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UNC-authored articles published by the Public Library of Science (PLoS)

Works (2127)

2061. Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions

Title Tesim:: Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions
Creator:: Pedersen, Nancy L., Chu, Audrey Y., Lindgren, Cecilia, Ong, Ken K., Morris, Andrew P., Magnusson, Patrik K. E., Winkler, Thomas W., Wareham, Nicholas J., Ingelsson, Erik, Paré, Guillaume, Scott, Robert A., Justice, Anne E., Metspalu, Andres, Ridker, Paul M., Loos, Ruth J. F., Franks, Paul W., Deng, Wei Q., Mihailov, Evelin, Hallmans, Göran, Cupples, L. Adrienne, Mägi, Reedik, Kilpeläinen, Tuomas O., Langenberg, Claudia, Chasman, Daniel I., Shungin, Dmitry, Rose, Lynda M., Varga, Tibor V., Luan, Jian'an, Forouhi, Nita G., and Graff, Mariaelisa
Date of publication:: 2017
Abstract Tesim:: Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman’s ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When Pv and Pm were compared for all pruned SNPs, only BMI was statistically significant (Spearman’s ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the Pv distribution (Pbinomial <0.05). SNPs from the top 1% of the Pm distribution for BMI had more significant Pv values (PMann–Whitney= 1.46×10−5), and the odds ratio of SNPs with nominally significant (<0.05) Pm and Pv was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (Pint<0.05) were enriched with nominally significant Pv values (Pbinomial = 8.63×10−9 and 8.52×10−7 for SNP × smoking and SNP × physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for G×E, and variance-based prioritization can be used to identify them.
Resource type:: Article
Affiliation Label Tesim:: Department of Epidemiology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/k3k5-mf58
Identifier:: PMID: 28614350, Publisher DOI: https://doi.org/10.1371/journal.pgen.1006812, Onescience id: 919738d2a07b2f6bed43a5651d81a8d420b9807b, and PMCID: PMC5489225
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 6
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Quantitative Trait Loci, Genetic Heterogeneity, European Continental Ancestry Group, Genotype, Single Nucleotide, Genome-Wide Association Study, Article, Cholesterol, Smoking, Risk Factors, Humans, Body Mass Index, Female, LDL, Male, Polymorphism, Gene-Environment Interaction, Obesity, HDL, and Genetic Predisposition to Disease
Language Label:: English
ORCID:: , 0000-0003-0292-5421, 0000-0003-1422-2993, and 0000-0002-6795-4760
Other Affiliation:: Department of Medical Epidemiology and Biostatistics; Karolinska Institutet, Harvard Medical School; Boston, Wellcome Trust Centre for Human Genetics; University of Oxford, Broad Institute of the Massachusetts Institute of Technology and Harvard University, MRC Epidemiology Unit; University of Cambridge; Institute of Metabolic Science; Addenbrooke’s Hospital, Department of Biostatistics; University of Liverpool, Estonian Genome Center; University of Tartu, Department of Genetic Epidemiology; University of Regensburg, Science for Life Laboratory; Uppsala University, Department of Medical Sciences; Molecular Epidemiology; Uppsala University, Department of Medicine; Division of Cardiovascular Medicine; Stanford University School of Medicine, Department of Pathology and Molecular Medicine; McMaster University, Institute of Molecular and Cell Biology; University of Tartu, Division of Preventive Medicine; Brigham and Women's Hospital, The Genetics of Obesity and Related Metabolic Traits Program; Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute; Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine; Icahn School of Medicine at Mount Sinai, Oxford Centre for Diabetes; Endocrinology & Metabolism; Radcliff Department of Medicine; University of Oxford, Department of Clinical Sciences; Genetic & Molecular Epidemiology Unit; Lund University Diabetes Centre; Skåne University Hospital, Department of Nutrition; Harvard TH Chan School of Public Health, Department of Public Health and Clinical Medicine; Unit of Medicine; Umeå University, Department of Statistical Sciences; University of Toronto, Department of Biobank Research; Umeå University, The NHLBI Framingham Heart Study, Department of Biostatistics; Boston University School of Public Health, The Novo Nordisk Foundation Center for Basic Metabolic Research; Section of Metabolic Genetics; Faculty of Health and Medical Sciences; University of Copenhagen, Department of Epidemiology and Public Health; UCL, Department of Odontology; Umeå University, Novo Nordisk Foundation Center for Protein Research; Translational Disease Systems Biology Group; Faculty of Health and Medical Sciences; University of Copenhagen, and Department of Health Sciences; Exercise Physiology Group; Lund University
Page Start:: e1006812
Person:: Pedersen, Nancy L., Chu, Audrey Y., Lindgren, Cecilia, Ong, Ken K., Morris, Andrew P., Magnusson, Patrik K. E., Winkler, Thomas W., Wareham, Nicholas J., Ingelsson, Erik, Paré, Guillaume, Scott, Robert A., Justice, Anne E., Metspalu, Andres, Ridker, Paul M., Loos, Ruth J. F., Franks, Paul W., Deng, Wei Q., Mihailov, Evelin, Hallmans, Göran, Cupples, L. Adrienne, Mägi, Reedik, Kilpeläinen, Tuomas O., Langenberg, Claudia, Chasman, Daniel I., Shungin, Dmitry, Rose, Lynda M., Varga, Tibor V., Luan, Jian'an, Forouhi, Nita G., and Graff, Mariaelisa
Rights Statement Label:: In Copyright
Source:: ms35tf486

2062. Genome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos

Title Tesim:: Genome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos
Creator:: Li, Yun, Sofer, Tamar, Auer, Paul L., Kurita, Ryo, McHugh, Caitlin P., Morrison, Jean V., Browning, Sharon R., Laurie, Cecilia A., Brown, Lisa, Browning, Brian L., Chen, Diane D., Reiner, Alex P., Schurmann, Claudia, Jain, Deepti, Liu, Yong Mei, Papanicolaou, George, Loos, Ruth J. F., Nakamura, Yukio, Bauer, Daniel E., Schick, Ursula M., Taylor, Kent D., Laurie, Cathy C., Pankratz, Nathan, Thornton, Timothy A., Rotter, Jerome I., North, Kari E., and Hodonsky, Chani J.
Date of publication:: 2017
Abstract Tesim:: Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/SOL Hispanics/Latinos, including African ancestral alpha- and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 (which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element harboring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos.
Resource type:: Article
Affiliation Label Tesim:: Department of Genetics and Department of Epidemiology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/mb9w-yv90
Identifier:: Publisher DOI: https://doi.org/10.1371/journal.pgen.1006760, Onescience id: 863f412647ae4a0c17a5c9279e7699d6a4ae592d, PMID: 28453575, and PMCID: PMC5428979
ISSN:: 1553-7404 and 1553-7390
Journal Issue:: 4
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Sex Chromosomes, Proteins, Biology and Life Sciences, Alleles, X Chromosomes, Blood Cells, Genomics, Quantitative Trait Loci, Genetics, Cellular Types, Animal Cells, Biochemistry, Computational Biology, Cell Biology, Genetic Loci, Chromosomes, Hemoglobin, Journal Article, Human Genetics, Genome Analysis, Red Blood Cells, Genome-Wide Association Studies, and Chromosome Biology
Language Label:: English
ORCID:: , 0000-0001-8520-8860, 0000-0001-7251-9715, 0000-0001-6569-2501, 0000-0001-6454-6633, 0000-0001-5629-2522, 0000-0003-2572-4040, and 0000-0001-8566-5877
Other Affiliation:: Department of Computer Science, Department of Biostatistics, Department of Biostatistics; University of Washington, Joseph J. Zilber School of Public Health; University of Wisconsin Milwaukee, Research and Development Department; Central Blood Institute; Blood Service Headquartersese Red Cross Society, New York Genome Center, Department of Medicine; University of Washington, Division of Hematology/Oncology; Boston Children's Hospital, Division of Public Health Sciences; Fred Hutchinson Cancer Research Center, The Charles Bronfman Institute for Personalized Medicine; Icahn School of Medicine at Mount Sinai, The Genetics of Obesity and Related Metabolic Traits Program; The Icahn School of Medicine at Mount Sinai, School of Medicine; Wake Forest University, Division of Cardiovascular Sciences; National Heart; Lung; and Blood Institute, The Mindich Child Health and Development Institute; Icahn School of Medicine at Mount Sinai, Comprehensive Human Sciences; Tsukuba University, Cell Engineering Division; RIKEN BioResource Center, Department of Pediatric Oncology; Dana-Farber Cancer Institute, Department of Pediatrics; Harvard Medical School and Harvard Stem Cell Institute; Harvard University, Department of Pediatrics; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Institute for Translational Genomics and Population Sciences; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Division of Laboratory Medicine & Pathology; University of Minnesota, and Department of Genetics
Page Start:: e1006760
Person:: Li, Yun, Sofer, Tamar, Auer, Paul L., Kurita, Ryo, McHugh, Caitlin P., Morrison, Jean V., Browning, Sharon R., Laurie, Cecilia A., Brown, Lisa, Browning, Brian L., Chen, Diane D., Reiner, Alex P., Schurmann, Claudia, Jain, Deepti, Liu, Yong Mei, Papanicolaou, George, Loos, Ruth J. F., Nakamura, Yukio, Bauer, Daniel E., Schick, Ursula M., Taylor, Kent D., Laurie, Cathy C., Pankratz, Nathan, Thornton, Timothy A., Rotter, Jerome I., North, Kari E., and Hodonsky, Chani J.
Rights Statement Label:: In Copyright
Source:: jw827h916

2063. Formation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis

Title Tesim:: Formation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis
Creator:: Herring, Laura E., Greco, Todd M., Cristea, Ileana M., Kennedy, Leslie, Conlon, Frank L., Kaltenbrun, Erin, and Temple, Brenda
Date of publication:: 2017
Abstract Tesim:: By the age of 40, one in five adults without symptoms of cardiovascular disease are at risk for developing congestive heart failure. Within this population, dilated cardiomyopathy (DCM) remains one of the leading causes of disease and death, with nearly half of cases genetically determined. Though genetic and high throughput sequencing-based approaches have identified sporadic and inherited mutations in a multitude of genes implicated in cardiomyopathy, how combinations of asymptomatic mutations lead to cardiac failure remains a mystery. Since a number of studies have implicated mutations of the transcription factor TBX20 in congenital heart diseases, we investigated the underlying mechanisms, using an unbiased systems-based screen to identify novel, cardiac-specific binding partners. We demonstrated that TBX20 physically and genetically interacts with the essential transcription factor CASZ1. This interaction is required for survival, as mice heterozygous for both Tbx20 and Casz1 die post-natally as a result of DCM. A Tbx20 mutation associated with human familial DCM sterically interferes with the TBX20-CASZ1 interaction and provides a physical basis for how this human mutation disrupts normal cardiac function. Finally, we employed quantitative proteomic analyses to define the molecular pathways mis-regulated upon disruption of this novel complex. Collectively, our proteomic, biochemical, genetic, and structural studies suggest that the physical interaction between TBX20 and CASZ1 is required for cardiac homeostasis, and further, that reduction or loss of this critical interaction leads to DCM. This work provides strong evidence that DCM can be inherited through a digenic mechanism.
Resource type:: Article
Affiliation Label Tesim:: University of North Carolina at Chapel Hill and Department of Biochemistry and Biophysics
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/j23a-ah29
Identifier:: Onescience id: c5f0dc04a314e7637522fb6a9073fe8c437e51ba, PMID: 28945738, Publisher DOI: https://doi.org/10.1371/journal.pgen.1007011, and PMCID: PMC5629033
ISSN:: 1553-7404 and 1553-7390
Journal Issue:: 9
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Proteomics, Mice, Mutation, Heart Failure, Animals, CASZ1 protein, human, Transcription Factors, Humans, Cardiomyopathy, Dilated, T-Box Domain Proteins, and DNA-Binding Proteins
Language Label:: English
ORCID:: , 0000-0002-5845-713X, and 0000-0002-9233-0191
Other Affiliation:: Department of Pharmacology, Department of Molecular Biology; Princeton University, Department of Biology, Integrative Program for Biological and Genome Sciences, and Department of Genetics
Page Start:: e1007011
Person:: Herring, Laura E., Greco, Todd M., Cristea, Ileana M., Kennedy, Leslie, Conlon, Frank L., Kaltenbrun, Erin, and Temple, Brenda
Rights Statement Label:: In Copyright
Source:: dj52wb19k

2064. Fine scale mapping of genomic introgressions within the Drosophila yakuba clade

Title Tesim:: Fine scale mapping of genomic introgressions within the Drosophila yakuba clade
Creator:: Matute, Daniel R. and Turissini, David A.
Date of publication:: 2017
Abstract Tesim:: The process of speciation involves populations diverging over time until they are genetically and reproductively isolated. Hybridization between nascent species was long thought to directly oppose speciation. However, the amount of interspecific genetic exchange (introgression) mediated by hybridization remains largely unknown, although recent progress in genome sequencing has made measuring introgression more tractable. A natural place to look for individuals with admixed ancestry (indicative of introgression) is in regions where species co-occur. In west Africa, D. santomea and D. yakuba hybridize on the island of São Tomé, while D. yakuba and D. teissieri hybridize on the nearby island of Bioko. In this report, we quantify the genomic extent of introgression between the three species of the Drosophila yakuba clade (D. yakuba, D. santomea), D. teissieri). We sequenced the genomes of 86 individuals from all three species. We also developed and applied a new statistical framework, using a hidden Markov approach, to identify introgression. We found that introgression has occurred between both species pairs but most introgressed segments are small (on the order of a few kilobases). After ruling out the retention of ancestral polymorphism as an explanation for these similar regions, we find that the sizes of introgressed haplotypes indicate that genetic exchange is not recent (>1,000 generations ago). We additionally show that in both cases, introgression was rarer on X chromosomes than on autosomes which is consistent with sex chromosomes playing a large role in reproductive isolation. Even though the two species pairs have stable contemporary hybrid zones, providing the opportunity for ongoing gene flow, our results indicate that genetic exchange between these species is currently rare.
Resource type:: Article
Affiliation Label Tesim:: Department of Biology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/kqsw-4v27
Identifier:: Publisher DOI: https://doi.org/10.1371/journal.pgen.1006971, Onescience id: 6d8bb5eb2d3e72c92b16ecf23c3ef787762cf477, PMCID: PMC5600410, and PMID: 28873409
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 9
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Drosophila, Genome, Insect, Chromosome Mapping, Haplotypes, Genomics, Hybridization, Genetic, Reproductive Isolation, Species Specificity, Genetic Speciation, and Animals
Language Label:: English
ORCID:: 0000-0002-7597-602X and 0000-0001-5021-3213
Page Start:: e1006971
Person:: Matute, Daniel R. and Turissini, David A.
Rights Statement Label:: In Copyright
Source:: mc87pw948

2065. Elucidation of the calcineurin-Crz1 stress response transcriptional network in the human fungal pathogen Cryptococcus neoformans

Title Tesim:: Elucidation of the calcineurin-Crz1 stress response transcriptional network in the human fungal pathogen Cryptococcus neoformans
Creator:: Billmyre, R. Blake, Averette, Anna Floyd, Mieczkowski, Piotr, Heitman, Joseph, Cardenas, Maria E., Granek, Joshua A., Chow, Eve W. L., and Clancey, Shelly A.
Date of publication:: 2017
Abstract Tesim:: Calcineurin is a highly conserved Ca2+/calmodulin-dependent serine/threonine-specific protein phosphatase that orchestrates cellular Ca2+ signaling responses. In Cryptococcus neoformans, calcineurin is activated by multiple stresses including high temperature, and is essential for stress adaptation and virulence. The transcription factor Crz1 is a major calcineurin effector in Saccharomyces cerevisiae and other fungi. Calcineurin dephosphorylates Crz1, thereby enabling Crz1 nuclear translocation and transcription of target genes. Here we show that loss of Crz1 confers phenotypes intermediate between wild-type and calcineurin mutants, and demonstrate that deletion of the calcineurin docking domain results in the inability of Crz1 to translocate into the nucleus under thermal stress. RNA-sequencing revealed 102 genes that are regulated in a calcineurin-Crz1-dependent manner at 37°C. The majority of genes were down-regulated in cna1Δ and crz1Δ mutants, indicating these genes are normally activated by the calcineurin-Crz1 pathway at high temperature. About 58% of calcineurin-Crz1 target genes have unknown functions, while genes with known or predicted functions are involved in cell wall remodeling, calcium transport, and pheromone production. We identified three calcineurin-dependent response element motifs within the promoter regions of calcineurin-Crz1 target genes, and show that Crz1 binding to target gene promoters is increased upon thermal stress in a calcineurin-dependent fashion. Additionally, we found a large set of genes independently regulated by calcineurin, and Crz1 regulates 59 genes independently of calcineurin. Given the intermediate crz1Δ mutant phenotype, and our recent evidence for a calcineurin regulatory network impacting mRNA in P-bodies and stress granules independently of Crz1, calcineurin likely acts on factors beyond Crz1 that govern mRNA expression/stability to operate a branched transcriptional/post-transcriptional stress response network necessary for fungal virulence. Taken together, our findings reveal the core calcineurin-Crz1 stress response cascade is maintained from ascomycetes to a pathogenic basidiomycete fungus, but its output in C. neoformans appears to be adapted to promote fungal virulence.
Resource type:: Article
Affiliation Label Tesim:: School of Medicine
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/wnhv-9v46
Identifier:: PMID: 28376087, PMCID: PMC5380312, Onescience id: 647ac87ab74f238e29c1df2081b65cf5492ad04c, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1006667
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 4
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Gene Regulatory Networks, Cell Wall, Gene Expression Regulation, Fungal, Transcription Factors, Fungal Proteins, Stress, Physiological, Calcineurin, Cryptococcus neoformans, Phenotype, and Humans
Language Label:: English
ORCID:: 0000-0003-4866-3711, , 0000-0001-6369-5995, and 0000-0001-5073-4035
Other Affiliation:: Department of Molecular Genetics and Microbiology; Duke University Medical Center, Department of Biostatistics and Bioinformatics; Duke University Medical Center, and Duke Center for the Genomics of Microbial Systems; Duke University Medical Center
Page Start:: e1006667
Person:: Billmyre, R. Blake, Averette, Anna Floyd, Mieczkowski, Piotr, Heitman, Joseph, Cardenas, Maria E., Granek, Joshua A., Chow, Eve W. L., and Clancey, Shelly A.
Rights Statement Label:: In Copyright
Source:: 7h149w09b

2066. Drosophila DNA polymerase theta utilizes both helicase-like and polymerase domains during microhomology-mediated end joining and interstrand crosslink repair

Title Tesim:: Drosophila DNA polymerase theta utilizes both helicase-like and polymerase domains during microhomology-mediated end joining and interstrand crosslink repair
Creator:: Baker, Amy E., Beagan, Kelly, Scharer, Orlando, Armstrong, Robin L., Renedo, Nikolai, Roy, Upasana, Witsell, Alice, and McVey, Mitch
Date of publication:: 2017
Abstract Tesim:: Double strand breaks (DSBs) and interstrand crosslinks (ICLs) are toxic DNA lesions that can be repaired through multiple pathways, some of which involve shared proteins. One of these proteins, DNA Polymerase θ (Pol θ), coordinates a mutagenic DSB repair pathway named microhomology-mediated end joining (MMEJ) and is also a critical component for bypass or repair of ICLs in several organisms. Pol θ contains both polymerase and helicase-like domains that are tethered by an unstructured central region. While the role of the polymerase domain in promoting MMEJ has been studied extensively both in vitro and in vivo, a function for the helicase-like domain, which possesses DNA-dependent ATPase activity, remains unclear. Here, we utilize genetic and biochemical analyses to examine the roles of the helicase-like and polymerase domains of Drosophila Pol θ. We demonstrate an absolute requirement for both polymerase and ATPase activities during ICL repair in vivo. However, similar to mammalian systems, polymerase activity, but not ATPase activity, is required for ionizing radiation-induced DSB repair. Using a site-specific break repair assay, we show that overall end-joining efficiency is not affected in ATPase-dead mutants, but there is a significant decrease in templated insertion events. In vitro, Pol θ can efficiently bypass a model unhooked nitrogen mustard crosslink and promote DNA synthesis following microhomology annealing, although ATPase activity is not required for these functions. Together, our data illustrate the functional importance of the helicase-like domain of Pol θ and suggest that its tethering to the polymerase domain is important for its multiple functions in DNA repair and damage tolerance.
Resource type:: Article
Affiliation Label Tesim:: Curriculum in Genetics and Molecular Biology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/15r3-3g03
Identifier:: Publisher DOI: https://doi.org/10.1371/journal.pgen.1006813, PMID: 28542210, PMCID: PMC5466332, and Onescience id: d4aa87cd8b18190e077bae3e3748b2f0cbd71cc0
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 5
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Mus308 protein, Drosophila, DNA End-Joining Repair, Drosophila Proteins, Drosophila melanogaster, Animals, DNA Repair Enzymes, and Catalytic Domain
Language Label:: English
ORCID:: , 0000-0002-8126-9698, and 0000-0001-8883-0188
Other Affiliation:: Department of Biology; Tufts University, Department of Microbiology and Immunology; Geisel School of Medicine at Dartmouth, Center for Genomic Integrity; Institute for Basic Science; Ulsan and Department of Biological Sciences; School of Life Sciences; Ulsan National Institute of Science and Technology, and Department of Chemistry and Department of Pharmacological Sciences; Stony Brook University
Page Start:: e1006813
Person:: Baker, Amy E., Beagan, Kelly, Scharer, Orlando, Armstrong, Robin L., Renedo, Nikolai, Roy, Upasana, Witsell, Alice, and McVey, Mitch
Rights Statement Label:: In Copyright
Source:: hm50tx82g

2067. Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

Title Tesim:: Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium
Creator:: Haiman, Christopher A., Young, Kristin, Ambs, Stefan, Lu, Yingchang, McKnight, Barbara, Levin, Albert M., Wojczynski, Mary K., Irvin, Marguerite R., Rohde, Rebecca, Ziegler, Regina G., Li, Yun, Tajuddin, Salman M., Hu, Jennifer, Cooper, Richard S., Chesi, Alessandra, Bandera, Elisa V., Graff, Mariaelisa, Sanderson, Maureen, Brody, Jennifer A., Yao, Jie, Bartz, Traci M., Ogunniyi, Adesola, Zhao, Wei, Hsu, Yu-Han H., Sale, Michele M., Zhu, Xiaofeng, Yanek, Lisa R., Rybicki, Benjamin A., Cushman, Mary, Hakonarson, Hakon, Freedman, Barry I., Hirschhorn, Joel N., John, Esther M., Faul, Jessica D., Shao, Yaming, Borecki, Ingrid B., Chen, Guanjie, Blot, William J., Weir, David R., Zheng, Wei, Rand, Kristin, Nayak, Uma, Vaidya, Dhananjay, Arnett, Donna K., Adeyemo, Adebowale, Olshan, Andrew, Rotimi, Charles N., Siscovick, David S., Zhi, Degui, Loos, Ruth J. F., Nemesure, Barbara, Bowden, Donald W., Wilson, James G., Evans, Michele K., Rao, , Zonderman, Alan B., Feitosa, Mary F., Harris, Tamara B., Stram, Alex, Liu, Ching-Ti, Berndt, Sonja I., Vedantam, Sailaja, Chen, Yii-Der Ida, Witte, John S., Kittles, Rick, Ingles, Sue A., Rotter, Jerome I., Carpten, John, Bradfield, Jonathan P., Williams, L. Keoki, Dimitrov, Latchezar, Kardia, Sharon L. R., Press, Michael F., Psaty, Bruce M., Klein, Eric, Strom, Sara S., Fornage, Myriam, Stanford, Janet L., Tayo, Bamidele O., Chen, Wei-Min, Li, Jin, Stevens, Victoria L., Guo, Xiuqing, Oloapde, Olufunmilayo I., Grant, Struan F. A., Bottinger, Erwin P., Bernstein, Leslie, Smith, Jennifer A., Cupples, L. Adrienne, Ambrosone, Christine B., Mudgal, Poorva, Lange, Leslie A., Nalls, Michael A., Becker, Diane M., Cade, Brian E., Duan, Qing, Garcia, Melissa, Goodman, Phyllis J., Zemel, Babette S., Conti, David V., Salako, Babatunde, Nathanson, Katherine L., Justice, Anne E., North, Kari E., Okut, Hayrettin, Ng, Maggie C. Y., Padhukasahasram, Badri, Patel, Sanjay R., Ware, Erin B., Huff, Chad D., Allison, Matthew A., and Chanock, Stephen J.
Date of publication:: 2017
Abstract Tesim:: Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
Resource type:: Article
Affiliation Label Tesim:: Department of Epidemiology and Department of Genetics
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/bkxg-ex81
Identifier:: Onescience id: c5bc1fb99fb2872cc7d56908a94e6e101ecc76de, Publisher DOI: https://doi.org/10.1371/journal.pgen.1006719, PMID: 28430825, and PMCID: PMC5419579
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 4
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Genomics Statistics, Genetic Loci, Ethnicities, Statistical Methods, Trait Locus Analysis, Genome Analysis, Meta-Analysis, Computational Biology, Genome-Wide Association Studies, Mathematical and Statistical Techniques, People and Places, Alleles, Africans, Signal Transduction, Genetics, Human Genetics, Genomics, Cell Biology, Physical Sciences, Biology and Life Sciences, Cell Signaling, Statistics (Mathematics), Population Groupings, and Mathematics
Language Label:: English
ORCID:: , 0000-0002-2420-162X, 0000-0001-5339-9535, 0000-0002-7919-8528, 0000-0001-8509-148X, 0000-0003-3403-8763, 0000-0002-2946-8956, 0000-0002-4032-5745, 0000-0003-1644-9040, 0000-0001-7117-1075, 0000-0003-3190-3467, 0000-0002-3105-3231, 0000-0001-5759-053X, 0000-0002-8278-6507, 0000-0003-3400-6614, 0000-0002-2643-2333, 0000-0003-0259-4407, 0000-0002-7692-6518, 0000-0002-3575-5468, and 0000-0002-9142-5172
Other Affiliation:: Norris Comprehensive Cancer Center; University of Southern California, Department of Preventive Medicine; Keck School of Medicine; University of Southern California, Laboratory of Human Carcinogenesis; National Cancer Institute, The Charles Bronfman Institute for Personalized Medicine; Icachn School of Medicine at Mount Sinai, Cardiovascular Health Research Unit; Department of Biostatistics; University of Washington, Department of Public Health Sciences; Henry Ford Health System, Division of Statistical Genomics; Department of Genetics; Washington University School of Medicine, Department of Epidemiology; University of Alabama at Birmingham, Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health, Department of Computer Science, Department of Biostatistics, National Institute on Aging; National Institutes of Health, Department of Public Health Sciences; University of Miami Leonard Miller School of Medicine, Sylvester Comprehensive Cancer Center; University of Miami Leonard Miller School of Medicine, Department of Public Health Sciences; Stritch School of Medicine; Loyola University Chicago, Division of Human Genetics; The Children’s Hospital of Philadelphia, Department of Population Science; Rutgers Cancer Institute of New Jersey, Department of Family and Community Medicine; Meharry Medical College, Cardiovascular Health Research Unit; Department of Medicine; University of Washington, Institute for Translational Genomics and Population Sciences; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Cardiovascular Health Research Unit; Departments of Medicine and Biostatistics; University of Washington, Department of Medicine; University of Ibadan, Department of Epidemiology; University of Michigan, Broad Institute of MIT and Harvard, Division of Endocrinology and Center for Basic and Translational Obesity Research; Boston Children's Hospital, Program in Bioinformatics and Integrative Genomics; Harvard Medical School, Department of Public Health Sciences and Center for Public Health Genomics; University of Virginia School of Medicine, Department of Epidemiology and Biostatistics; Case Western Reserve University, Department of Medicine; Johns Hopkins University School of Medicine, Department of Medicine; University of Vermont College of Medicine, Department of Pediatrics; Perelman School of Medicine; University of Pennsylvania, Center for Applied Genomics; The Children’s Hospital of Philadelphia, Department of Internal Medicine; Wake Forest School of Medicine, Departments of Genetics and Pediatrics; Harvard Medical School, Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute; Stanford University School of Medicine, Cancer Prevention Institute of California, Survey Research Center; Institute for Social Research; University of Michigan, Regeneron Genetics Center; Regeneron Pharmaceuticals; Inc, Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institutes of Health, International Epidemiology Institute, Division of Epidemiology; Department of Medicine; Vanderbilt Epidemiology Center; Vanderbilt University School of Medicine, Center for Public Health Genomics; University of Virginia School of Medicine, Department of Epidemiology; Bloomberg School of Public Health, School of Public Health; University of Kentucky, University of North Carolina at Chapel Hill, The New York Academy of Medicine, School of Biomedical Informatics; University of Texas Health Science Center at Houston, The Mindich Child Health and Development Institute; Ichan School of Medicine at Mount Sinai, Department of Preventive Medicine; Stony Brook University, Center for Genomics and Personalized Medicine Research; Wake Forest School of Medicine, Department of Biochemistry; Wake Forest School of Medicine, Center for Diabetes Research; Wake Forest School of Medicine, Department of Physiology and Biophysics; University of Mississippi Medical Center, Division of Biostatistics; Washington University School of Medicine, Department of Biostatistics; Boston University School of Public Health, Division of Cancer Epidemiology and Genetics; National Cancer Institute, Institute for Human Genetics; University of California; San Francisco, Department of Epidemiology and Biostatistics; University of California; San Francisco, Division of Urology; Department of Surgery; The University of Arizona, Division of Genomic Outcomes; Departments of Pediatrics and Medicine; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Department of Translational Genomics; Keck School of Medicine; University of Southern California, Center for Health Policy and Health Services Research; Henry Ford Health System, Department of Internal Medicine; Henry Ford Health System, Department of Pathology and Norris Comprehensive Cancer Center; University of Southern California Keck School of Medicine, Cardiovascular Health Research Unit; Departments of Medicine; Epidemiology; and Health Services; University of Washington, Kaiser Permanente Washington Health Research Institute, Glickman Urological and Kidney Institute; Cleveland Clinic, Department of Epidemiology; University of Texas M.D. Anderson Cancer Center, Center for Human Genetics; University of Texas Health Science Center at Houston, Department of Epidemiology; School of Public Health; University of Washington, Division of Public Health Sciences; Fred Hutchinson Cancer Research Center, Division of Cardiovascular Medicine; Department of Medicine; Stanford University School of Medicine, Epidemiology Research Program; American Cancer Society, Center for Clinical Cancer Genetics; Department of Medicine and Human Genetics; University of Chicago, Division of Endocrinology; The Children’s Hospital of Philadelphia, Beckman Research Institute of the City of Hope, NHLBI Framingham Heart Study, Department of Cancer Prevention and Control; Roswell Park Cancer Institute, Laboratory of Neurogenetics; National Institute on Aging; National Institutes of Health, Data Tecnica International, Division of Sleep and Circadian Disorders; Brigham and Women's Hospital, Harvard Medical School, SWOG Statistical Center; Fred Hutchinson Cancer Research Center, Division of Gastroenterology; Hepatology and Nutrition; The Children’s Hospital of Philadelphia, Department of Medicine; University of Pennsylvania, Department of Medicine; University of Pittsburgh, and Division of Preventive Medicine; Department of Family Medicine and Public Health; University of California San Diego
Page Start:: e1006719
Person:: Haiman, Christopher A., Young, Kristin, Ambs, Stefan, Lu, Yingchang, McKnight, Barbara, Levin, Albert M., Wojczynski, Mary K., Irvin, Marguerite R., Rohde, Rebecca, Ziegler, Regina G., Li, Yun, Tajuddin, Salman M., Hu, Jennifer, Cooper, Richard S., Chesi, Alessandra, Bandera, Elisa V., Graff, Mariaelisa, Sanderson, Maureen, Brody, Jennifer A., Yao, Jie, Bartz, Traci M., Ogunniyi, Adesola, Zhao, Wei, Hsu, Yu-Han H., Sale, Michele M., Zhu, Xiaofeng, Yanek, Lisa R., Rybicki, Benjamin A., Cushman, Mary, Hakonarson, Hakon, Freedman, Barry I., Hirschhorn, Joel N., John, Esther M., Faul, Jessica D., Shao, Yaming, Borecki, Ingrid B., Chen, Guanjie, Blot, William J., Weir, David R., Zheng, Wei, Rand, Kristin, Nayak, Uma, Vaidya, Dhananjay, Arnett, Donna K., Adeyemo, Adebowale, Olshan, Andrew, Rotimi, Charles N., Siscovick, David S., Zhi, Degui, Loos, Ruth J. F., Nemesure, Barbara, Bowden, Donald W., Wilson, James G., Evans, Michele K., Rao, , Zonderman, Alan B., Feitosa, Mary F., Harris, Tamara B., Stram, Alex, Liu, Ching-Ti, Berndt, Sonja I., Vedantam, Sailaja, Chen, Yii-Der Ida, Witte, John S., Kittles, Rick, Ingles, Sue A., Rotter, Jerome I., Carpten, John, Bradfield, Jonathan P., Williams, L. Keoki, Dimitrov, Latchezar, Kardia, Sharon L. R., Press, Michael F., Psaty, Bruce M., Klein, Eric, Strom, Sara S., Fornage, Myriam, Stanford, Janet L., Tayo, Bamidele O., Chen, Wei-Min, Li, Jin, Stevens, Victoria L., Guo, Xiuqing, Oloapde, Olufunmilayo I., Grant, Struan F. A., Bottinger, Erwin P., Bernstein, Leslie, Smith, Jennifer A., Cupples, L. Adrienne, Ambrosone, Christine B., Mudgal, Poorva, Lange, Leslie A., Nalls, Michael A., Becker, Diane M., Cade, Brian E., Duan, Qing, Garcia, Melissa, Goodman, Phyllis J., Zemel, Babette S., Conti, David V., Salako, Babatunde, Nathanson, Katherine L., Justice, Anne E., North, Kari E., Okut, Hayrettin, Ng, Maggie C. Y., Padhukasahasram, Badri, Patel, Sanjay R., Ware, Erin B., Huff, Chad D., Allison, Matthew A., and Chanock, Stephen J.
Rights Statement Label:: In Copyright
Source:: 6t053n09g

2068. DAF-18/PTEN signals through AAK-1/AMPK to inhibit MPK-1/MAPK in feedback control of germline stem cell proliferation

Title Tesim:: DAF-18/PTEN signals through AAK-1/AMPK to inhibit MPK-1/MAPK in feedback control of germline stem cell proliferation
Creator:: Labbé, Jean-Claude, Maddox, Paul S., and Narbonne, Patrick
Date of publication:: 2017
Abstract Tesim:: Under replete growth conditions, abundant nutrient uptake leads to the systemic activation of insulin/IGF-1 signalling (IIS) and the promotion of stem cell growth/proliferation. Activated IIS can stimulate the ERK/MAPK pathway, the activation of which also supports optimal stem cell proliferation in various systems. Stem cell proliferation rates can further be locally refined to meet the resident tissue’s need for differentiated progeny. We have recently shown that the accumulation of mature oocytes in the C. elegans germ line, through DAF-18/PTEN, inhibits adult germline stem cell (GSC) proliferation, despite high systemic IIS activation. We show here that this feedback occurs through a novel cryptic signalling pathway that requires PAR-4/LKB1, AAK-1/AMPK and PAR-5/14-3-3 to inhibit the activity of MPK-1/MAPK, antagonize IIS, and inhibit both GSC proliferation and the production of additional oocytes. Interestingly, our results imply that DAF-18/PTEN, through PAR-4/LKB1, can activate AAK-1/AMPK in the absence of apparent energy stress. As all components are conserved, similar signalling cascades may regulate stem cell activities in other organisms and be widely implicated in cancer.
Resource type:: Article
Affiliation Label Tesim:: Department of Biology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/crsg-vj21
Identifier:: Onescience id: f37d920ae7f651ae129ab9bc7743568bf00e3b46, PMID: 28410423, Publisher DOI: https://doi.org/10.1371/journal.pgen.1006738, and PMCID: PMC5409174
ISSN:: 1553-7404 and 1553-7390
Journal Issue:: 4
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Insulin-Like Growth Factor I, Caenorhabditis elegans, Aging, Germ Cells, AMP-Activated Protein Kinases, Insulin, Cell Differentiation, Longevity, Animals, Oocytes, Mitogen-Activated Protein Kinase 1, Caenorhabditis elegans Proteins, and Cell Proliferation
Language Label:: English
ORCID:: 0000-0003-0520-4566 and
Other Affiliation:: Department of Pathology and Cell Biology; Institut de Recherche en Immunologie et en Cancérologie (IRIC); Université de Montréal and Département de Biologie Médicale; Université du Québec à Trois-Rivières
Page Start:: e1006738
Person:: Labbé, Jean-Claude, Maddox, Paul S., and Narbonne, Patrick
Rights Statement Label:: In Copyright
Source:: m326m704h

2069. Correction: Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults

Title Tesim:: Correction: Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults
Creator:: Rivera, Natalia V., Justesen, Johanne Marie, Amin, Najaf, North, Kari E., Ahluwalia, Tarunveer S., Willemsen, Gonneke, de Geus, Eco J. C., Völker, Uwe, Whitfield, John B., Hansen, Torben, Hadley, David, Xue, Luting, Järvelin, Marjo-Riitta, Luan, Jian’an, Harald, Kennet, Lim, Unhee, Loos, Ruth J. F., Balkau, Beverley, Corre, Tanguy, Völzke, Henry, Tuomilehto, Jaakko, Hocking, Lynne J., Barroso, Inês, Sanna, Serena, Musk, , Martin, Nicholas G., Chu, Audrey Y., Peyser, Patricia A., Hayes, James E., Wilson, James F., Qi, Lu, Kähönen, Mika, Rose, Lynda M., Delgado, Graciela E., Koistinen, Heikki A., Cadby, Gemma, O’Connell, Jeffrey R., Quaye, Lydia, Eriksson, Joel, Haller, Toomas, Walker, Mark, Haiman, Christopher A., Gläser, Sven, Wright, Alan F., Raitakari, Olli T., Kinnunen, Leena, Salomaa, Veikko, Gordon-Larsen, Penny, Puolijoki, Hannu, Zubair, Niha, Kuusisto, Johanna, Heid, Iris M., Liu, Yongmei, Abecasis, Gonçalo R., Bertoni, Alain G., Tanaka, Toshiko, Grarup, Niels, Ong, Ken K., Hutri-Kähönen, Nina, Vollenweider, Peter, Aadahl, Mette, Ngwa, Julius S., Bielak, Lawrence F., Peters, Ulrike, Liu, Ching-Ti, Nettleton, Jennifer A., Holmens, Oddgeir L., Marten, Jonathan, Nolte, Ilja M., Navarro, Pau, Boerwinkle, Eric, Rivadeneira, Fernando, van Grootheest, Gerard, Smith, Albert Vernon, Borecki, Ingrid B., van Duijn, Cornelia M., Froguel, Philippe, Kolcic, Ivana, Stringham, Heather M., Rasmussen-Torvik, Laura J., Peters, Annette, Lyytikäinen, Leo-Pekka, Olden, Matthias, den Hoed, Marcel, Kooner, Jaspal S., Chasman, Daniel I., Mägi, Reedik, Rankinen, Tuomo, Lakka, Timo A., Hofman, Albert, Palmer, Lyle J., Paternoster, Lavinia, Snitker, Søren, Collins, Francis S., Smith, Blair H., Huppertz, Charlotte, Heard-Costa, Nancy L., Huffman, Jennifer E., Hernandez, Dena, Fornage, Myriam, Huang, Jie, Männistö, Satu, Wu, Ying, Dueker, Nicole, Johansson, Åsa, Tan, Sian-Tsung, Rudan, Igor, Montgomery, Grant W., Kuh, Diana, Perez, Jeremiah, Metspalu, Andres, Hirschhorn, Joel N., Bergmann, Sven, Bergman, Richard N., Havulinna, Aki S., Qi, Qibin, Ebeling, Tapani, Luben, Robert, Mangino, Massimo, Feitosa, Mary F., Polasek, Ozren, Rauramaa, Rainer, Gyllensten, Ulf, Cucca, Francesco, Thuillier, Dorothée, Færch, Kristine, Lohman, Kurt, Vitart, Veronique, Wareham, Nicholas J., Snieder, Harold, Johnson, Andrew D., Lemarchand, Loic, Workalemahu, Tsegaselassie, Holzapfel, Christina, Tönjes, Anke, Mulas, Antonella, Müller-Nurasyid, Martina, Frayling, Timothy M., Komulainen, Pirjo, Zhao, Wei, Gudnason, Vilmundur, Sternfeld, Barbara, James, Alan L., Hallmans, Göran, Huang, Tao, Bandinelli, Stefania, Bonnycastle, Lori L., Griffin, Paula J., Zhang, Weihua, Swift, Amy J., Shuldiner, Alan R., Oldehinkel, Albertine J., Scott, William R., Zhao, Jing Hua, Eicher, John D., Hassinen, Maija, Cheng, Yu-Ching, Brage, Søren, Pedersen, Oluf, Blangero, John, Peyrot, Wouter J., Gieger, Christian, Bellis, Claire, Hayward, Caroline, Jackson, Anne U., Esko, Tõnu, Langenberg, Claudia, Narisu, Narisu, Harder, Marie Neergaard, Ohlsson, Claes, Eiriksdottir, Gudny, Buyske, Steve, Sørensen, Thorkild I. A., Vestergaard, Henrik, Wong, Andrew, Weir, David R., Juonala, Markus, Cornelis, Marilyn, Campbell, Harry, McCarthy, Mark I., Milaneschi, Yuri, Uitterlinden, André G., Demirkan, Ayse, Grammer, Tanja B., Marre, Michel, Hollensted, Mette, Beilby, John, Smith, Jennifer A., Stančáková, Alena, Gong, Jian, Borja, Judith B., Vohl, Marie-Claude, Hindorff, Lucia, Harris, Tamara B., Savonen, Kai, Barata, Llilda, Dörr, Marcus, Bouchard, Claude, Kilpeläinen, Tuomas O., Rawal, Rajesh, Smith, George Davey, Silbernagel, Günther, Faul, Jessica D., Kutalik, Zoltan, Waeber, Gérard, Winkler, Thomas W., Hartman, Catharina A., Prokopenko, Inga, Launer, Lenore J., Strauch, Konstantin, Hveem, Kristian, Lim, Elise, Tammelin, Tuija, Hui, Jennie, Mohlke, Karen L., Wild, Sarah, Graff, Mariaelisa, Kumari, Meena, Busonero, Fabio, Boomsma, Dorret I., Hottenga, Jouke Jan, Justice, Anne E., Zillikens, M. Carola, Jhun, Min A., Kleber, Marcus E., Chines, Peter S., Penninx, Brenda W. J. H., Auvinen, Juha, Jansson, John-Olov, Scott, Robert A., De Moor, Marleen H. M., Adair, Linda S., Bien, Stephanie, van der Most, Peter J., Pasko, Dorota, Renström, Frida, Fu, Mao, Young, Kristin L., Ridker, Paul M., Vandenput, Liesbeth, Sarti, Cinzia, Porteous, David J., Fox, Caroline S., Kooperberg, Charles, Yengo, Loic, Padmanabhan, Sandosh, Strachan, David P., Huth, Cornelia, Sarzynski, Mark A., Kvaløy, Kirsti, Bonnefond, Amélie, Sidney, Steve, Männikkö, Reija, Kardia, Sharon L. R., van Vliet-Ostaptchouk, Jana V., Franks, Paul W., Kristiansson, Kati, Mahajan, Anubha, Lehtimäki, Terho, Chambers, John C., Linneberg, Allan, Nauck, Matthias, Grallert, Harald, Marques-Vidal, Pedro M., Kivimäki, Mika, Klein, Robert J., Bragg-Gresham, Jennifer L., Ahmad, Shafqat, Laakso, Markku, Teumer, Alexander, Perola, Markus, März, Winfried, Monda, Keri L., Boehnke, Michael, Lorentzon, Mattias, Lehne, Benjamin, Hastie, Nicholas D., Cupples, L. Adrienne, Pérusse, Louis, Lindgren, Cecilia M., and Thorand, Barbara
Date of publication:: 2017
Abstract Tesim:: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Resource type:: Article
Affiliation Label Tesim:: Carolina Center for Genome Sciences, Carolina Population Center, Department of Genetics, Department of Epidemiology, and Department of Nutrition
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/v0aq-7b55
Identifier:: PMCID: PMC5407576, Onescience id: c9a75c100fc0938e1c57a646bf87fcc084e7499b, Publisher DOI: https://doi.org/10.1371/journal.pgen.1006528, and PMID: 28448500
ISSN:: 1553-7404 and 1553-7390
Journal Issue:: 8
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Cancer Research UK, Waist Circumference, Male, Obesity, 284167, Arthritis Research UK (ARUK), Genotype, Journal Article, 323195, Humans, European Commission, 692145, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Waist-Hip Ratio, Meta-Analysis, Genetic Predisposition to Disease, Chief Scientist Office (CSO), Exercise, QH426 Genetics, Epigenomics, 230374, Female, Genome-Wide Association Study, Body Mass Index, and Adiposity
Language Label:: English
ORCID:: , 0000-0002-0703-0742, 0000-0003-0292-5421, 0000-0001-6380-1735, 0000-0001-7854-1366, and 0000-0003-3539-5391
Other Affiliation:: Karolinska Institutet; Respiratory Unit; Department of Medicine Solna, Novo Nordisk Foundation Center for Basic Metabolic Research; Section of Metabolic Genetics; Faculty of Health and Medical Sciences; University of Copenhagen, Genetic Epidemiology Unit; Department of Epidemiology; Erasmus MC, Steno Diabetes Center, Department of Biological Psychology; Vrije Universiteit, EMGO+ Institute; Vrije Universiteit & VU University Medical Center, Interfaculty Institute for Genetics and Functional Genomics; University Medicine Greifswald, DZHK (German Center for Cardiovascular Research); partner site Greifswald, Genetic Epidemiology; QIMR Berghofer Medical Research Institute, Division of Population Health Sciences and Education; St. George's; University of London, Department of Biostatistics; Boston University School of Public Health, National Heart; Lung; and Blood Institute; Framingham Heart Study, Biocenter Oulu; University of Oulu, Center for Life Course Health Research; Faculty of Medicine; University of Oulu, Department of Epidemiology and Biostatistics; School of Public Health; Imperial College London, MRC-PHE Centre for Environment and Health; Imperial College London, Unit of Primary Care; Oulu University Hospital, MRC Epidemiology Unit; Institute of Metabolic Science; University of Cambridge, National Institute for Health and Welfare; Department of Health, Epidemiology Program; University of Hawaii Cancer Center, The Department of Preventive Medicine; The Icahn School of Medicine at Mount Sinai, Genetics of Obesity and Related Metabolic Traits Program; Charles Bronfman Institute for Personalized Medicine; Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute; Icahn School of Medicine at Mount Sinai, INSERM U-1018; CESP; Renal and Cardiovascular Epidemiology; UVSQ-UPS, Department of Medical Genetics; University of Lausanne, Swiss Institute of Bioinformatics, Institute for Community Medicine; University Medicine Greifswald, Diabetes Research Group; King Abdulaziz University, Centre for Vascular Prevention; Danube-University Krems, Musculoskeletal Research Programme; Division of Applied Medicine; University of Aberdeen; Foresterhill, Generation Scotland; Centre for Genomic and Experimental Medicine; University of Edinburgh, The University of Cambridge Metabolic Research Laboratories; Wellcome Trust-MRC Institute of Metabolic Science, NIHR Cambridge Biomedical Research Centre; Institute of Metabolic Science; Addenbrooke’s Hospital, Wellcome Trust Sanger Institute, Istituto di Ricerca Genetica e Biomedica (IRGB); Consiglio Nazionale Delle Ricerche (CNR); Cittadella Universitaria di Monserrato, Department of Respiratory Medicine; Sir Charles Gairdner Hospital, Busselton Population Medical Research Institute, School of Population Health; The University of Western Australia, Division of Preventive Medicine; Brigham and Women's Hospital, Department of Epidemiology; School of Public Health; University of Michigan, Cell and Developmental Biology Graduate Program; Weill Cornell Graduate School of Medical Sciences; Cornell University, Icahn Institute for Genomics and Multiscale Biology; Icahn School of Medicine at Mount Sinai, Centre for Global Health Research; Usher Institute for Population Health Sciences and Informatics, MRC Human Genetics Unit; Institute of Genetics and Molecular Medicine; University of Edinburgh; Western General Hospital, Department of Nutrition; Harvard T.H. Chan School of Public Health, Department of Clinical Physiology; University of Tampere School of Medicine, Department of Clinical Physiology; Tampere University Hospital, Vth Department of Medicine; Medical Faculty Mannheim; Heidelberg University, Minerva Foundation Institute for Medical Research, Department of Medicine and Abdominal Center: Endocrinology; University of Helsinki and Helsinki University Central Hospital, Centre for Genetic Origins of Health and Disease; University of Western Australia, Division of Endocrinology; Diabetes; and Nutrition; University of Maryland School of Medicine, Department of Twin Research and Genetic Epidemiology; King's College London, Centre for Bone and Arthritis Research; Department of Internal Medicine and Clinical Nutrition; Institute of Medicine; Sahlgrenska Academy; University of Gothenburg, Estonian Genome Center; University of Tartu, Institute of Cellular Medicine; Newcastle University, Department of Preventive Medicine; Norris Comprehensive Cancer Center; Keck School of Medicine; University of Southern California, Department of Internal Medicine B; University Medicine Greifswald, Department of Clinical Physiology and Nuclear Medicine; Turku University Hospital, Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Department of Nutrition, South Ostrobothnia Central Hospital, Division of Public Health Sciences; Fred Hutchinson Cancer Research Center, Department of Medicine; University of Eastern Finland and Kuopio University Hospital, Department of Genetic Epidemiology; University of Regensburg, Department of Epidemiology and Prevention; Division of Public Health Sciences; Wake Forest School of Medicine, Center for Statistical Genetics; Department of Biostatistics; University of Michigan, Department of Internal Medicine; Wake Forest School of Medicine, Translational Gerontology Branch; National Institute on Aging, Department of Pediatrics; University of Tampere School of Medicine, Department of Pediatrics; Tampere University Hospital, Department of Internal Medicine; Internal Medicine; Lausanne University Hospital, Department of Public Health; Faculty of Health and Medical Sciences; University of Copenhagen, Research Centre for Prevention and Health; Glostrup University Hospital, Howard University; Department of Internal Medicine, Division of Epidemiology; Human Genetics; and Environmental Sciences; University of Texas Health Science Center at Houston, St. Olav Hospital; Trondheim University Hospital, Department of Epidemiology; University of Groningen; University Medical Center Groningen, Department of Epidemiology; Erasmus MC, Department of Internal Medicine; Erasmus MC, Netherlands Consortium for Healthy Aging; Leiden University Medical Center, Department of Psychiatry; EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam; VU University Medical Center/GGZ InGeest, Faculty of Medicine; University of Iceland, Icelandic Heart Association, Department of Genetics; Washington University School of Medicine, Center of Medical Systems Biology, University of Lille; CNRS; Institut Pasteur de Lille; UMR 8199 - EGID, Hammersmith Hospital, Department of Public Health; Faculty of Medicine; University of Split, Department of Preventive Medicine; Northwestern University Feinberg School of Medicine, German Center for Diabetes Research (DZD), Institute of Epidemiology II; Helmholtz Zentrum München-German Research Center for Environmental Health, DZHK (German Centre for Cardiovascular Research); partner site Munich Heart Alliance, Department of Clinical Chemistry; University of Tampere School of Medicine, Department of Clinical Chemistry; Fimlab Laboratories, Department of Immunology; Genetics and Pathology and Science for Life Laboratory; Uppsala University, Department of Cardiology; Ealing Hospital HNS Trust, Imperial College Healthcare NHS Trust, National Heart and Lung Institute; Imperial College London, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Harvard Medical School; Boston, Human Genomics Laboratory; Pennington Biomedical Research Center, Institute of Biomedicine; Physiology; University of Eastern Finland, Kuopio Research Institute of Exercise Medicine, School of Public Health; University of Adelaide; Adelaide, MRC Integrative Epidemiology Unit & School of Social and Community Medicine; University of Bristol, Medical Genomics and Metabolic Genetics Branch; National Human Genome Research Institute; NIH, School of Medicine; University of Dundee; Ninewells Hospital and Medical School, Department of Public and Occupational Health; VU University Medical Center, Department of Neurology; Boston University School of Medicine, Laboratory of Neurogenetics; National Institute on Aging, Institute of Molecular Medicine; University of Texas Health Science Center at Houston, Department of Human Genetics; Wellcome Trust Sanger Institute; Hinxton, University of Maryland School of Medicine; Department of Epidemiology & Public Health, Department of Immunology; Genetics and Pathology; Uppsala University, MRC Unit for Lifelong Health and Ageing at UCL, Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research; Boston Children's Hospital, Department of Genetics; Harvard Medical School, Diabetes and Obesity Research Institute; Cedars-Sinai Medical Center, Department of Epidemiology and Population Health; Albert Einstein College of Medicine, Institute of Clinical Medicine; Faculty of Medicine; University of Oulu, Department of Medicine; Oulu University Hospital, Department of Public Health and Primary Care; University of Cambridge, National Institute for Health Research Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, Department of Clinical Physiology and Nuclear Medicine; Kuopio University Hospital, Dipartimento di Scienze Biomediche; Università degli Studi di Sassari, Department of Biostatistical Sciences; Division of Public Health Sciences; Wake Forest School of Medicine, Population Sciences Branch; National Heart; Lung; and Blood Institute; National Institutes of Health; The Framingham Heart Study, Research Unit of Molecular Epidemiology; Helmholtz Zentrum München - German Research Center for Environmental Health, Institute for Nutritional Medicine; Klinikum Rechts der Isar; Technische Universität München, University of Leipzig; Medical Department, Institute of Genetic Epidemiology; Helmholtz Zentrum München; German Research Center for Environmental Health, Department of Medicine I; Ludwig-Maximilians-Universität, Genetics of Complex Traits; University of Exeter Medical School; University of Exeter, Division of Research; Kaiser Permanente Northern California, School of Medicine and Pharmacology; The University of Western Australia, Department of Pulmonary Physiology and Sleep Medicine; Sir Charles Gairdner Hospital, Department of Biobank Research; Umeå University, Geriatric Unit; Azienda Sanitaria Firenze, Veterans Affairs Maryland Health Care System; University of Maryland, Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE); University of Groningen; University Medical Center Groningen, Texas Biomedical Research Institute; San Antonio, Genomics Research Centre; Institute of Health and Biomedical Innovation; Queensland University of Technology, Human Genetics; Genome Institute of Singapore; Agency for Science; Technology and Research of Singapore, Division of Endocrinology; Boston Children's Hospital, Department of Genetics; Rutgers University, Department of Statistics and Biostatistics; Rutgers University, Survey Research Center; Institute for Social Research; University of Michigan, Department of Medicine; University of Turku, Division of Medicine; Turku University Hospital, Channing Division of Network Medicine; Department of Medicine; Brigham and Women's Hospital and Harvard Medical School, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics; University of Oxford, Oxford Centre for Diabetes; Endocrinology and Metabolism; University of Oxford; Churchill Hospital, Department of Human Genetics; Leiden University Medical Center, INSERM U-1138; Équipe 2: Pathophysiology and Therapeutics of Vascular and Renal diseases Related to Diabetes; Centre de Recherche des Cordeliers, Department of Endocrinology; Diabetology; Nutrition; and Metabolic Diseases; Bichat Claude Bernard Hospital, PathWest Laboratory Medicine of WA; Sir Charles Gairdner Hospital, School of Pathology and Laboratory Medicine; The University of Western Australia, Department of Nutrition and Dietetics; University of San Carlos, USC-Office of Population Studies Foundation; Inc.; University of San Carlos, School of Nutrition; Laval University, Institute of Nutrition and Functional Foods, Division of Genomic Medicine; National Human Genome Research Institute; National Institutes of Health, Laboratory of Epidemiology and Population Science; National Institute on Aging, Division of Angiology; Department of Internal Medicine; Medical University Graz, Institute of Social and Preventive Medicine; Lausanne University Hospital, Department of Psychiatry; University of Groningen; University Medical Center Groningen, Genomics of Common Disease; Imperial College London, Neuroepidemiology Section; National Institute on Aging; National Institutes of Health, Institute of Medical Informatics; Biometry and Epidemiology; Chair of Genetic Epidemiology; Ludwig-Maximilians-Universität, HUNT Research Centre; Department of Public Health and General Practice; Norwegian University of Science and Technology, LIKES Research Center for Sport and Health Sciences, Centre for Population Health Sciences; Usher Institute for Population Health Sciences and Informatics; Teviot Place, ISER; University of Essex; Colchester, NCA Institute; VU University & VU Medical Center, Institute of Nutrition; Friedrich Schiller University Jena, Department of Physiology; Institute of Neuroscience and Physiology; Sahlgrenska Academy; University of Gothenburg, Section of Clinical Child and Family Studies; Department of Educational and Family Studies; Vrije Universiteit, Department of Clinical Sciences; Genetic and Molecular Epidemiology Unit; Lund University, Carolina Population Center, Social Services and Health Care Department; City of Helsinki, Centre for Genomic and Experimental Medicine; Institute of Genetics and Molecular Medicine; University of Edinburgh, Institute of Cardiovascular and Medical Sciences; BHF Glasgow Cardiovascular Research Centre; University of Glasgow, Population Health Research Institute; St. George's University of London, Department of Endocrinology; University of Groningen; University Medical Center Groningen, Department of Public Health & Clinical Medicine; Umeå University, Institute for Molecular Medicine Finland; University of Helsinki, Department of Clinical Experimental Research; Rigshospitalet, Department of Clinical Medicine; Faculty of Health and Medical Sciences; University of Copenhagen, Institute of Clinical Chemistry and Laboratory Medicine; University Medicine Greifswald, Department of Epidemiology and Public Health; University College London, University of Tartun Genome Centre, Synlab Academy; Synlab Services LLC, Clinical Institute of Medical and Chemical Laboratory Diagnostics; Medical University of Graz, Center for Observational Research; Amgen Inc., Geriatric Medicine; Sahlgrenska University Hospital, Department of Kinesiology; Laval University, The Big Data Institute; University of Oxford, and Program in Medical and Population Genetics; Broad Institute
Page Start:: e1006972
Person:: Rivera, Natalia V., Justesen, Johanne Marie, Amin, Najaf, North, Kari E., Ahluwalia, Tarunveer S., Willemsen, Gonneke, de Geus, Eco J. C., Völker, Uwe, Whitfield, John B., Hansen, Torben, Hadley, David, Xue, Luting, Järvelin, Marjo-Riitta, Luan, Jian’an, Harald, Kennet, Lim, Unhee, Loos, Ruth J. F., Balkau, Beverley, Corre, Tanguy, Völzke, Henry, Tuomilehto, Jaakko, Hocking, Lynne J., Barroso, Inês, Sanna, Serena, Musk, , Martin, Nicholas G., Chu, Audrey Y., Peyser, Patricia A., Hayes, James E., Wilson, James F., Qi, Lu, Kähönen, Mika, Rose, Lynda M., Delgado, Graciela E., Koistinen, Heikki A., Cadby, Gemma, O’Connell, Jeffrey R., Quaye, Lydia, Eriksson, Joel, Haller, Toomas, Walker, Mark, Haiman, Christopher A., Gläser, Sven, Wright, Alan F., Raitakari, Olli T., Kinnunen, Leena, Salomaa, Veikko, Gordon-Larsen, Penny, Puolijoki, Hannu, Zubair, Niha, Kuusisto, Johanna, Heid, Iris M., Liu, Yongmei, Abecasis, Gonçalo R., Bertoni, Alain G., Tanaka, Toshiko, Grarup, Niels, Ong, Ken K., Hutri-Kähönen, Nina, Vollenweider, Peter, Aadahl, Mette, Ngwa, Julius S., Bielak, Lawrence F., Peters, Ulrike, Liu, Ching-Ti, Nettleton, Jennifer A., Holmens, Oddgeir L., Marten, Jonathan, Nolte, Ilja M., Navarro, Pau, Boerwinkle, Eric, Rivadeneira, Fernando, van Grootheest, Gerard, Smith, Albert Vernon, Borecki, Ingrid B., van Duijn, Cornelia M., Froguel, Philippe, Kolcic, Ivana, Stringham, Heather M., Rasmussen-Torvik, Laura J., Peters, Annette, Lyytikäinen, Leo-Pekka, Olden, Matthias, den Hoed, Marcel, Kooner, Jaspal S., Chasman, Daniel I., Mägi, Reedik, Rankinen, Tuomo, Lakka, Timo A., Hofman, Albert, Palmer, Lyle J., Paternoster, Lavinia, Snitker, Søren, Collins, Francis S., Smith, Blair H., Huppertz, Charlotte, Heard-Costa, Nancy L., Huffman, Jennifer E., Hernandez, Dena, Fornage, Myriam, Huang, Jie, Männistö, Satu, Wu, Ying, Dueker, Nicole, Johansson, Åsa, Tan, Sian-Tsung, Rudan, Igor, Montgomery, Grant W., Kuh, Diana, Perez, Jeremiah, Metspalu, Andres, Hirschhorn, Joel N., Bergmann, Sven, Bergman, Richard N., Havulinna, Aki S., Qi, Qibin, Ebeling, Tapani, Luben, Robert, Mangino, Massimo, Feitosa, Mary F., Polasek, Ozren, Rauramaa, Rainer, Gyllensten, Ulf, Cucca, Francesco, Thuillier, Dorothée, Færch, Kristine, Lohman, Kurt, Vitart, Veronique, Wareham, Nicholas J., Snieder, Harold, Johnson, Andrew D., Lemarchand, Loic, Workalemahu, Tsegaselassie, Holzapfel, Christina, Tönjes, Anke, Mulas, Antonella, Müller-Nurasyid, Martina, Frayling, Timothy M., Komulainen, Pirjo, Zhao, Wei, Gudnason, Vilmundur, Sternfeld, Barbara, James, Alan L., Hallmans, Göran, Huang, Tao, Bandinelli, Stefania, Bonnycastle, Lori L., Griffin, Paula J., Zhang, Weihua, Swift, Amy J., Shuldiner, Alan R., Oldehinkel, Albertine J., Scott, William R., Zhao, Jing Hua, Eicher, John D., Hassinen, Maija, Cheng, Yu-Ching, Brage, Søren, Pedersen, Oluf, Blangero, John, Peyrot, Wouter J., Gieger, Christian, Bellis, Claire, Hayward, Caroline, Jackson, Anne U., Esko, Tõnu, Langenberg, Claudia, Narisu, Narisu, Harder, Marie Neergaard, Ohlsson, Claes, Eiriksdottir, Gudny, Buyske, Steve, Sørensen, Thorkild I. A., Vestergaard, Henrik, Wong, Andrew, Weir, David R., Juonala, Markus, Cornelis, Marilyn, Campbell, Harry, McCarthy, Mark I., Milaneschi, Yuri, Uitterlinden, André G., Demirkan, Ayse, Grammer, Tanja B., Marre, Michel, Hollensted, Mette, Beilby, John, Smith, Jennifer A., Stančáková, Alena, Gong, Jian, Borja, Judith B., Vohl, Marie-Claude, Hindorff, Lucia, Harris, Tamara B., Savonen, Kai, Barata, Llilda, Dörr, Marcus, Bouchard, Claude, Kilpeläinen, Tuomas O., Rawal, Rajesh, Smith, George Davey, Silbernagel, Günther, Faul, Jessica D., Kutalik, Zoltan, Waeber, Gérard, Winkler, Thomas W., Hartman, Catharina A., Prokopenko, Inga, Launer, Lenore J., Strauch, Konstantin, Hveem, Kristian, Lim, Elise, Tammelin, Tuija, Hui, Jennie, Mohlke, Karen L., Wild, Sarah, Graff, Mariaelisa, Kumari, Meena, Busonero, Fabio, Boomsma, Dorret I., Hottenga, Jouke Jan, Justice, Anne E., Zillikens, M. Carola, Jhun, Min A., Kleber, Marcus E., Chines, Peter S., Penninx, Brenda W. J. H., Auvinen, Juha, Jansson, John-Olov, Scott, Robert A., De Moor, Marleen H. M., Adair, Linda S., Bien, Stephanie, van der Most, Peter J., Pasko, Dorota, Renström, Frida, Fu, Mao, Young, Kristin L., Ridker, Paul M., Vandenput, Liesbeth, Sarti, Cinzia, Porteous, David J., Fox, Caroline S., Kooperberg, Charles, Yengo, Loic, Padmanabhan, Sandosh, Strachan, David P., Huth, Cornelia, Sarzynski, Mark A., Kvaløy, Kirsti, Bonnefond, Amélie, Sidney, Steve, Männikkö, Reija, Kardia, Sharon L. R., van Vliet-Ostaptchouk, Jana V., Franks, Paul W., Kristiansson, Kati, Mahajan, Anubha, Lehtimäki, Terho, Chambers, John C., Linneberg, Allan, Nauck, Matthias, Grallert, Harald, Marques-Vidal, Pedro M., Kivimäki, Mika, Klein, Robert J., Bragg-Gresham, Jennifer L., Ahmad, Shafqat, Laakso, Markku, Teumer, Alexander, Perola, Markus, März, Winfried, Monda, Keri L., Boehnke, Michael, Lorentzon, Mattias, Lehne, Benjamin, Hastie, Nicholas D., Cupples, L. Adrienne, Pérusse, Louis, Lindgren, Cecilia M., and Thorand, Barbara
Rights Statement Label:: In Copyright
Source:: 37720j724

2070. Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study

Title Tesim:: Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study
Creator:: Ala-Korpela, Mika, Huyghe, Jeroen R., Sim, Xueling, Narisu, Narisu, Chines, Peter S., Jackson, Anne U., Teslovich, Tanya M., Mohlke, Karen L., Locke, Adam E., Soininen, Pasi, Boehnke, Michael, Kangas, Antti J., Laakso, Markku, Davis, James P., Welch, Ryan P., Fuchsberger, Christian, Kuusisto, Johanna, and Stringham, Heather M.
Date of publication:: 2017
Abstract Tesim:: Lipid and lipoprotein subclasses are associated with metabolic and cardiovascular diseases, yet the genetic contributions to variability in subclass traits are not fully understood. We conducted single-variant and gene-based association tests between 15.1M variants from genome-wide and exome array and imputed genotypes and 72 lipid and lipoprotein traits in 8,372 Finns. After accounting for 885 variants at 157 previously identified lipid loci, we identified five novel signals near established loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG. Four of the signals were identified with a low-frequency (0.005<minor allele frequency [MAF]<0.05) or rare (MAF<0.005) variant, including Arg123His in LCAT. Gene-based associations (P<10−10) support a role for coding variants in LIPC and LIPG with lipoprotein subclass traits. 30 established lipid-associated loci had a stronger association for a subclass trait than any conventional trait. These novel association signals provide further insight into the molecular basis of dyslipidemia and the etiology of metabolic disorders.
Resource type:: Article
Affiliation Label Tesim:: Department of Genetics
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/y0sn-w291
Identifier:: Onescience id: 8f69dc9ac1328097639e10f6d38fa7d5eefdaeae, PMID: 29084231, PMCID: PMC5679656, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1007079
ISSN:: 1553-7404 and 1553-7390
Journal Issue:: 10
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Lipoproteins, Lipids, Lipid Metabolism, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Principal Component Analysis, Cholesterol, HDL, Exome, Gene Frequency, Genotype, Middle Aged, Finland, Polymorphism, Single Nucleotide, and Male
Language Label:: English
ORCID:
Other Affiliation:: NMR Metabolomics Laboratory; School of Pharmacy; University of Eastern Finland, Department of Epidemiology and Preventive Medicine; School of Public Health and Preventive Medicine; Faculty of Medicine Nursing and Health Sciences; The Alfred Hospital; Monash University, Computational Medicine; Faculty of Medicine; University of Oulu and Biocenter Oulu, Systems Epidemiology; Baker Heart and Diabetes Institute, Population Health Science; Bristol Medical School; University of Bristol and Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Department of Biostatistics and Center for Statistical Genetics; University of Michigan, National Human Genome Research Institute; National Institutes of Health, and Institute of Clinical Medicine; Internal Medicine; University of Eastern Finland and Kuopio University Hospital
Page Start:: e1007079
Person:: Ala-Korpela, Mika, Huyghe, Jeroen R., Sim, Xueling, Narisu, Narisu, Chines, Peter S., Jackson, Anne U., Teslovich, Tanya M., Mohlke, Karen L., Locke, Adam E., Soininen, Pasi, Boehnke, Michael, Kangas, Antti J., Laakso, Markku, Davis, James P., Welch, Ryan P., Fuchsberger, Christian, Kuusisto, Johanna, and Stringham, Heather M.
Rights Statement Label:: In Copyright
Source:: kh04dv97h