M. Ferraro, Michael J. Gloudemans, Abhiram S. Rao, Craig Smail, Tiffany Y. Eulalio, François Aguet, Bernard Ng, Jishu Xu, Alvaro N. Barbeira, Stephane E. Castel, Sarah Kim-Hellmuth, YoSon Park, Alexandra J. Scott, Benjamin J. Strober, Christopher D. Brown, Xiaoquan Wen, Ira M. Hall, Alexis Battle, Tuuli Lappalainen, Hae Kyung Im, Kristin G. Ardlie, Sara Mostafavi, Thomas Quertermous, Karla Kirkegaard, Stephen B. Montgomery, Shankara Anand, Stacey Gabriel, Gad A. Getz, Aaron Graubert, Kane Hadley, Robert E. Handsaker, Katherine H. Huang, Xiao Li, Daniel G. MacArthur, Samuel R. Meier, Jared L. Nedzel, Duyen T. Nguyen, Ayellet V. Segrè, Ellen Todres, Brunilda Balliu, Rodrigo Bonazzola, Andrew Brown, Donald F. Conrad, Daniel J. Cotter, Nancy Cox, Sayantan Das, Emmanouil T. Dermitzakis, Jonah Einson, Barbara E. Engelhardt, Eleazar Eskin, Elise D. Flynn, Laure Fresard, Eric R. Gamazon, Diego Garrido-Martín, Nicole R. Gay, Roderic Guigó, Andrew R. Hamel, Yuan He, Paul J. Hoffman, Farhad Hormozdiari, Lei Hou, Brian Jo, Silva Kasela, Seva Kashin, Manolis Kellis, Alan Kwong, Xin Li, Yanyu Liang, Serghei Mangul, Pejman Mohammadi, Manuel Muñoz-Aguirre, Andrew B. Nobel, Meritxell Oliva, Yongjin Park, Princy Parsana, Ferran Reverter, John M. Rouhana, Chiara Sabatti, Ashis Saha, Matthew Stephens, Barbara E. Stranger, Nicole A. Teran, Ana Viñuela, Gao Wang, Fred Wright, Valentin Wucher, Yuxin Zou, Pedro G. Ferreira, Gen Li, Marta Melé, Esti Yeger-Lotem, Debra Bradbury, Tanya Krubit, Jeffrey A. McLean, Liqun Qi, Karna Robinson, Nancy V. Roche, Anna M. Smith, David E. Tabor, Anita Undale, Jason Bridge, Lori E. Brigham, Barbara A. Foster, Bryan M. Gillard, Richard Hasz, Marcus Hunter, Christopher Johns, Mark Johnson, Ellen Karasik, Gene Kopen, William F. Leinweber, Alisa McDonald, Michael T. Moser, Kevin Myer, Kimberley D. Ramsey, Brian Roe, Saboor Shad, Jeffrey A. Thomas, Gary Walters, Michael Washington, Joseph Wheeler, Scott D. Jewell, Daniel C. Rohrer, Dana R. Valley, David A. Davis, Deborah C. Mash, Mary E. Barcus, Philip A. Branton, Leslie Sobin, Laura K. Barker, Heather M. Gardiner, Maghboeba Mosavel, Laura A. Siminoff, Paul Flicek, Maximilian Haeussler, Thomas Juettemann, W. James Kent, Christopher M. Lee, Conner C. Powell, Kate R. Rosenbloom, Magali Ruffier, Dan Sheppard, Kieron Taylor, Stephen J. Trevanion, Daniel R. Zerbino, Nathan S. Abell, Joshua Akey, Lin Chen, Kathryn Demanelis, Jennifer A. Doherty, Andrew P. Feinberg, Kasper D. Hansen, Peter F. Hickey, Farzana Jasmine, Lihua Jiang, Rajinder Kaul, Muhammad G. Kibriya, Jin Billy Li, Qin Li, Shin Lin, Sandra E. Linder, Brandon L. Pierce, Lindsay F. Rizzardi, Andrew D. Skol, Kevin S. Smith, Michael Snyder, John Stamatoyannopoulos, Hua Tang, Meng Wang, Latarsha J. Carithers, Ping Guan, Susan E. Koester, A. Roger Little, Helen M. Moore, Concepcion R. Nierras, Abhi K. Rao, Jimmie B. Vaught, and Simona Volpi

Subjects
Multifactorial Inheritance, Population, Quantitative Trait Loci, Coronary Artery Disease, Disease, Computational biology, Quantitative trait locus, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Humans, education, Gene, 030304 developmental biology, 0303 health sciences, education.field_of_study, Gene Expression Profiling, Genetic Variation, Inflammatory Bowel Diseases, Long non-coding RNA, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Organ Specificity, Expression quantitative trait loci, Trait, RNA, Long Noncoding, 030217 neurology & neurosurgery
Abstract

Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.

Published
2021

11. ForestPMPlot: A Flexible Tool for Visualizing Heterogeneity Between Studies in Meta-analysis

Author

Eleazar Eskin, Xiao Li, Eun Yong Kang, Yu Rang Park, Buhm Han, and Ayellet V. Segrè

Subjects
0301 basic medicine, genetic association studies, Quantitative Trait Loci, Genome-wide association study, Computational biology, Investigations, Quantitative trait locus, Biology, QH426-470, 03 medical and health sciences, Mice, Genetic Heterogeneity, 0302 clinical medicine, Meta-Analysis as Topic, Models, Computer Graphics, Genetics, Animals, Humans, GWAS, Molecular Biology, Genetics (clinical), Selection Bias, Models, Statistical, Genetic heterogeneity, Statistical, Visualization, meta-analysis, 030104 developmental biology, Phenotype, Meta-analysis, Sample Size, Expression quantitative trait loci, heterogeneity, 030217 neurology & neurosurgery, Software
Abstract

Meta-analysis has become a popular tool for genetic association studies to combine different genetic studies. A key challenge in meta-analysis is heterogeneity, or the differences in effect sizes between studies. Heterogeneity complicates the interpretation of meta-analyses. In this paper, we describe ForestPMPlot, a flexible visualization tool for analyzing studies included in a meta-analysis. The main feature of the tool is visualizing the differences in the effect sizes of the studies to understand why the studies exhibit heterogeneity for a particular phenotype and locus pair under different conditions. We show the application of this tool to interpret a meta-analysis of 17 mouse studies, and to interpret a multi-tissue eQTL study.

Published
2016

12. A Quantitative Proteome Map of the Human Body

Author

Lihua Jiang, Meng Wang, Shin Lin, Ruiqi Jian, Xiao Li, Joanne Chan, Guanlan Dong, Huaying Fang, Aaron E. Robinson, Michael P. Snyder, François Aguet, Shankara Anand, Kristin G. Ardlie, Stacey Gabriel, Gad Getz, Aaron Graubert, Kane Hadley, Robert E. Handsaker, Katherine H. Huang, Seva Kashin, Daniel G. MacArthur, Samuel R. Meier, Jared L. Nedzel, Duyen Y. Nguyen, Ayellet V. Segrè, Ellen Todres, Brunilda Balliu, Alvaro N. Barbeira, Alexis Battle, Rodrigo Bonazzola, Andrew Brown, Christopher D. Brown, Stephane E. Castel, Don Conrad, Daniel J. Cotter, Nancy Cox, Sayantan Das, Olivia M. de Goede, Emmanouil T. Dermitzakis, Barbara E. Engelhardt, Eleazar Eskin, Tiffany Y. Eulalio, Nicole M. Ferraro, Elise Flynn, Laure Fresard, Eric R. Gamazon, Diego Garrido-Martín, Nicole R. Gay, Roderic Guigó, Andrew R. Hamel, Yuan He, Paul J. Hoffman, Farhad Hormozdiari, Lei Hou, Hae Kyung Im, Brian Jo, Silva Kasela, Manolis Kellis, Sarah Kim-Hellmuth, Alan Kwong, Tuuli Lappalainen, Xin Li, Yanyu Liang, Serghei Mangul, Pejman Mohammadi, Stephen B. Montgomery, Manuel Muñoz-Aguirre, Daniel C. Nachun, Andrew B. Nobel, Meritxell Oliva, YoSon Park, Yongjin Park, Princy Parsana, Ferran Reverter, John M. Rouhana, Chiara Sabatti, Ashis Saha, Andrew D. Skol, Matthew Stephens, Barbara E. Stranger, Benjamin J. Strober, Nicole A. Teran, Ana Viñuela, Gao Wang, Xiaoquan Wen, Fred Wright, Valentin Wucher, Yuxin Zou, Pedro G. Ferreira, Gen Li, Marta Melé, Esti Yeger-Lotem, Mary E. Barcus, Debra Bradbury, Tanya Krubit, Jeffrey A. McLean, Liqun Qi, Karna Robinson, Nancy V. Roche, Anna M. Smith, Leslie Sobin, David E. Tabor, Anita Undale, Jason Bridge, Lori E. Brigham, Barbara A. Foster, Bryan M. Gillard, Richard Hasz, Marcus Hunter, Christopher Johns, Mark Johnson, Ellen Karasik, Gene Kopen, William F. Leinweber, Alisa McDonald, Michael T. Moser, Kevin Myer, Kimberley D. Ramsey, Brian Roe, Saboor Shad, Jeffrey A. Thomas, Gary Walters, Michael Washington, Joseph Wheeler, Scott D. Jewell, Daniel C. Rohrer, Dana R. Valley, David A. Davis, Deborah C. Mash, Philip A. Branton, Laura K. Barker, Heather M. Gardiner, Maghboeba Mosavel, Laura A. Siminoff, Paul Flicek, Maximilian Haeussler, Thomas Juettemann, W. James Kent, Christopher M. Lee, Conner C. Powell, Kate R. Rosenbloom, Magali Ruffier, Dan Sheppard, Kieron Taylor, Stephen J. Trevanion, Daniel R. Zerbino, Nathan S. Abell, Joshua Akey, Lin Chen, Kathryn Demanelis, Jennifer A. Doherty, Andrew P. Feinberg, Kasper D. Hansen, Peter F. Hickey, Farzana Jasmine, Rajinder Kaul, Muhammad G. Kibriya, Jin Billy Li, Qin Li, Sandra E. Linder, Brandon L. Pierce, Lindsay F. Rizzardi, Kevin S. Smith, John Stamatoyannopoulos, Hua Tang, Latarsha J. Carithers, Ping Guan, Susan E. Koester, A. Roger Little, Helen M. Moore, Concepcion R. Nierras, Abhi K. Rao, Jimmie B. Vaught, and Simona Volpi

Subjects
Proteomics, Cell signaling, Proteome, Quantitative proteomics, Gene Expression, Disease, Computational biology, Biology, ENCODE, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Humans, Secretion, RNA, Messenger, Gene, 030304 developmental biology, 0303 health sciences, Gene Expression Profiling, RNA, Metabolism, Phenotype, Secretory protein, 030217 neurology & neurosurgery
Abstract

Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from 12,627 genes across 32 normal human tissue types prepared by the GTEx project. Known and new tissue specific or enriched proteins (5,499) were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode highly tissue specific proteins. Discordance in the sites of RNA expression and protein detection also revealed potential sites of synthesis and action of protein signaling molecules. Overall, these results provide an extraordinary resource, and demonstrate that understanding protein levels can provide insights into metabolism, regulation, secretome, and human diseases.SummaryQuantitative proteome study of 32 human tissues and integrated analysis with transcriptome data revealed that understanding protein levels could provide in-depth knowledge to post transcriptional or translational regulations, human metabolism, secretome, and diseases.

Published
2020

13. Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation

Author

Nancy J. Cox, Mark I. McCarthy, Martijn van de Bunt, Anuar Konkashbaev, Halit Ongen, Farhad Hormozdiari, Eric R. Gamazon, Xiaoquan Wen, Hualin S. Xi, Jie Quan, Manolis Kellis, Eleazar Eskin, Emmanouil T. Dermitzakis, François Aguet, Ayellet V. Segrè, Gad Getz, Eske M. Derks, Kristin G. Ardlie, Dan L. Nicolae, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory

Subjects
0301 basic medicine, Linkage disequilibrium, Genotype, ddc:025.063/570, Quantitative Trait Loci, Gene Expression, Genome-wide association study, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Quantitative Trait, Heritable, ddc:590, Genetics, Humans, Disease, ddc:576.5, Regulation of gene expression, Gene Expression Profiling, Heritability, 3. Good health, Phenotype, 030104 developmental biology, Gene Expression Regulation, Expression quantitative trait loci, Trait, Functional genomics, Genome-Wide Association Study
Abstract

We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to metabolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40-80%). For most traits, tissue-shared eQTLs underlie a greater proportion of trait associations, although tissue-specific eQTLs have a greater contribution to some traits, such as blood pressure. By integrating information from biological pathways with eQTL target genes and applying a gene-based approach, we validate previously implicated causal genes and pathways, and propose new variant and gene associations for several complex traits, which we replicate in the UK BioBank and BioVU., National Institutes of Health (U.S.) (Contract HHSN268201000029C)

Published
2018

14. A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project

Author

Latarsha J, Carithers, Kristin, Ardlie, Mary, Barcus, Philip A, Branton, Angela, Britton, Stephen A, Buia, Carolyn C, Compton, David S, DeLuca, Joanne, Peter-Demchok, Ellen T, Gelfand, Ping, Guan, Greg E, Korzeniewski, Nicole C, Lockhart, Chana A, Rabiner, Abhi K, Rao, Karna L, Robinson, Nancy V, Roche, Sherilyn J, Sawyer, Ayellet V, Segrè, Charles E, Shive, Anna M, Smith, Leslie H, Sobin, Anita H, Undale, Kimberly M, Valentino, Jim, Vaught, Taylor R, Young, Helen M, Moore, Jun, Zhu, and Other departments

Subjects
Knowledge management, Biomedical Research, Tissue and Organ Procurement, Genomic data, media_common.quotation_subject, Medicine (miscellaneous), Tissue Banks, Biospecimen Collection, General Biochemistry, Genetics and Molecular Biology, World Wide Web, Procurement, Common fund, Humans, Quality (business), Guest Editorial, media_common, business.industry, Cell Biology, General Medicine, Expressió gènica, 3. Good health, Organ procurement, Tissue bank, Postmortem tissue, Business
Abstract

The Genotype-Tissue Expression (GTEx) project, sponsored by the NIH Common Fund, was established to study the correlation between human genetic variation and tissue-specific gene expression in non-diseased individuals. A significant challenge was the collection of high-quality biospecimens for extensive genomic analyses. Here we describe how a successful infrastructure for biospecimen procurement was developed and implemented by multiple research partners to support the prospective collection, annotation, and distribution of blood, tissues, and cell lines for the GTEx project. Other research projects can follow this model and form beneficial partnerships with rapid autopsy and organ procurement organizations to collect high quality biospecimens and associated clinical data for genomic studies. Biospecimens, clinical and genomic data, and Standard Operating Procedures guiding biospecimen collection for the GTEx project are available to the research community. This work was supported by the National Institutes of Health (HHSN261200800001E (Leidos Prime contract with NCI); 10XS170 (NDRI), 10XS171 (Roswell Park Cancer Institute), 10X172 (Science Care Inc.), 12ST1039 (IDOX); 10ST1035 (Van Andel Institute); HHSN268201000029C (Broad Institute); and R01 DA006227-17 (U Miami Brain Bank).

Published
2015

15. Co-expression networks reveal the tissue-specific regulation of transcription and splicing

Author

Morgan Diegel, Laure Fresard, Lindsay F. Rizzardi, Yuan He, Monkol Lek, Daniel C. Rohrer, Boxiang Liu, Maximilian Haeussler, Heather M. Traino, Concepcion R. Nierras, Joseph Wheeler, Serghei Mangul, Fan Wu, Hualin S. Xi, Andrew D. Skol, Steven Hunter, Yaping Liu, Casandra A. Trowbridge, Brandon L. Pierce, Daniel Bates, Peter Hickey, Susan E. Koester, Bryan Gillard, Eric R. Gamazon, Jennifer A. Doherty, Jared L. Nedzel, Eric Haugen, Lori E. Brigham, Gao Wang, Dana R. Valley, Zachary Zappala, Emmanouil T. Dermitzakis, Seva Kashin, Ira M. Hall, John Vivian, Philip A. Branton, Barbara E. Stranger, Magali Ruffier, Melina Claussnitzer, Nancy Roche, Michael Washington, Halit Ongen, Brian Jo, Rachna Kumar, Jean Monlong, Yi-Hui Zhou, Kristen Lee, Stephane E. Castel, Mark Miklos, Alisa McDonald, Diego Garrido-Martín, Jimmie B. Vaught, Hae Kyung Im, Leslie H. Sobin, John T. Lonsdale, Audra K. Johnson, Rui Zhang, Nancy J. Cox, Christopher D. Brown, Paul Flicek, Ferran Reverter, Roderic Guigó, Tuuli Lappalainen, Sarah E. Gould, Deborah C. Mash, Michael T. Moser, Andrew B. Nobel, Takunda Matose, Jingchun Zhu, Joe R. Davis, Andrey A. Shabalin, Jie Quan, Pedro G. Ferreira, Taru Tukiainen, Ellen Gelfand, Cédric Howald, Buhm Han, Emily K. Tsang, Andrew P. Feinberg, Caroline Linke, Kane Hadley, Richard Sandstrom, Mark D. Johnson, Joshua M. Akey, Ian C. McDowell, Daniel R. Zerbino, Alexis Battle, Brian Roe, Daniel G. MacArthur, Ellen Karasik, Marcus Hunter, Anjené M. Addington, Thomas Juettemann, Konrad J. Karczewski, Duyen T. Nguyen, Lei Hou, Stephen B. Montgomery, YoSon Park, Nicole C. Lockart, Lin Chen, Rajinder Kaul, Ruiqi Jian, Robert G. Montroy, Xiao Li, Michael Snyder, Beryl B. Cummings, Kimberly M. Valentino, Ariel D. H. Gewirtz, François Aguet, Jeffrey McLean, Gary Walters, Farhad Hormozdiari, William F. Leinweber, Gad Getz, Jeffery P. Struewing, Anne Ndungu, Dan L. Nicolae, Benoit Molinie, Lihua Jiang, Michael Sammeth, W. James Kent, John Palowitch, Brian Craft, Donald F. Conrad, Kathryn Demanelis, Jason Bridge, Jin Billy Li, A. Roger Little, Nicholas Van Wittenberghe, Stephen J. Trevanion, Pejman Mohammadi, Michael S. Noble, Kate R. Rosenbloom, Marian S. Fernando, Benjamin J. Strober, Ping Guan, Brunilda Balliu, Yungil Kim, Kevin Myer, Christine B. Peterson, Pushpa Hariharan, Jae Hoon Sul, Abhi Rao, Michael F. Salvatore, Qin Li, Eun Yong Kang, Matthew T. Maurano, Ayellet V. Segrè, Dan Sheppard, Fred A. Wright, Matthew Stephens, Kasper D. Hansen, Chiara Sabatti, Kevin S. Smith, Xin Li, Ruth Barshir, Muhammad G. Kibriya, Farhan N. Damani, Manolis Kellis, Olivier Delaneau, Shin Lin, Richard Hasz, Michael J. Gloudemans, Anita H. Undale, Mary Goldman, Fidencio J. Neri, Katherine H. Huang, David E. Tabor, Manuel Muñoz-Aguirre, Maghboeba Mosavel, Simona Volpi, Latarsha J. Carithers, Anna M. Smith, Genna Gliner, Eleazar Eskin, Nikolaos I Panousis, Benedict Paten, Andrew A. Brown, Jessica Lin, Kieron Taylor, Robert E. Handsaker, Laura Barker, Casey Martin, Meng Wang, Farzana Jasmine, Scott D. Jewell, Nathan S. Abell, Kristin G. Ardlie, Shilpi Singh, Mary Barcus, Anthony Payne, Christopher Lee, Xiaoquan Wen, Nicola J. Rinaldi, Hua Tang, Yongjin Park, Christopher Johns, Saboor Shad, Judith B. Zaugg, Reza Sodaei, Maria M. Tomaszewski, David A. Davis, Joanne Chan, Laura A. Siminoff, Mark I. McCarthy, Ki Sung Um, Karna Robinson, Esti Yeger-Lotem, Martijn van de Bunt, Meritxell Oliva, Jemma Nelson, Negin Vatanian, Colby Chiang, Jeffrey A. Thomas, Alexandra J. Scott, Omer Basha, Jessica Halow, Panagiotis Papasaikas, Barbara A. Foster, Barbara E. Engelhardt, Sarah Kim-Hellmuth, Li Wang, Gireesh K. Bogu, Sandra Linder, Sarah Urbut, Ashis Saha, Gen Li, Bernadette Mestichelli, Chuan Gao, John A. Stamatoyannopoulos, Liqun Qi, Princy Parsana, Helen M. Moore, Gene Kopen, and GTEx, Consortium

Subjects
Gene isoform, 0301 basic medicine, Genotyping Techniques, Bioinformatics, RNA Splicing, 1.1 Normal biological development and functioning, Gene regulatory network, Method, Genomics, Computational biology, Biology, Medical and Health Sciences, GTEx Consortium, Transcriptome, 03 medical and health sciences, Databases, 0302 clinical medicine, Genetic, Transcription (biology), Underpinning research, Genetic variation, Gene expression, Genetics, Humans, ddc:576.5, Gene Regulatory Networks, Polymorphism, Gene, Genetics (clinical), 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Gene Expression Profiling, Human Genome, Bayes Theorem, Single Nucleotide, Biological Sciences, Gene expression profiling, 030104 developmental biology, Gene Expression Regulation, Organ Specificity, RNA splicing, RNA, Generic health relevance, Sequence Analysis, 030217 neurology & neurosurgery, Biotechnology
Abstract

Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of regulatory genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single or small sets of tissues. Here, we have reconstructed networks that capture a much more complete set of regulatory relationships, specifically including regulation of relative isoform abundance and splicing, and tissue-specific connections unique to each of a diverse set of tissues. Using the Genotype-Tissue Expression (GTEx) project v6 RNA-sequencing data across 44 tissues in 449 individuals, we evaluated shared and tissue-specific network relationships. First, we developed a framework called Transcriptome Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the complex interplay between the regulation of splicing and transcription. We built TWNs for sixteen tissues, and found that hubs with isoform node neighbors in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome, and providing a set of candidate shared and tissue-specific regulatory hub genes. Next, we used a Bayesian biclustering model that identifies network edges between genes with co-expression in a single tissue to reconstruct tissue-specific networks (TSNs) for 27 distinct GTEx tissues and for four subsets of related tissues. Using both TWNs and TSNs, we characterized gene co-expression patterns shared across tissues. Finally, we found genetic variants associated with multiple neighboring nodes in our networks, supporting the estimated network structures and identifying 33 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships between genes in the human transcriptome, including tissue-specificity of gene co-expression, regulation of splicing, and the coordinated impact of genetic variation on transcription.

Published
2017

16. Widespread Allelic Heterogeneity in Complex Traits

Author

Chelsea J.-T. Ju, Sriram Sankararaman, Anthony Zhu, Sagiv Shifman, Hyejung Won, Eleazar Eskin, Gleb Kichaev, Jong Wha J. Joo, Bogdan Pasaniuc, Farhad Hormozdiari, and Ayellet V. Segrè

Subjects
Models, Molecular, 0301 basic medicine, Quantitative Trait Loci, causal variants, Genome-wide association study, Locus (genetics), Biology, eQTL, Medical and Health Sciences, Article, Linkage Disequilibrium, complex traits, 03 medical and health sciences, Databases, 0302 clinical medicine, Gene Frequency, Genetic, Models, Databases, Genetic, Genetics, Humans, Association mapping, Allele frequency, Genetics (clinical), Alleles, Genetic Association Studies, 030304 developmental biology, Genetic association, Genetics & Heredity, 0303 health sciences, allelic heterogeneity, Prevention, Human Genome, Molecular, Biological Sciences, Genetic architecture, 030104 developmental biology, Phenotype, Sample size determination, Expression quantitative trait loci, gene expression, Allelic heterogeneity, 030217 neurology & neurosurgery, Biotechnology
Abstract

Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as allele frequency and effect size. One lesser-known aspect of complex traits is the extent of allelic heterogeneity (AH) arising from multiple causal variants at a locus. We developed a computational method to infer the probability of AH and applied it to three GWAS and four expression quantitative trait loci (eQTL) datasets. We identified a total of 4152 loci with strong evidence of AH. The proportion of all loci with identified AH is 4-23% in eQTLs, 35% in GWAS of High-Density Lipoprotein (HDL), and 23% in schizophrenia. For eQTLs, we observed a strong correlation between sample size and the proportion of loci with AH (R2=0.85, P = 2.2e-16), indicating that statistical power prevents identification of AH in other loci. Understanding the extent of AH may guide the development of new methods for fine mapping and association mapping of complex traits.

Published
2017

17. Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease

Author

Steven Horner, Sekar Kathiresan, Chris C. A. Spencer, Virendar K. Kaushik, Pradeep Natarajan, Kristin G. Ardlie, Amit Khera, Connor A. Emdin, Michael E. Weale, François Aguet, Mark Chaffin, Ayellet V. Segrè, Derek Klarin, Alison Leed, Qiuyu Martin Zhu, and Brian J. McMillan

Subjects
0301 basic medicine, Adult, Male, Genotype, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Genetic analysis, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, Health Information Systems, 0302 clinical medicine, Insulin resistance, Polymorphism (computer science), Genetics, medicine, Human Umbilical Vein Endothelial Cells, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, Leukocyte Rolling, Cells, Cultured, Aged, Transendothelial and Transepithelial Migration, population genetics, Middle Aged, medicine.disease, Phenotype, Biobank, gene-expression, United Kingdom, 3. Good health, Cytoskeletal Proteins, 030104 developmental biology, HEK293 Cells, Logistic Models, Immunology, genome-wide association studies, Female, Insulin Resistance, Carrier Proteins, Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract

UK Biobank is among the world's largest repositories for phenotypic and genotypic information in individuals of European ancestry. We performed a genome-wide association study in UK Biobank testing ∼9 million DNA sequence variants for association with coronary artery disease (4,831 cases and 115,455 controls) and carried out meta-analysis with previously published results. We identified 15 new loci, bringing the total number of loci associated with coronary artery disease to 95 at the time of analysis. Phenome-wide association scanning showed that CCDC92 likely affects coronary artery disease through insulin resistance pathways, whereas experimental analysis suggests that ARHGEF26 influences the transendothelial migration of leukocytes.

Published
2017

18. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author

Emmi Tikkanen, Pascal Guénel, Rico Rueedi, Hamdi Mbarek, Gerardo Heiss, Hilary K. Finucane, Jing Hua Zhao, Peter K. Joshi, Mark I. McCarthy, Frank B. Hu, Stephen J. Chanock, Manjeet K. Bolla, Sandosh Padmanabhan, Vilmundur Gudnason, Chunyan He, Aarno Palotie, Reedik Mägi, Joe Dennis, Nicholas G. Martin, Behrooz Z. Alizadeh, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Magdalena Zoledziewska, Ayellet V. Segrè, Fergus J. Couch, Massimo Mangino, Melissa C. Southey, Immaculata De Vivo, Yongmei Liu, Ute Hamann, Angela Cox, Maartje J. Hooning, Iffat Rahman, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Tanguy Corre, Kathryn L. Lunetta, Thérèse Truong, Anna Marie Mulligan, Caterina Barbieri, Robert Winqvist, Lili Milani, Cristina Menni, Frits R. Rosendaal, Pau Navarro, Christian Gieger, Ken K. Ong, Stig E. Bojesen, Susan M. Ring, Marjanka K. Schmidt, George McMahon, Deborah J. Thompson, Robert Karlsson, Nicholas J. Timpson, M. Arfan Ikram, Alexander Teumer, Jingmei Li, Christa Meisinger, Diana L. Cousminer, Doris Stöckl, Heli Nevanlinna, Teresa Nutile, Tim D. Spector, Eva Albrecht, Murielle Bochud, Linda Broer, Felix R. Day, Sven Bergmann, Renée de Mutsert, Nicholas J. Wareham, Marjo-Riitta Järvelin, Marzyeh Amini, Elisabeth Altmaier, Isabel dos-Santos-Silva, Peter Vollenweider, Douglas F. Easton, Tamara B. Harris, Ellen A. Nohr, Paul D.P. Pharoah, David J. Porteous, Jenny A. Visser, Ilja M. Nolte, Genevieve Lachance, Thomas Meitinger, Archie Campbell, Thomas Brüning, Graham G. Giles, Johan G. Eriksson, Nancy L. Pedersen, George Davey Smith, Gonneke Willemsen, Joanne M. Murabito, Francesco Cucca, Daniel I. Chasman, Eleonora Porcu, Nora Franceschini, Thibaud Boutin, Ulla Sovio, Roger L. Milne, Annette Peters, Lisette Stolk, Paul M. Ridker, Claudia Langenberg, Patrick Sulem, Toshiko Tanaka, Marike Gabrielson, Judith S. Brand, Unnur Thorsteindottir, Alison M. Dunning, Marina Ciullo, Julie E. Buring, Harold Snieder, Lude Franke, Meir J. Stampfer, Po-Ru Loh, Julian Peto, Ellen W. Demerath, Sheila Ulivi, Ivana Kolcic, Maristella Steri, Jouke J. Hottenga, Amanda B. Spurdle, Tõnu Esko, Katherine S. Pollard, Eulalia Catamo, Anneli Pouta, Kyriaki Michailidou, Dieter Flesch-Janys, James F. Wilson, Kamila Czene, Sean Whalen, Diether Lambrechts, Abhishek Sarkar, Laura Crisponi, Jonathan Tyrer, Antonietta Robino, Sara Lindström, Harald Grallert, Stefania Lenarduzzi, Peter Kraft, Patrik K. E. Magnusson, Lavinia Paternoster, Digna R. Velez Edwards, Mike A. Nalls, Per Hall, Joyce Y. Tung, Cinzia Sala, Lindsay Fernández-Rhodes, Ayush Giri, Hiltrud Brauch, André G. Uitterlinden, Alkes L. Price, Tracy A. O'Mara, Lynda M. Rose, John L. Hopper, David A. Hinds, Katherine S. Ruth, Arto Mannermaa, Uwe Völker, Rossella Sorice, Zoltán Kutalik, Debbie A Lawlor, Georgia Chenevix-Trench, Anna Murray, Albertine J. Oldehinkel, Bruce H. R. Wolffenbuttel, Hae Kyung Im, Dale R. Nyholt, Lenore J. Launer, Andres Metspalu, Irene L. Andrulis, Konstantin Strauch, Albert V. Smith, Daniela Toniolo, Eco J. C. de Geus, Jenny Chang-Claude, Marek Zygmunt, Dorret I. Boomsma, Harry Campbell, Peter Devilee, Henry Völzke, Daniela Ruggiero, Dennis O. Mook-Kanamori, John R. B. Perry, Javier Benitez, Grant W. Montgomery, David J. Hunter, David Karasik, Luigi Ferrucci, Emily Hallberg, Stefania Bandinelli, Hermann Brenner, Raymond Noordam, Sarah E. Medland, Peter A. Fasching, Qin Wang, Ilaria Gandin, Manolis Kellis, Hannes Helgason, Igor Rudan, Paolo Radice, Michela Traglia, Jian'an Luan, Robert A. Scott, Brumat Marco, Veronique Vitart, Kari Stefansson, Katharina E. Schraut, Ko Willems van Dijk, Ozren Polasek, Daniel F. Gudbjartsson, Natalia Perjakova, Joop S.E. Laven, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Art and Culture, History, Antiquity, Day, Felix R., Thompson, Deborah J., Helgason, Hanne, Chasman, Daniel I., Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S., Whalen, Sean, Sarkar, Abhishek K., Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, CATERINA MARIA, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J., Karlsson, Robert, Kolcic, Ivana, Loh, Po Ru, Lunetta, Kathryn L., Mangino, Massimo, Brumat, Marco, Mcmahon, George, Medland, Sarah E., Nolte, Ilja M., Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M., Schraut, Katharina E., Segrã¨, Ayellet V., Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L., Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brã¼ning, Thoma, Buring, Julie E., Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cousminer, Diana L., Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, De Geus, Eco J. C. N., De Mutsert, Renã©e, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos Santos Silva, Isabel, Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., Fernández Rhodes, Lindsay, Ferrucci, Luigi, Flesch Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Guã©nel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B., Hartman, Catharina A., Heiss, Gerardo, Hooning, Maartje J., Hopper, John L., Hu, Frank, Hunter, David J., Ikram, M. Arfan, Im, Hae Kyung, Jã¤rvelin, Marjo Riitta, Joshi, Peter K., Karasik, David, Kellis, Manoli, Kutalik, Zoltan, Lachance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A., Lindstrom, Sara, Liu, Yongmei, Luan, Jian'An, Mã¤gi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, Mccarthy, Mark I., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Metspalu, Andre, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mulligan, Anna M., Nalls, Mike A., Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R., Oldehinkel, Albertine J., O'Mara, Tracy A., Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D. P., Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M., Robino, Antonietta, Rosendaal, Frits R., Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Schmidt, Marjanka K., Scott, Robert A., Shah, Mitul, Sorice, Rossella, Southey, Melissa C., Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J., Traglia, Michela, Truong, Thã©rã¨se, Tyrer, Jonathan P., Uitterlinden, André G., Edwards, Digna R. Velez, Vitart, Veronique, Vã¶lker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, Van Dijk, Ko Willem, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z., Boomsma, Dorret I., Ciullo, Marina, Cucca, Francesco, Esko, Tãµnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A., Magnusson, Patrik K. E., Martin, Nicholas G., Mook Kanamori, Dennis O., Nohr, Ellen A., Polasek, Ozren, Porteous, David, Price, Alkes L., Ridker, Paul M., Snieder, Harold, Spector, Tim D., Stã¶ckl, Dori, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A., Vã¶lzke, Henry, Wareham, Nicholas J., Wilson, James F., LifeLines Cohort, Study, Interact, Consortium, Kconfab/aocs, Investigator, Endometrial Cancer Association, Consortium, Ovarian Cancer Association, Consortium, Practical, Consortium, Spurdle, Amanda B., Thorsteindottir, Unnur, Pollard, Katherine S., Easton, Douglas F., Tung, Joyce Y., Chang Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M., Stefansson, Kari, Ong, Ken K., Perry, John R. B., Internal Medicine, Erasmus MC other, Medical Oncology, Epidemiology, Obstetrics & Gynecology, Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Massachusetts Institute of Technology. Department of Mathematics, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Ovarian Cancer Association Consortium, LOCI, Genome-wide association study, cancer risk, Menarche/genetics, Bioinformatics, GWAS, menarche, puberty, Body Mass Index, Risk Factors, Neoplasms, Databases, Genetic, WIDE ASSOCIATION, Endometrial Cancer Association Consortium, Ribonucleoproteins/genetics, 2. Zero hunger, Genetics, Age Factors, Genetics GWAS menarche, reproductive disorders, Neoplasms/genetics, 3. Good health, Ribonucleoproteins, Menarche, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, GROWTH, Female, TRAITS, Population variance, Intercellular Signaling Peptides and Proteins/genetics, Adolescent, Ubiquitin-Protein Ligases, kConFab/AOCS Investigators, Quantitative Trait Loci, Quantitative trait locus, Biology, METABOLISM, INHERITANCE, Polymorphism, Single Nucleotide, PRACTICAL consortium, 03 medical and health sciences, Genomic Imprinting, SDG 3 - Good Health and Well-being, Mendelian randomization, REGRESSION, medicine, Journal Article, Humans, cancer, Genetic Predisposition to Disease, 1000 Genomes Project, Membrane Proteins/genetics, METAANALYSIS, Puberty, Calcium-Binding Proteins, Membrane Proteins, Cancer, InterAct Consortium, Heritability, medicine.disease, BODY-MASS INDEX, 030104 developmental biology, genome-wide association studies, Puberty/genetics, LifeLines Cohort Study, Genome-Wide Association Study
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P

Published
2017

19. Pathways Targeted by Antidiabetes Drugs Are Enriched for Multiple Genes Associated With Type 2 Diabetes Risk

Author

Nancy Wei, Ayellet V. Segrè, David Altshuler, Jose C. Florez, Magic Investigators, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
MECHANISM, Peroxisome proliferator-activated receptor gamma, SUSCEPTIBILITY LOCI, Genotype, endocrine system diseases, METFORMIN, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Type 2 diabetes, Polymorphism, Single Nucleotide, ABCC8, GLUCOSE, Databases, Genetic, GLYCEMIC TRAITS, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Gene Regulatory Networks, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Thiazolidinedione, Gene, Genetic association, Genetics, INSULIN-RESISTANCE, biology, LARGE-SCALE ASSOCIATION, COMMON VARIANTS, nutritional and metabolic diseases, Genetics/Genomes/Proteomics/Metabolomics, medicine.disease, 3. Good health, Diabetes Mellitus, Type 2, Drug development, biology.protein, PPAR-GAMMA
Abstract

Genome-wide association studies (GWAS) have uncovered >65 common variants associated with type 2 diabetes (T2D); however, their relevance for drug development is not yet clear. Of note, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of antidiabetes medications. We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D. We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis (MAGENTA [Meta-Analysis Gene-set Enrichment of variaNT Associations]) to this gene set, using available GWAS meta-analyses for T2D and seven quantitative glycemic traits. We detected a strong enrichment of drug target genes associated with T2D (P = 2 × 10−5; 14 potential new associations), primarily driven by insulin and thiazolidinedione (TZD) targets, which was replicated in an independent meta-analysis (Metabochip). The glycemic traits yielded no enrichment. The T2D enrichment signal was largely due to multiple genes of modest effects (P = 4 × 10−4, after removing known loci), highlighting new associations for follow-up (ACSL1, NFKB1, SLC2A2, incretin targets). Furthermore, we found that TZD targets were enriched for LDL cholesterol associations, illustrating the utility of this approach in identifying potential side effects. These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design.

Published
2014

20. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author

Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. Hanis, Thomas WMühleisen, Congrong Wang, Sonia Shah, Kyle J. Gaulton, Jaspal S. Kooner, Jiro Nakamura, Mustafa Atalay, Linda S. Adair, S Wiltshire, Tõnu Esko, Anna Jonsson, Antigone S. Dimas, Karin Leander, Li Ching Chang, George B. Grant, Bo Isomaa, Anne U. Jackson, Claudia Langenberg, Kristian Hveem, Yoon Shin Cho, Astradur B. Hreidarsson, Xu Wang, Keizo Ohnaka, Alexandra C. Nica, Simon D. Rees, Pau Navarro, Sekar Kathiresan, Rob M. van Dam, Zafar I. Hydrie, Bok Ghee Han, Francis S. Collins, Fuu Jen Tsai, Unnur Thorsteinsdottir, Ross M. Fraser, Caroline Hayward, Cornelia M. van Duijn, Samuli Ripatti, Mieke D. Trip, Hyung Lae Kim, Rafn Benediktsson, Candace Guiducci, Bruna Gigante, Kyong Soo Park, Wen Hong L. Kao, Tom Wilsgaard, Leena Kinnunen, John Danesh, Alan James, Alan R. Shuldiner, Mitsuhiro Yokota, Jen Mai Lee, Kari Stefansson, Erik Ingelsson, Colin N. A. Palmer, David J. Hunter, Paul Zimmet, Manickam Chidambaram, Sirkka Keinänen-Kiukaanniemi, Laura J. Scott, Susanne Moebus, Benjamin F. Voight, Wolfgang Rathmann, Hassan Khan, Thomas Illig, Prasad Katulanda, Christian Gieger, Andrew D. Morris, Yik Ying Teo, Andrew P. Morris, Venkatesan Radha, N. William Rayner, Johan G. Eriksson, Christian Dina, Igor Rudan, Sailaja Vedantam, Cheng Hu, James S. Pankow, Ann-Christine Syvänen, Karl Gertow, Valeriya Lyssenko, Guillaume Charpentier, Albert Hofman, Chiea Chuen Khor, Joseph Trakalo, Peter Kraft, Takashi Kadowaki, Qiuyin Cai, John C. Chambers, André G. Uitterlinden, Simon C. Potter, Nicholas J. Wareham, Soumya Raychaudhuri, Jian'an Luan, Tiinamaija Tuomi, Anthony H. Barnett, Juha Saltevo, Robert A. Scott, Valgerdur Steinthorsdottir, Peng Keat Ng, Mark I. McCarthy, Åsa K. Hedman, Kerrin S. Small, Julia Meyer, Frank B. Hu, Cecilia M. Lindgren, Jennifer E. Below, Nancy J. Cox, Jennie Hui, Andrew Crenshaw, Latonya F. Been, Nam H. Cho, Janani Pinidiyapathirage, A. Samad Shera, Bernhard OBoehm, Jason Carey, Augustine Kong, Twee Hee Ong, Philippe M. Frossard, Donald W. Bowden, Toshimasa Yamauchi, Steve E. Humphries, Cordelia Langford, Xinzhong Li, Hiroshi Ikegami, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Debashish Das, John Beilby, Robin Young, Christian Herder, Asif Rasheed, Neil Robertson, Raimund Erbel, Fumihiko Takeuchi, Markku Laakso, Esteban J. Parra, Panos Deloukas, Eric Boerwinkle, Adan Valladares-Salgado, Chien-Hsiun Chen, Kay-Tee Khaw, Damiano Baldassarre, Ashok Kumar, E. Shyong Tai, Peter S. 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Inst Metab Sci, Cambridge CB2 2QQ, England [ 28 ] Addenbrookes Hosp, Inst Metab Sci, Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 29 ] Baqai Inst Diabetol & Endocrinol, Karachi, Pakistan [ 30 ] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Genet, Oklahoma City, OK 73190 USA [ 31 ] Sir Charles Gairdner Hosp, Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia [ 32 ] Queen Elizabeth II Med Ctr, PathWest Lab Med Western Australia, Nedlands, WA, Australia [ 33 ] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia [ 34 ] Univ Chicago, Dept Med, Chicago, IL 60637 USA [ 35 ] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA [ 36 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 37 ] Landspitali Univ Hosp, Reykjavik, Iceland [ 38 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 39 ] Univ Med Ctr Ulm, Div Endocrinol & Diabet, Dept Internal Med, Ulm, Germany [ 40 ] Nanyang Technol Univ, Lee Kong Chian LKC Sch Med, Singapore 639798, Singapore [ 41 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 42 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 43 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 44 ] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA [ 45 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med, Nashville, TN 37212 USA [ 46 ] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland [ 47 ] Univ Edinburgh, Western Gen Hosp, MRC, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland [ 48 ] CNRS, Unite Mixte Rech UMR 8199, Inst Biol, Lille, France [ 49 ] Univ Lille 2, Inst Pasteur, Lille, France [ 50 ] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England [ 51 ] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Barts & London Genome Ctr, London, England [ 52 ] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China [ 53 ] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan [ 54 ] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan [ 55 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 56 ] China Med Univ, Sch Chinese Med, Taichung, Taiwan [ 57 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 58 ] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore [ 59 ] Indian Council Med Res, Adv Ctr Genom Diabet, Madras Diabet Res Fdn, Dept Mol Genet, Madras, Tamil Nadu, India [ 60 ] Ajou Univ, Sch Med, Dept Prevent Med, Suwon 441749, South Korea [ 61 ] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea [ 62 ] Natl Taiwan Univ, Sch Med, Grad Inst Clin Med, Taipei 10764, Taiwan [ 63 ] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA [ 64 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 65 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 66 ] Ealing Hosp NHS Trust, Southall, Middx, England [ 67 ] Karolinska Inst, Inst Environm Med, Divis Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 68 ] Harokopio Univ, Dept Dietet Nutr, Athens, Greece [ 69 ] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland [ 70 ] Biomed Sci Res Ctr Alexander Fleming, Vari, Greece [ 71 ] INSERM, UMR 1087, Nantes, France [ 72 ] CNRS, UMR 6291, Nantes, France [ 73 ] Univ Nantes, Nantes, France [ 74 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland [ 75 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 76 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 77 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 78 ] Netherlands Consortium Healthy Ageing, Netherland Genom Initiat, Rotterdam, Netherlands [ 79 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 80 ] Univ London Imperial Coll Sci Technol & Med, MRC, Hlth Protect Agcy, Ctr Environm & Hlth, London, England [ 81 ] Iceland Heart Assoc, Kopavogur, Iceland [ 82 ] Univ Duisburg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 83 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 84 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 85 ] Univ Helsinki, Gen Hosp, Unit Gen Practice, Helsinki, Finland [ 86 ] Folkhalsan Res Ctr, Helsinki, Finland [ 87 ] Inst Mexicano Seguro Social, Hosp Gen Reg 1, Unidad Invest Epidemiol Clin, Mexico City, DF, Mexico [ 88 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 89 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 90 ] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA [ 91 ] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA [ 92 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 93 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 94 ] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA [ 95 ] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England [ 96 ] Vaasa Hlth Care Ctr, Vaasa, Finland [ 97 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 98 ] Harvard Univ, Sch Med, Boston, MA USA [ 99 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 100 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 101 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 102 ] Karolinska Univ, Hosp Solna, Ctr Mol Med, Stockholm, Sweden [ 103 ] Helmholtz Zentrum Muenchen, Inst Genet Epidemiol, Neuherberg, Germany [ 104 ] Helmholtz Zentrum Muenchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 105 ] Univ Munich, Clin Cooperat Grp Diabet, Munich, Germany [ 106 ] Helmholtz Zentrum Muenchen, Munich, Germany [ 107 ] Tech Univ Munich, Clin Cooperat Grp Nutrigen & Type Diabet 2, Munich, Germany [ 108 ] German Ctr Diabet Res DZD, 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Hosp, Unit Gen Practice, Oulu, Finland [ 135 ] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore [ 136 ] Ewha Womans Univ, Sch Med, Dept Biochem, Seoul, South Korea [ 137 ] Soongsil Univ, Sch Syst Biomed Sci, Seoul, South Korea [ 138 ] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland [ 139 ] deCODE Genet, Reykjavik, Iceland [ 140 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 141 ] Minist Hlth, Port Louis, Mauritius [ 142 ] Univ Toronto, Dept Anthropol, Mississauga, ON L5L 1C6, Canada [ 143 ] Fdn IMSS, Mexico City, DF, Mexico [ 144 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 145 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 146 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 147 ] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Nedlands, WA 6009, Australia [ 148 ] Univ San Carlos, Off Populat Studies Fdn Inc, Cebu, Philippines [ 149 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England [ 150 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 151 ] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA [ 152 ] Beijing Genom Inst, Shenzhen, Peoples R China [ 153 ] Uppsala Univ, Akad Sjukhuset, Dept Med Sci, Uppsala, Sweden [ 154 ] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA [ 155 ] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA [ 156 ] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA [ 157 ] Shanghai Inst Prevent Med, Shanghai, Peoples R China [ 158 ] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA [ 159 ] Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India [ 160 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 161 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 162 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany [ 163 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 164 ] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia [ 165 ] Nagoya Univ, Grad Sch Med, Div Endocrinol & Diabet, Dept Internal Med, Nagoya, Aichi 4648601, Japan [ 166 ] Chubu Rosai Hosp, Dept Endocrinol & Diabet, Nagoya, Aichi, Japan [ 167 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 168 ] Kyushu Univ, Grad Sch Med Sci, Dept Geriatr Med, Higashi Ku, Fukuoka 812, Japan [ 169 ] Churchill Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford OX3 7LJ, England [ 170 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 171 ] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, World Class Univ Program, Seoul, South Korea [ 172 ] Seoul Natl Univ, Coll Med, Seoul, South Korea [ 173 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 174 ] Inst Mol Med Finland FIMM, Helsinki, Finland [ 175 ] Helmholtz Zentrum Muenchen, Inst Epidemiol 2, Neuherberg, Germany [ 176 ] Univ Kelaniya, Fac Med, Dept Publ Hlth, Ragama, Sri Lanka [ 177 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 178 ] Univ Gen Hosp Attikon, Athens, Greece [ 179 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany [ 180 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 181 ] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA [ 182 ] Partners Ctr Personalized Genom Med, Boston, MA USA [ 183 ] Univ Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 184 ] Univ Dusseldorf, Dept Metab Dis, Dusseldorf, Germany [ 185 ] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA [ 186 ] MIT, Boston, MA USA [ 187 ] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA [ 188 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 189 ] Finnish Diabet Assoc, Tampere, Finland [ 190 ] Pirkanmaa Hosp Dist, Tampere, Finland [ 191 ] Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland [ 192 ] South Karelia Cent Hosp, Lappeenranta, Finland [ 193 ] UCL, Dept Genet Evolut & Environm, Genet Inst, London, England [ 194 ] Diabet Assoc Pakistan, Karachi, Pakistan [ 195 ] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA [ 196 ] Baltimore Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA [ 197 ] Univ Maryland, Sch Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA [ 198 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 199 ] Univ Ulm, Dept Clin Chem, D-89069 Ulm, Germany [ 200 ] Univ Ulm, Cent Lab, D-89069 Ulm, Germany [ 201 ] Uppsala Univ, Dept Med Sci, Uppsala, Sweden [ 202 ] Kyushu Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan [ 203 ] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland [ 204 ] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain [ 205 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 206 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 207 ] IMSS, Ctr Med Nacl Siglo 21, Hosp Especialidades, Unidad Invest Med Bioquim, Mexico City, DF, Mexico [ 208 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 209 ] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia [ 210 ] Kyushu Univ, Med Inst Bioregulat, Res Ctr Genet Informat, Div Genome Anal,Higashi Ku, Fukuoka 812, Japan [ 211 ] Univ Lille 1, Math Lab, CNRS UMR 8524, MODAL Team,INRIA Lille Nord Europe, F-59655 Villeneuve Dascq, France [ 212 ] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan [ 213 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 214 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 215 ] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA [ 216 ] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA [ 217 ] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA [ 218 ] Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea [ 219 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 220 ] Imperial Coll Healthcare NHS Trust, London, England [ 221 ] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA [ 222 ] Blood Syst Res Inst, San Francisco, CA USA [ 223 ] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore [ 224 ] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore [ 225 ] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore [ 226 ] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore [ 227 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Surgery, Epidemiology, Dermatology, Internal Medicine, Medical Microbiology & Infectious Diseases, Medical Research Council (MRC), National Institute for Health Research, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology

Subjects
CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

Published
2014

21. Colocalization of GWAS and eQTL Signals Detects Target Genes

Author

Michael Bilow, Jae Hoon Sul, Eleazar Eskin, Jong Wha J. Joo, Bogdan Pasaniuc, Martijn van de Bunt, Ayellet V. Segrè, Xiao Li, Sriram Sankararaman, and Farhad Hormozdiari

Subjects
0301 basic medicine, Linkage disequilibrium, Genotype, Posterior probability, Quantitative Trait Loci, Datasets as Topic, Genome-wide association study, Locus (genetics), Disease, Computational biology, Biology, Medical and Health Sciences, Genome, Linkage Disequilibrium, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic, Models, Genetics, 2.1 Biological and endogenous factors, Humans, Insulin, Genetic Predisposition to Disease, Aetiology, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, Probability, Genetics & Heredity, 0303 health sciences, Models, Statistical, Models, Genetic, Prevention, Human Genome, Statistical, Biological Sciences, 030104 developmental biology, Glucose, Gene Expression Regulation, Organ Specificity, Sample Size, Expression quantitative trait loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The vast majority of genome-wide association studies (GWAS) risk loci fall in non-coding regions of the genome. One possible hypothesis is that these GWAS risk loci alter the individual’s disease risk through their effect on gene expression in different tissues. In order to understand the mechanisms driving a GWAS risk locus, it is helpful to determine which gene is affected in specific tissue types. For example, the relevant gene and tissue may play a role in the disease mechanism if the same variant responsible for a GWAS locus also affects gene expression. Identifying whether or not the same variant is causal in both GWAS and eQTL studies is challenging due to the uncertainty induced by linkage disequilibrium (LD) and the fact that some loci harbor multiple causal variants. However, current methods that address this problem assume that each locus contains a single causal variant. In this paper, we present a new method, eCAVIAR, that is capable of accounting for LD while computing the quantity we refer to as the colocalization posterior probability (CLPP). The CLPP is the probability that the same variant is responsible for both the GWAS and eQTL signal. eCAVIAR has several key advantages. First, our method can account for more than one causal variant in any loci. Second, it can leverage summary statistics without accessing the individual genotype data. We use both simulated and real datasets to demonstrate the utility of our method. Utilizing publicly available eQTL data on 45 different tissues, we demonstrate that computing CLPP can prioritize likely relevant tissues and target genes for a set of Glucose and Insulin-related traits loci. eCAVIAR is available at http://genetics.cs.ucla.edu/caviar/

Published
2016

22. Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development

Author

Leslie B. Smoot, Blake C. Ballif, Patricia K. Donahoe, Lars Allan Larsen, Amy E. Roberts, Sonia M Mesquita, Lisa G. Shaffer, Jonathan G. Seidman, Alexandre C. Pereira, Søren Brunak, Ayellet V. Segrè, Kasper Lage, Niels Tommerup, Steven C. Greenway, Mark J. Daly, Hiroko Wakimoto, Jill A. Rosenfeld, Joshua M. Gorham, Christine E. Seidman, and William T. Pu

Subjects
Heart disease, Anatomical structures, ved/biology.organism_classification_rank.species, Environment, Biology, Bioinformatics, Statistics, Nonparametric, Environmental risk, Risk Factors, Databases, Genetic, medicine, Humans, Genetic Predisposition to Disease, Protein Interaction Maps, cardiovascular diseases, Model organism, Genetics, Multidisciplinary, Heart development, ved/biology, Infant, Newborn, Heart, Biological Sciences, medicine.disease, Atrial septum, Transcriptome, Hand Deformities, Congenital, Protein network, Chd risk
Abstract

Congenital heart disease (CHD) occurs in ∼1% of newborns. CHD arises from many distinct etiologies, ranging from genetic or genomic variation to exposure to teratogens, which elicit diverse cell and molecular responses during cardiac development. To systematically explore the relationships between CHD risk factors and responses, we compiled and integrated comprehensive datasets from studies of CHD in humans and model organisms. We examined two alternative models of potential functional relationships between genes in these datasets: direct convergence, in which CHD risk factors significantly and directly impact the same genes and molecules and functional convergence, in which risk factors significantly impact different molecules that participate in a discrete heart development network. We observed no evidence for direct convergence. In contrast, we show that CHD risk factors functionally converge in protein networks driving the development of specific anatomical structures (e.g., outflow tract, ventricular septum, and atrial septum) that are malformed by CHD. This integrative analysis of CHD risk factors and responses suggests a complex pattern of functional interactions between genomic variation and environmental exposures that modulate critical biological systems during heart development.

Published
2012

23. Hundreds of variants clustered in genomic loci and biological pathways affect human height

Author

Vilmundur Gudnason, Robert J. Weyant, Robert C. Kaplan, Jeffrey R. O'Connell, Panos Deloukas, Barbara McKnight, Alessandro De Grandi, Gert-Jan B. van Ommen, Eric Boerwinkle, Liming Liang, Douglas F. Levinson, Richard B. Hayes, Mark I. McCarthy, Andrew P. Morris, Joel N. Hirschhorn, Jaakko Kaprio, Nilesh J. Samani, Inke R. König, Frank B. Hu, Nicholas J. Wareham, Ozren Polasek, Michael C. Turchin, Daniel F. Gudbjartsson, Wilmar Igl, Vincent Mooser, Aki S. Havulinna, Themistocles L. Assimes, Cameron D. Palmer, Lachlan J. M. Coin, Eva Albrecht, Hana Lango Allen, Inês Barroso, Eco J. C. de Geus, H.-Erich Wichmann, Michael A. Province, Sarah H. Wild, Patricia B. Munroe, Jeanette Erdmann, Mattias Lorentzon, Michael Preuss, Nelson B. Freimer, Mika Kähönen, Tushar Bhangale, Nicole L. Glazer, Markku S. Nieminen, Andrew A. Hicks, Jonathan Tyrer, Grant W. Montgomery, Ruth J. F. Loos, Shaun Purcell, Manfred Kayser, Marjo-Riitta Järvelin, Guillaume Paré, Terho Lehtimäki, Irene Pichler, Ida Surakka, Tõnu Esko, Peter Kraft, Talin Haritunians, Juha Sinisalo, Mari Nelis, Veronique Vitart, Alan R. Sanders, Alistair S. Hall, Carlos Iribarren, Mark E. Cooper, André G. Uitterlinden, Peter Kovacs, David Schlessinger, Florian Ernst, Marja-Liisa Lokki, M. Juhani Junttila, Martin Ridderstråle, Jorma Viikari, Inga Prokopenko, Christopher J. O'Donnell, Jennie Hui, Aila Rissanen, Gonçalo R. Abecasis, Jouke-Jan Hottenga, Tomi Pastinen, Kevin B. Jacobs, Jan Smit, Kristin G. Ardlie, Niina Pellikka, Neil R. Robertson, Martina Müller, John F. Peden, Mary F. Feitosa, Thomas W. Winkler, Kari Stefansson, Jianjun Liu, Jaana Laitinen, Shen Haiqing, Martin Farrall, Nilanjan Chatterjee, Eleanor Wheeler, Tamara B. Harris, Åsa Johansson, Anders Hamsten, Elizabeth K. Speliotes, Larry D. Atwood, Valgerdur Steinthorsdottir, Elin Grundberg, Nicole Soranzo, Anna-Liisa Hartikainen, Devin Absher, Cecilia M. Lindgren, Rany M. Salem, Lorena Citterio, Karol Estrada, Sven Bergmann, Tony Kwan, Thomas Meitinger, Alan F. Wright, Richard N. Bergman, Sailaja Vedantam, Kirsi H. Pietiläinen, Lina Zgaga, Anne U. Jackson, Stefan Schreiber, Ju-Hyun Park, Nicola Glorioso, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Lenore J. Launer, Heribert Schunkert, Thomas Quertermous, Mari Liis Tammesoo, Dorret I. Boomsma, Harry Campbell, Albert V. Smith, Andrew R. Wood, Caroline S. Fox, Paavo Zitting, Gabrielle Boucher, Alex N. Parker, Jennifer G. Sambrook, Joyce B. J. van Meurs, Heather M. Stringham, Marjolein J. Peters, Sekar Kathiresan, Elisabeth Widen, Caroline Hayward, Tim D. Spector, Dawn M. Waterworth, Carlo Rivolta, Antti Jula, Albert Hofman, Hugh Watkins, Wendy L. McArdle, Roberto Elosua, Markku Koiranen, Paul M. Ridker, Iris M. Heid, Lee M. Kaplan, Brenda W.J.H. Penninx, Peter M. Visscher, Claes Ohlsson, Per Hall, Benjamin F. Voight, Ben A. Oostra, Anna F. Dominiczak, Martin den Heijer, Andrea Maschio, Quince Gibson, Peter P. Pramstaller, Nigel W. Rayner, Carsten Oliver Schmidt, Toby Johnson, Henrik Grönberg, M. Carola Zillikens, Alan R. Shuldiner, Cornelia M. van Duijn, Samuli Ripatti, Erik Ingelsson, John R. Thompson, Stephen J. Chanock, Johannes Kettunen, David J. Hunter, Lyle J. Palmer, Ulf Gyllensten, Jianfeng Xu, Astrid Petersmann, Johan G. Eriksson, Guillaume Lettre, Teresa Ferreira, Fredrik Wiklund, Andreas Ziegler, Andres Metspalu, Jerome I. Rotter, Suzanne Rafelt, Julius S. Ngwa, Francis S. Collins, Michael N. Weedon, Thomas Illig, Wolfgang Hoffman, Nancy L. Heard-Costa, Anke Tönjes, Daniel I. Chasman, Alice M. Arnold, Olli T. Raitakari, Anna L. Dixon, Lu Qi, Michael E. Goddard, Anneli Pouta, Mark J. Caulfield, Liesbeth Vandenput, Christian Gieger, L. Adrienne Cupples, Veikko Salomaa, Elizabeth L. Altmaier, Nicholas G. Martin, Thomas D. Kocher, Jubao Duan, David S. Siscovick, Heikki V. Huikuri, Willem H. Ouwehand, Kari E. North, Christian Hengstenberg, Jacques S. Beckmann, Constance Chen, John Perry, Ana Marušić, Olle Melander, John D. Rioux, Erika Salvi, Andrew T. Hattersley, Paul Elliott, Leif Groop, Cristen J. Willer, Manuela Uda, Gudmar Thorleifsson, Eric E. Schadt, Charles C. White, Pablo V. Gejman, Serena Sanna, Ulla Sovio, Robert W. Lawrence, Unnur Thorsteinsdottir, Ayellet V. Segrè, Daniele Cusi, G. Bragi Walters, Ken Sin Lo, Ivana Kolcic, Igor Rudan, Sonja I. Berndt, Keri L. Monda, Soumya Raychaudhuri, Jian'an Luan, Joshua C. Randall, Anthony J. Balmforth, Yurii S. Aulchenko, Peter Almgren, Karen L. Mohlke, Timothy M. Frayling, Shamika Ketkar, Thomas H. Mosley, Markus Perola, Henry Völzke, Laura Zagato, Leena Peltonen, Seppo Koskinen, Massimo Mangino, Ke Hao, Tsegaselassie Workalemahu, Lambertus A. Kiemeney, Helene Alavere, Jaakko Tuomilehto, Reedik Mägi, James F. Wilson, Ingrid B. Borecki, Zoltán Kutalik, Michael Stumvoll, Dominique J. Verlaan, Arthur W. Musk, Eero Kajantie, Jian Yang, Joshua W. Knowles, Tuomas O. Kilpeläinen, Michael Boehnke, G. Mark Lathrop, John Beilby, Fernando Rivadeneira, Gudny Eiriksdottir, Gonneke Willemsen, Andrew C. Heath, Antonella Mulas, Katja K.H. Aben, David P. Strachan, Thor Aspelund, Jing Hua Zhao, Psychiatry, NCA - Anxiety & Depression, EMGO - Mental health, Internal Medicine, Epidemiology, Intensive Care, Clinical Genetics, Genetic Identification, Medical Research Council (MRC), Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Genetics of Complex Traits, University of Exeter, Department of Epidemiology, Erasmus Medical Centre, Netherlands Genomics Initiative (NGI), Netherlands Genomics Initiative, Department of Medicine, Montreal, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, deCODE Genetics, deCODE genetics [Reykjavik], Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, the Genetic Investigation of ANthropocentric Traits (GIANT) Consortium, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Netherlands Twin Register (NTR), Multifactorial Inheritance, [SDV]Life Sciences [q-bio], Genome-wide association study, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, POPULATION, SNPS, Genetics, 0303 health sciences, Multidisciplinary, HERITABILITY, COMMON VARIANTS, Phenotype, DISEASES, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, GROWTH, Allelic heterogeneity, Chromosomes, Human, Pair 3, Metabolic Networks and Pathways, TRAITS, Common disease-common variant, General Science & Technology, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, ADULT, STRATIFICATION, MD Multidisciplinary, Humans, Genetic Predisposition to Disease, Genetic variability, 030304 developmental biology, Science & Technology, MULTIDISCIPLINARY SCIENCES, Genome, Human, Hormonal regulation [IGMD 6], Body Height, Genetic architecture, wide association analysis common variants heritability population adult stratification diseases traits growth snps, WIDE ASSOCIATION ANALYSIS, Genetic Loci, Evaluation of complex medical interventions [NCEBP 2], Polygene, Expression quantitative trait loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways ( P=0.016) and that underlie skeletal growth defects ( P

Published
2010

24. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans

Author

Mehran Taherian, Debra Bradbury, Emmanouil T. Dermitzakis, Manuel A. Rivas, Deborah C. Mash, Ayellet V. Segrè, Luan Lin, Ping Guan, Kimberly Ramsey, Mary Barcus, Deborah Colantuoni, Xiaoquan Wen, Julian Maller, Ferran Reverter, Laura A. Siminoff, Bryan Gillard, Dana R. Valley, Gen Li, Jeffery P. Struewing, Philip A. Branton, Roderic Guigó, Nancy Roche, Charles Shive, Christopher Choi, Johnell Fleming, Timothée Flutre, Latarsha J. Carithers, Taylor Young, Anuar Konkashbaev, Matthew Stephens, Daniel G. MacArthur, Rick Hasz, Mark I. McCarthy, Joel N. Hirschhorn, Sara Mostafavi, Lucas D. Ward, Amanda Brown, Ki Sung Um, Manolis Kellis, Robin Burges, Eric R. Gamazon, Heather M. Traino, Gary F. Temple, Karna Robinson, Leslie H. Sobin, Daphne Koller, Halit Ongen, Bernadette Mestichelli, John T. Lonsdale, Kimberly M. Valentino, Ellen Gelfand, David Tabor, Taru Tukiainen, Mike Salvatore, Gary Walters, Susan L. Sullivan, Jason Bridge, Carolyn C. Compton, Kenneth W. Hambright, Joy T. Boyer, Bin Zhang, Anita H. Undale, Michael Sammeth, Helen M. Moore, Nancy J. Cox, Andrey A. Shabalin, Kenyon Erickson, Nicole C. Lockhart, Gad Getz, Pushpa Hariharan, Benjamin Iriarte, Jakob M. Goldmann, Pouya Kheradpour, John Syron, Jimmie B. Vaught, Jun Zhu, Hae Kyung Im, Jean Monlong, John Seleski, Marta Melé, Edmund Lo, Yvonne Marcus, Pedro G. Ferreira, Stephen A. Buia, Liqun Qi, Greg E. Korzeniewski, Michael T. Moser, Ivan Rusyn, Andrew B. Nobel, Casandra A. Trowbridge, Timothy J. Sullivan, Chunrong Lu, Barbara A. Foster, Laura Barker, Jun Liu, Shenpei Wu, Anna M. Smith, Joanne P. Demchok, Dan L. Nicolae, Jeffrey A. Thomas, Jonathan K. Pritchard, Sherilyn Sawyer, Fred A. Wright, Wendy Winckler, Angela Britton, Zhidong Tu, Jorge Tejada, David S. DeLuca, Yi-Hui Zhou, Roger Little, Jeffrey McLean, Simona Volpi, Tõnu Esko, Kristin G. Ardlie, Monkol Lek, Daniel C. Rohrer, Susan E. Koester, Harold Magazine, Mark Miklos, Quan Long, Jialiang Yang, Cameron D. Palmer, Maghboeba Mosavel, Scott D. Jewell, Tuuli Lappalainen, Alexis Battle, Ellen Karasik, Margaret J. Basile, Saboor Shad, Denee Tidwell, Yan Meng, Chana A. Rabiner, Tao Huang, Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), NIH, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
RNA, Untranslated, Genotype, RNA Splicing, [SDV]Life Sciences [q-bio], Quantitative Trait Loci, Blood Pressure, Pilot Projects, Quantitative trait locus, Biology, Expression quantitative trait loci, eQTL, Article, Human disease, Genotype-Tissue Expression, Genetic variation, Humans, Disease, Gene Regulatory Networks, Alleles, Biomedicine, Genetics, Regulation of gene expression, Multidisciplinary, Genome, Human, Sequence Analysis, RNA, business.industry, GTPase-Activating Proteins, Genetic Variation, Tibial Arteries, Gene Expression Regulation, Organ Specificity, Multigene Family, Transcriptome, business, Genome-Wide Association Study
Abstract

UMR AGAP - équipe DAAV (Diversité, adaptation et amélioration de la vigne)139 auteurs : Ardlie KG, Deluca DS, Segrè AV, Sullivan TJ, Young TR, Gelfand ET, Trowbridge CA, Maller JB, Tukiainen T, Lek M, Ward LD, Kheradpour P, Iriarte B, Meng Y, Palmer CD, Esko T, Winckler W, Hirschhorn JN, Kellis M, MacArthur DG, Getz G, Shabalin AA, Li G, Zhou YH, Nobel AB, Rusyn I, Wright FA, Lappalainen T, Ferreira PG, Ongen H, Rivas MA, Battle A, Mostafavi S, Monlong J, Sammeth M, Melé M, Reverter F, Goldmann JM, Koller D, Guigó R, McCarthy MI, Dermitzakis ET, Gamazon ER, Im HK, Konkashbaev A, Nicolae DL, Cox NJ, Flutre T, Wen X, Stephens M, Pritchard JK, Tu Z, Zhang B, Huang T, Long Q, Lin L, Yang J, Zhu J, Liu J, Brown A, Mestichelli B, Tidwell D, Lo E, Salvatore M, Shad S, Thomas JA, Lonsdale JT, Moser MT, Gillard BM, Karasik E, Ramsey K, Choi C, Foster BA, Syron J, Fleming J, Magazine H, Hasz R, Walters GD, Bridge JP, Miklos M, Sullivan S, Barker LK, Traino HM, Mosavel M, Siminoff LA, Valley DR, Rohrer DC, Jewell SD, Branton PA, Sobin LH, Barcus M, Qi L, McLean J, Hariharan P, Um KS, Wu S, Tabor D, Shive C, Smith AM, Buia SA, Undale AH, Robinson KL, Roche N, Valentino KM, Britton A, Burges R, Bradbury D, Hambright KW, Seleski J, Korzeniewski GE, Erickson K, Marcus Y, Tejada J, Taherian M, Lu C, Basile M, Mash DC, Volpi S, Struewing JP, Temple GF, Boyer J, Colantuoni D, Little R, Koester S, Carithers LJ, Moore HM, Guan P, Compton C, Sawyer SJ, Demchok JP, Vaught JB, Rabiner CA, Lockhart NC, Ardlie KG, Getz G, Wright FA, Kellis M, Volpi S, Dermitzakis ET.; Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.

Published
2015

25. Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases

Author

Mark I. McCarthy, Joel N. Hirschhorn, Karna Robinson, Edmund Lo, Shenpei Wu, Stephen A. Buia, Jeffrey A. Thomas, David S. DeLuca, Francesca Petralia, Saboor Shad, Casandra A. Trowbridge, Simona Volpi, Debra Bradbury, Gad Getz, Zhidong Tu, Jialiang Yang, Magboeba Mosavel, Eric R. Gamazon, Carmen Argmann, Tuuli Lappalainen, Rick Hasz, Kimberly Ramsey, Deborah Colantuoni, Xiaoquan Wen, Nicole C. Lockhart, Gary F. Temple, Margaret J. Basile, Jonathan K. Pritchard, Julian Maller, Monkol Lek, Alexis Battle, Ellen Gelfand, Bryan Gillard, Dana R. Valley, Quan Long, Ellen Karasik, Anna M. Smith, Roderic Guigó, Daphne Koller, Halit Ongen, John T. Lonsdale, Daniel C. Rohrer, Helen M. Moore, Kristin G. Ardlie, Charles Shive, Ping Guan, Charles V. Mobbs, Taru Tukiainen, Nancy Roche, Taylor Young, Philip A. Branton, Anuar Konkashbaev, Matthew Stephens, Fred A. Wright, Gary Walters, Amanda M. V. Brown, Pedro G. Ferreira, Christopher Choi, Denee Tidwell, Greg E. Korzeniewski, Lucas D. Ward, Andrey A. Shablin, Scott Jewel, Manuel A. Rivas, Yan Meng, Timothée Flutre, Pushpa Hariharan, Deborah C. Mash, Susan E. Koester, John Seleski, Johnelle Fleming, Susan L. Sullivan, Kimberly M. Valentino, Yi-Hui Zhou, Harold Magazine, Latarsha J. Carithers, Jorge Tejada, Daniel G. MacArthur, Mark Miklos, Dan L. Nicolae, Chana A. Rabiner, Roger Little, Nancy J. Cox, Pouya Kheradpour, Jeff Struewing, Barnaby E. Robles, Sara Mostafavi, Yong Zhao, Kenneth W. Hambright, Michael Sammeth, Sherilyn Sawyer, Joy T. Boyer, Manolis Kellis, Robin Burges, Mike Salvatore, Wendy Winckler, Angela Britton, Gen Li, Cameron D. Palmer, Jason Bridge, Tao Huang, Laura Barker, Emmanouil T. Dermitzakis, Mehran Taherian, Ayellet V. Segrè, Luan Lin, Laura A. Siminoff, Ferran Reverter, John Syron, Jimmie B. Vaught, Jun Zhu, Bin Zhang, Benjamin Iriarte, Jean Monlong, Jakob Goldman, Marta Melé, Michael T. Moser, Ivan Rusyn, Andrew B. Nobel, Timothy J. Sullivan, Heather M. Traino, Carolyn C. Compton, Chunrong Lu, Jun Liu, Anita H. Undale, Kenyon Erickson, Eric E. Schadt, Leslie H. Sobin, Bernadette Mestichelli, David Tabor, Yvonne Marcus, Liqun Qi, Barbara A. Foster, Joanne P. Demchok, Dermitzakis, Emmanouil, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Ward, Lucas D., Kheradpour, Pouya, Iriarte, Benjamin, and Kellis, Manolis

Subjects
Adult, Male, Systems biology, Gene Expression, Computational biology, Biology, medicine.disease_cause, Biologia computacional, Article, Organ Specificity/genetics, Transcriptome, 03 medical and health sciences, Mice, Young Adult, 0302 clinical medicine, Gene expression, medicine, Aging/genetics, Animals, Cluster Analysis, Humans, ddc:576.5, Gene, Genetic Association Studies, 030304 developmental biology, Aged, Genetics, Regulation of gene expression, 0303 health sciences, Mutation, Multidisciplinary, Gene Expression Profiling, Molecular Sequence Annotation, Computational Biology/methods, Middle Aged, 3. Good health, Gene expression profiling, Gene Expression Regulation, Female, Organ Specificity, 030217 neurology & neurosurgery
Abstract

Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross-tissue synchronization of age-related gene expression changes are observed, and some essential tissues (e.g., heart and lung) show much stronger “co-aging” than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases., National Cancer Institute (U.S.), National Human Genome Research Institute (U.S.), National Heart, Lung, and Blood Institute, National Institute on Drug Abuse (NIDA), National Institute of Mental Health (U.S.), National Institute of Neurological Disorders and Stroke (U.S.)

Published
2015

26. Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease

Author

Christina Willenborg, Xia Yang, Winfried März, Ruth McPherson, Sekar Kathiresan, Thomas Quertermous, Christopher B. Granger, Alexandre F.R. Stewart, Svati H. Shah, Nilesh J. Samani, Themistocles L. Assimes, Majid Nikpay, Stefan Blankenberg, Sujoy Ghosh, Ayellet V. Segrè, Stanley L. Hazen, Ville-Petteri Mäkinen, Christopher P. Nelson, Juan C. Vivar, Heribert Schunkert, Christopher J. O'Donnell, Stephen E. Epstein, J Erdmann, Reijo Laaksonen, and Muredach P. Reilly

Subjects
Receptor complex, 1.1 Normal biological development and functioning, Clinical Sciences, Genome-wide association study, Context (language use), Coronary Artery Disease, Cardiorespiratory Medicine and Haematology, Biology, Cardiovascular, Genome, Article, Underpinning research, Genetic variation, Genetics, 2.1 Biological and endogenous factors, Humans, Aetiology, Gene, Heart Disease - Coronary Heart Disease, Genetic association, Human Genome, Atherosclerosis, Genetic architecture, pathway analysis, Heart Disease, Cardiovascular System & Hematology, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Objective— Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Approaches and Results— Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11 089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15 502 cases/55 730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P P NCAM1 , FYN , FURIN , etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. Conclusions— These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD.

Published
2014

27. 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

28. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Author

Tom Forsén, Lars Lind, Shobha Potluri, Leif Groop, Yik Ying Teo, Andrew P. Morris, Frank Burslem, Jason Flannick, Torben Jørgensen, Tanya M. Teslovich, Noël P. Burtt, Jaspal S. Kooner, Patrick Sulem, Nicola L. Beer, Sekar Kathiresan, Ivan Brandslund, Heather M. Stringham, James G. Wilson, Jeff K. Trimmer, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Zachary Dymek, Yossi Farjoun, Tim Rolph, Unnur Thorsteinsdottir, Karen L. Mohlke, Jaakko Tuomilehto, John C. Chambers, Gudmar Thorleifsson, Rasmus Ribel-Madsen, Anubha Mahajan, Christian Fuchsberger, Jasmina Kravic, Kari Stefansson, Benjamin F. Voight, Craig L. Hanis, John Blangero, Veikko Salomaa, Desiree Douglas, Rafn Benediktsson, Benjamin Glaser, David R. Cox, Ann Marie Richard, Torben Hansen, Hanna Skärstrand, Gil Atzmon, Pål R. Njølstad, Suzanne B.R. Jacobs, Erik Ingelsson, Bo Isomaa, Yoon Shin Cho, Ayellet V. Segrè, Julia Brosnan, Thomas Meitinger, David Altshuler, Kristian Hveem, Astradur B. Hreidarsson, Pierre Fontanillas, Gisli Masson, Daniel F. Gudbjartsson, Cramer Christensen, Tiinamaija Tuomi, Augustine Kong, Fariba Vaziri-Sani, Anders Molven, Rainer Rauramaa, Niels Grarup, Stacey Gabriel, Michael Boehnke, Ravindranath Duggirala, Donald W. Bowden, Oluf Pedersen, Marit E. Jørgensen, Markku Laakso, Jong-Young Lee, Stefan Johansson, E. Shyong Tai, Allan Linneberg, Mark I. McCarthy, Timothy Fennell, and [ 1 ] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02141 USA [ 2 ] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA [ 3 ] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA [ 4 ] Amgen Inc, deCODE Genet, Reykjavik, Iceland [ 5 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England [ 6 ] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn,Ctr Basic Metab Res, Copenhagen, Denmark [ 7 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 8 ] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA [ 9 ] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA [ 10 ] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA [ 11 ] Landspitali Univ Hosp, Dept Endocrinol & Metab, Reykjavik, Iceland [ 12 ] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA [ 13 ] Wake Forest Univ, Bowman Gray Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA [ 14 ] Wake Forest Univ, Bowman Gray Sch Med, Ctr Diabet Res, Winston Salem, NC USA [ 15 ] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC USA [ 16 ] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC USA [ 17 ] Vejle Hosp, Dept Clin Biochem, Vejle, Denmark [ 18 ] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark [ 19 ] Pfizer Inc, Cardiovasc & Metab Dis Res Unit, Cambridge, MA USA [ 20 ] Prescient Life Sci, Cardiovasc & Metab Dis Practice, London, England [ 21 ] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England [ 22 ] Univ London Imperial Coll Sci Technol & Med, Healthcare Natl Hlth Serv NHS Trust, London, England [ 23 ] Ealing Hosp NHS Trust, Southall, Middx, England [ 24 ] Hallym Univ, Dept Biomed Sci, Chunchon, South Korea [ 25 ] Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark [ 26 ] Lund Univ, Dept Clin Sci, Unit Diabet & Celiac Dis, Malmo, Sweden [ 27 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 28 ] Vaasa Hlth Care Ctr, Diabetes Care Unit, Vaasa, Finland [ 29 ] Hadassah Hebrew Univ, Med Ctr, Endocrinol & Metab Serv, Jerusalem, Israel [ 30 ] IDRG, Holon, Israel [ 31 ] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA [ 32 ] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark [ 33 ] Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, Levanger, Norway [ 34 ] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 35 ] Folkhalsan Res Ctr, Helsinki, Finland [ 36 ] Dept Social Serv & Hlth Care, Pietarsaari, Finland [ 37 ] Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, Bergen, Norway [ 38 ] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway [ 39 ] Univ Bergen, Dept Biomed, Bergen, Norway [ 40 ] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark [ 41 ] Univ Copenhagen, Fac Hlth & Med, Copenhagen, Denmark [ 42 ] Aalborg Univ, Fac Med, Aalborg, Denmark [ 43 ] Steno Diabet Ctr, DK-2820 Gentofte, Denmark [ 44 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 45 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Div Cardiol, Boston, MA 02114 USA [ 46 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 47 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, NHLI, London, England [ 48 ] Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden [ 49 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 50 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 51 ] Korea Natl Inst Hlth, Osong Hlth Technol, Ctr Genome Sci, Seoul, Chungcheongbuk, South Korea [ 52 ] Uppsala Univ, Dept Med Sci, Uppsala, Sweden [ 53 ] Glostrup Univ Hosp, Dept Clin Expt Res, Glostrup, Denmark [ 54 ] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany [ 55 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 56 ] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway [ 57 ] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway [ 58 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England [ 59 ] Pfizer Inc, Appl Quantitat Genotherapeut, San Francisco, CA USA [ 60 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 61 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 62 ] Natl Inst Hlth & Welf THL, Helsinki, Finland [ 63 ] Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 64 ] Natl Univ Singapore, Natl Univ Hlth Syst, Dept Med, Singapore 117548, Singapore [ 65 ] Duke Natl Univ Singapore, Grad Sch Med, Dept Med, Singapore, Singapore [ 66 ] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore [ 67 ] Genome Inst Singapore, Agcy Sci Technol & Res, Singapore, Singapore [ 68 ] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore [ 69 ] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore [ 70 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 71 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 72 ] Natl Inst Hlth & Welf, Diabetes Prevent Unit, Helsinki, Finland [ 73 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 74 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 75 ] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA [ 76 ] Univ Mississippi, Med Ctr, Dept Phys & Biophys, Jackson, MS 39216 USA [ 77 ] Churchill Hosp, Hlth Res NIHR Biomed Res Ctr, Oxford Natl Inst, Oxford, England [ 78 ] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway [ 79 ] Univ Helsinki, Finnish Inst Mol Med FIMM, Helsinki, Finland [ 80 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 81 ] MIT, Dept Biol, Cambridge, MA 02139 USA

Subjects
Blood Glucose, endocrine system diseases, Genotype, Ion Transport/genetics, Molecular Sequence Data, Mutation, Missense, Genome-wide association study, Blood Glucose/genetics, Zinc Transporter 8, Biology, medicine.disease_cause, Insúlín, Frameshift mutation, Sykursýki, Mutation, Missense/genetics, Mice, Cation Transport Proteins/genetics, Genetics, medicine, Glucose homeostasis, Animals, Humans, Cation Transport Proteins, Genetic Association Studies, Mice, Knockout, Mutation, Ion Transport, SLC30A8, Base Sequence, Genetic heterogeneity, nutritional and metabolic diseases, Sequence Analysis, DNA, Arfgengi, Blóðsykur, 3. Good health, Proinsulin/blood, Diabetes Mellitus, Type 2/genetics, Diabetes Mellitus, Type 2, biology.protein, Haploinsufficiency, Proinsulin
Abstract

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/Open Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention. US National Institutes of Health (NIH) Training 5-T32-GM007748-33 Doris Duke Charitable Foundation 2006087 Fulbright Diabetes UK Fellowship BDA 11/0004348 Broad Institute from Pfizer, Inc. NIH U01 DK085501 U01 DK085524 U01 DK085545 U01 DK085584 Swedish Research Council Dnr 521-2010-3490 Dnr 349-2006-237 European Research Council (ERC) GENETARGET T2D GA269045 ENGAGE 2007-201413 CEED3 2008-223211 Sigrid Juselius Foundation Folkh lsan Research Foundation ERC AdG 293574 Research Council of Norway 197064/V50 KG Jebsen Foundation University of Bergen Western Norway Health Authority Lundbeck Foundation Novo Nordisk Foundation Wellcome Trust WT098017 WT064890 WT090532 WT090367 WT098381 Uppsala University Swedish Research Council and the Swedish Heart- Lung Foundation Academy of Finland 124243 102318 123885 139635 Finnish Heart Foundation Finnish Diabetes Foundation, Tekes 1510/31/06 Commission of the European Community HEALTH-F2-2007-201681 Ministry of Education and Culture of Finland European Commission Framework Programme 6 Integrated Project LSHM-CT-2004-005272 City of Kuopio and Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Disease NIH/NIDDK U01-DK085545 National Heart, Lung, and Blood Institute (NHLBI) National Institute on Minority Health and Health Disparities N01 HC-95170 N01 HC-95171 N01 HC-95172 European Union Seventh Framework Programme, DIAPREPP Swedish Child Diabetes Foundation (Barndiabetesfonden) 5U01DK085526 DK088389 U54HG003067 R01DK072193 R01DK062370 Z01HG000024 info:eu-repo/grantAgreement/EC/FP7/202013

Published
2014

29. Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems

Author

Sorin Draghici, Silvia Mora, David Torrents, Ayellet V. Segrè, Evarist Planet, David Sebastián, Chenjing Yang, Sílvia Bonàs-Guarch, Antoni Vidal-Puig, Josée Dupuis, Antonio Zorzano, Montserrat Puiggròs, Eleonora Sorianello, Vicent Ribas, Sergio Rodriguez-Cuenca, Jose C. Florez, Josep M. Mercader, and Universitat de Barcelona

Subjects
Cancer Research, Candidate gene, Genome-wide association study, Genome, 0302 clinical medicine, Insulin, Genetics (clinical), Genetics, 0303 health sciences, Diabetis, biology, Systems Biology, Diabetes, Genomics, 3. Good health, Mitochondria, Functional Genomics, Crosstalk (biology), Cardiovascular diseases, Functional genomics, Metabolic Networks and Pathways, Research Article, lcsh:QH426-470, Systems biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Metabolic Networks, Insulin resistance, medicine, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Obesity, Molecular Biology, Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Malalties cardiovasculars, Computational Biology, medicine.disease, Signaling Networks, lcsh:Genetics, Insulin receptor, Glucose, Diabetes Mellitus, Type 2, Gene Expression Regulation, biology.protein, Insulin Resistance, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein–protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10−5). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases., Author Summary It has been shown that the crosstalk between insulin signaling and the mitochondria may be involved in the etiology of type 2 diabetes. In order to characterize the molecular basis of this crosstalk, we mined and filtered several interaction databases of different natures, including protein–protein interactions, gene co-expression, signaling, and metabolic pathway interactions, to identify reliable direct and indirect interactions between insulin signaling cascade and mitochondria genes. This allowed us to identify 286 genes that are associated simultaneously with insulin signaling and mitochondrial genes and therefore could act as a molecular bridge between both systems. We performed in vitro and in vivo experiments where the insulin signaling or the mitochondrial function were disrupted, and we found deregulation of these connecting genes. Finally, we found that common variants in genomic regions where these genes lie are enriched for genetic associations with type 2 diabetes and glycemic traits according to large genome-wide association meta-analyses. In summary, we reconstructed the network implicated in the crosstalk between the mitochondria and the insulin signaling and provide a list of genes connecting both systems. We also propose new potential type 2 diabetes candidate genes.

Published
2012

30. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Author

Sarah Edkins, Anubha Mahajan, Nita G. Forouhi, Danish Saleheen, Lori L. Bonnycastle, Jackie F. Price, Lu Qi, Jasmina Kravic, Laura J. Scott, Susanne Moebus, Timothy M. Frayling, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Lars Lind, James F. Wilson, John Beilby, Emil Rehnberg, Veikko Salomaa, Richard N. Bergman, Thomas Illig, Ruth J. F. Loos, Martina Müller-Nurasyid, Andrew Crenshaw, Karl-Heinz Jöckel, Krista Fischer, James B. Meigs, Rob M. van Dam, George Dedoussis, Christopher J. Groves, Julia Meyer, Valur Emilsson, Timo Saaristo, Kees Hovingh, Joseph Trakalo, Peter Kraft, André G. Uitterlinden, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Denis Rybin, Gonçalo R. Abecasis, Andrew T. Hattersley, Sonia Shah, Bruna Gigante, Jaakko Tuomilehto, Pierre Fontanillas, Kay-Tee Khaw, Annette Peters, Andrew D. Johnson, Rafn Benediktsson, Candace Guiducci, Andrew P. Morris, Tõnu Esko, Bo Isomaa, Anne U. Jackson, Beverley Balkau, Peter Donnelly, Thomas W. Mühleisen, Barbara Thorand, Tom Wilsgaard, Alan R. Shuldiner, David J. Hunter, Roman Wennauer, Karl Gertow, Wen Hong L. Kao, Alan James, Cordelia Langford, Christian Herder, Timo A. Lakka, Soumya Raychaudhuri, Jian'an Luan, Katharine R. Owen, Jennie Hui, Francis S. Collins, Juha Saltevo, David Couper, Bernhard O. Boehm, Sonali Pechlivanis, Raimund Erbel, Suthesh Sivapalaratnam, Markku Laakso, Augustine Kong, Heather M. Stringham, Leena Kinnunen, Kathleen Stirrups, Markus M. Nöthen, Ashok Kumar, Andrew R. Wood, Delilah Zabaneh, Rona J. Strawbridge, Bill Musk, Noël P. Burtt, Eeva Korpi-Hyövälti, Oddgeir L. Holmen, Inga Prokopenko, Marilyn C. Cornelis, Elodie Eury, Angela Silveira, Inês Barroso, Michael Roden, Unnur Thorsteinsdottir, Josée Dupuis, Han Chen, Cornelia M. van Duijn, Samuli Ripatti, Anna Jonsson, Gerald Steinbach, George B. Grant, Kristian Hveem, Andres Metspalu, Astradur B. Hreidarsson, Guillaume Charpentier, John Danesh, Claudia Langenberg, Sirkka Keinänen-Kiukaanniemi, Christian Dina, James S. Pankow, Panos Deloukas, Rainer Rauramaa, Satu Männistö, Kaarel Krjutškov, Eric Boerwinkle, Wendy Winckler, Valeriya Lyssenko, Anders Hamsten, Philippe Froguel, Nancy L. Pedersen, Harry Campbell, Sailaja Vedantam, Nicholas J. Wareham, Hassan Khan, Simon C. Potter, Damiano Baldassarre, Tiinamaija Tuomi, Vasiliki Lagou, Mozhgan Dorkhan, Stavroula Kanoni, Benjamin F. Voight, Wolfgang Rathmann, Tanya M. Teslovich, Antigone S. Dimas, Bengt Sennblad, Olle Melander, Albert Hofman, Mark I. McCarthy, Andrew D. Morris, Fabrizio Veglia, Karen L. Mohlke, Melissa Parkin, Sarah E. Hunt, Frank B. Hu, Elena Tremoli, Gudmar Thorleifsson, Steve E. Humphries, Jason Carey, Eero Lindholm, Alex S. F. Doney, Peter Almgren, Erik Ingelsson, Colin N. A. Palmer, Johanna Kuusisto, Inger Njølstad, Ann-Christine Syvänen, Leena Peltonen, Eric J.G. Sijbrands, Ross M. Fraser, Mieke D. Trip, Ghazala Mirza, Robert W. Lawrence, Neil Robertson, David Altshuler, Harald Grallert, Gunnar Sigurðsson, Kari Stefansson, N. William Rayner, Johan G. Eriksson, Christian Gieger, Emmi Tikkanen, Mustafa Atalay, S Wiltshire, Eleftheria Zeggini, Alena Stančáková, Loukianos S. Rallidis, Jouko Saramies, Stéphane Lobbens, Man Li, Hyun Min Kang, Loic Yengo, Norman Klopp, Ayellet V. Segrè, Carl G. P. Platou, Tom Forsén, Qi Sun, Karin Leander, Caroline S. Fox, Sekar Kathiresan, Jose C. Florez, Leif Groop, Teresa Ferreira, John R. B. Perry, Ulf de Faire, Peter S. Chines, Elizabeth J. Rossin, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Surgery, Dermatology, Epidemiology, and Internal Medicine

Subjects
Male, Linkage disequilibrium, Medizin, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, Genetic Predisposition to Disease, Pakistan, Gene, 030304 developmental biology, Genetic association, 0303 health sciences, Case-control study, medicine.disease, Genetic architecture, 3. Good health, Diabetes Mellitus, Type 2, Genes, Evolutionary biology, Case-Control Studies, Female, Genome-Wide Association Study
Abstract

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Published
2012

31. 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

32. 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

33. 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

34. Common genetic variants and modification of penetrance of BRCA2-Associated breast cancer

Author

Mia M Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M Korn, Candace Guiducci, Ayellet V Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Nicoline Hoogerbrugge, Kees E P van Roozendaal, HEBON Study Collaborators, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T Johannsson, Rosa B Barkardottir, Peter Devilee, Olofunmilayo I Olopade, Susan L Neuhausen, Xianshu Wang, Zachary S Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, OCGN, Amanda E Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J Ramus, Susan M Domchek, Katherine L Nathanson, Tim Rebbeck, Amanda B Spurdle, Xiaoqing Chen, Helene Holland, kConFab, Esther M John, John L Hopper, Saundra S Buys, Mary B Daly, Melissa C Southey, Mary Beth Terry, Nadine Tung, Thomas V Overeem Hansen, Finn C Nielsen, Mark H Greene, Phuong L Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N Weitzel, Judy Garber, Ute Hamann, EMBRACE, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J Klein, Fergus J Couch, Georgia Chenevix-Trench, Douglas F Easton, Mark J Daly, Antonis C Antoniou, David M Altshuler, Kenneth Offit, Broad Institute of MIT and Harvard, Korn, Joshua Marc, Korn, Joshua M., Green, Todd, Guiducci, Candace, Segre, Ayellet V., Daly, Mark J., Altshuler, David, Clinical Genetics, Internal Medicine, Pediatric Surgery, Department of Obstetrics and Gynecology, Department of Medical and Clinical Genetics, Genome-Scale Biology (GSB) Research Program, Human genetics, EMGO - Quality of care, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, and Universitat de Barcelona

Subjects
Cancer Research, Linkage disequilibrium, Chromosomes, Human, Pair 20, Genome-wide association study, Penetrance, RECURRENT BRCA1, 312 Clinical medicine, QH426-470, PHENOTYPE, Linkage Disequilibrium, 0302 clinical medicine, Breast cancer, Gene Frequency, Risk Factors, BRCA2 MUTATION CARRIERS, POPULATION, Genetics (clinical), Genetics and Genomics/Genetics of Disease, RISK, Genetics, Genetics and Genomics/Medical Genetics, 0303 health sciences, Genetics and Genomics/Functional Genomics, ASSOCIATION, Middle Aged, 3. Good health, DNA-Binding Proteins, Genetics and Genomics/Gene Function, SUSCEPTIBILITY GENES, 030220 oncology & carcinogenesis, Female, Genetics and Genomics/Gene Discovery, Research Article, Adult, Heterozygote, education, BRCA2 MUTATION CARRIERS, SUSCEPTIBILITY GENES, RECURRENT BRCA1, RISK, POPULATION, MODEL, PREDISPOSITION, ASSOCIATION, PHENOTYPE, FREQUENCY, Single-nucleotide polymorphism, Breast Neoplasms, Biology, FREQUENCY, Polymorphism, Single Nucleotide, White People, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Receptor, Fibroblast Growth Factor, Type 2, Genetics and Genomics/Genomics, Molecular Biology, Allele frequency, Genetics and Genomics/Cancer Genetics, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, BRCA2 Protein, brca2 mutation carriers susceptibility genes recurrent brca1 risk population model predisposition association phenotype frequency, Chromosomes, Human, Pair 10, Haplotype, Genetics and Genomics, medicine.disease, PREDISPOSITION, MODEL, Minor allele frequency, Haplotypes, Cancer and Oncology, Mutation, Genome-Wide Association Study, Transcription Factors
Abstract

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors.1 To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, National Breast Cancer Foundation (U.S.), Starr Cancer Consortium, National Institutes of Health (U.S.) (NCI: P20CA103694-3 ), Lymphoma Foundation

Published
2010

35. 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. 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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. 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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

36. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

Author

Barbara E. Engelhardt, Sarah Kim-Hellmuth, Sarah Urbut, Ashis Saha, Gen Li, Jessica Halow, Panagiotis Papasaikas, Simona Volpi, Alvaro N. Barbeira, Jared L. Nedzel, Meng Wang, Nikolaos I Panousis, Benedict Paten, Lori E. Brigham, Gao Wang, Mary Barcus, Anthony Payne, Xiaoquan Wen, Nicola J. Rinaldi, Hua Tang, Seva Kashin, Casey Martin, Steven Hunter, Yi-Hui Zhou, Kristen Lee, Ian C. McDowell, Jason M. Torres, Alexandra J. Scott, Kane Hadley, Duyen T. Nguyen, Leslie H. Sobin, Jiamao Zheng, Paul Flicek, Casandra A. Trowbridge, Anjené M. Addington, Omer Basha, Brandon L. Pierce, Pejman Mohammadi, Xiao Li, Halit Ongen, Ki Sung Um, John T. Lonsdale, Alexis Battle, Takunda Matose, Kathryn Demanelis, Yuan He, Bernadette Mestichelli, Kasper D. Hansen, Marcus Hunter, Shin Lin, Richard Hasz, Thomas Juettemann, Ellen Karasik, Taru Tukiainen, Lin Chen, Fred A. Wright, Martijn van de Bunt, Meritxell Oliva, Fidencio J. Neri, François Aguet, Todd L. Edwards, Judith B. Zaugg, Michael Snyder, Gary Walters, Yongjin Park, Mary Goldman, Michael Sammeth, Kristin G. Ardlie, A. Roger Little, Reza Sodaei, Stephen J. Trevanion, Kevin S. Smith, Stephen B. Montgomery, Katherine H. Huang, John A. Stamatoyannopoulos, David E. Tabor, Gene Kopen, Melina Claussnitzer, Nancy Roche, Rodrigo Bonazzola, Deborah C. Mash, Helen M. Moore, Anne Ndungu, Lihua Jiang, Konrad J. Karczewski, Marian S. Fernando, Liqun Qi, Princy Parsana, Ping Guan, Eleazar Eskin, Kate R. Rosenbloom, Jason Bridge, Maria M. Tomaszewski, David A. Davis, Joseph Wheeler, Sarah E. Gould, Morgan Diegel, Eric S. Torstenson, Nancy J. Cox, Daniel R. Zerbino, Joshua M. Akey, Kimberly M. Valentino, Brunilda Balliu, Jingchun Zhu, Joe R. Davis, Nicholas Van Wittenberghe, Michael F. Salvatore, Susan E. Koester, Barbara A. Foster, Andrey A. Shabalin, Ira M. Hall, John Vivian, Eun Yong Kang, Nathan S. Abell, Laure Fresard, Lindsay F. Rizzardi, Ayellet V. Segrè, Dan Sheppard, Rajinder Kaul, Jeffrey McLean, Michael Washington, Joanne Chan, Mark Miklos, Benoit Molinie, Christopher Johns, Laura M. Huckins, Monkol Lek, Christopher D. Brown, Laura A. Siminoff, Alisa McDonald, Abhi Rao, Jean Monlong, Jie Quan, Diego Garrido-Martín, Barbara E. Stranger, Donald F. Conrad, Farhan N. Damani, Cédric Howald, Buhm Han, Michael S. Noble, Caroline Linke, Daniel C. Rohrer, Jimmie B. Vaught, Hae Kyung Im, Audra K. Johnson, Rui Zhang, Muhammad G. Kibriya, Matthew Stephens, Chiara Sabatti, Brian Roe, Latarsha J. Carithers, Robert E. Handsaker, Pushpa Hariharan, Boxiang Liu, Manolis Kellis, YoSon Park, Manuel Muñoz-Aguirre, Lei Hou, Matthew T. Maurano, Ariel D. H. Gewirtz, Ruth Barshir, Michael J. Gloudemans, Li Wang, Gireesh K. Bogu, Christopher Lee, Anita H. Undale, Genna Gliner, Sandra Linder, Serghei Mangul, Andrew A. Brown, Tzintzuni Garcia, Eric Haugen, Michael T. Moser, Jessica Lin, Andrew B. Nobel, Richard Sandstrom, Emmanouil T. Dermitzakis, Kieron Taylor, Brian Jo, Rachna Kumar, Laura Barker, Magali Ruffier, Ferran Reverter, Saboor Shad, Jin Billy Li, Eli A. Stahl, Mark I. McCarthy, William F. Leinweber, Gad Getz, Karna Robinson, Xin Li, Esti Yeger-Lotem, Jemma Nelson, Negin Vatanian, Scott P. Dickinson, Colby Chiang, Jeffrey A. Thomas, Kaanan P. Shah, Maximilian Haeussler, Heather M. Traino, Concepcion R. Nierras, Fan Wu, Hualin S. Xi, Yaping Liu, Daniel Bates, Peter Hickey, Eric R. Gamazon, Jennifer A. Doherty, Ellen Gelfand, Jae Hoon Sul, Jeffery P. Struewing, Beryl B. Cummings, W. James Kent, John Palowitch, Brian Craft, Anna M. Smith, Pedro G. Ferreira, Emily K. Tsang, Andrew P. Feinberg, Nicole C. Lockart, Ruiqi Jian, Robert G. Montroy, Dan L. Nicolae, Yungil Kim, Kevin Myer, Christine B. Peterson, Benjamin J. Strober, Andrew D. Skol, Qin Li, Bryan Gillard, Dana R. Valley, Zachary Zappala, Philip A. Branton, Stephane E. Castel, Daniel G. MacArthur, Mark H. Johnson, Olivier Delaneau, Maghboeba Mosavel, Roderic Guigó, Farzana Jasmine, Scott D. Jewell, Shilpi Singh, Tuuli Lappalainen, Farhad Hormozdiari, and Heather E. Wheeler

Subjects
0301 basic medicine, Science, Quantitative Trait Loci, Gene Expression, General Physics and Astronomy, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Meta-Analysis as Topic, Genetic variation, Humans, Computer Simulation, lcsh:Science, Gene, Genetics, Multidisciplinary, Models, Genetic, Chromosome Mapping, Genetic Variation, Tissue-Specific Gene Expression, Robustness (evolution), General Chemistry, Phenotype, 030104 developmental biology, Organ Specificity, Trait, lcsh:Q, Data integration, Genome-Wide Association Study
Abstract

Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes., Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.

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