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13 results on '"T2D-Genes Consortium"'

1. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Author

Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, and Hattersley, Andrew T

Subjects
Clinical Research, Obesity, Genetics, Nutrition, Prevention, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Cardiovascular, Animals, Body Fat Distribution, Body Mass Index, Case-Control Studies, Drosophila, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeostasis, Humans, Lipids, Male, Proteins, Risk Factors, Waist-Hip Ratio, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF

Published
2019

2. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Author

Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, and Easton, Douglas F

Subjects
CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Nutrition, Obesity, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

Published
2018

3. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D’Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, and Easton, Douglas F

Subjects
Genetics, Biotechnology, Nutrition, Obesity, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Cancer, Stroke, Metabolic and endocrine, Cardiovascular, Oral and gastrointestinal, Adult, Animals, Body Mass Index, Drosophila, Energy Intake, Energy Metabolism, Female, Gene Frequency, Genetic Variation, Humans, Male, Proteins, Syndrome, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Published
2018

4. Rare and low-frequency coding variants alter human adult height

Author

Marouli, Eirini, Graff, Mariaelisa, Medina-Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R, Kjaer, Troels R, Fine, Rebecca S, Lu, Yingchang, Schurmann, Claudia, Highland, Heather M, Rüeger, Sina, Thorleifsson, Gudmar, Justice, Anne E, Lamparter, David, Stirrups, Kathleen E, Turcot, Valérie, Young, Kristin L, Winkler, Thomas W, Esko, Tõnu, Karaderi, Tugce, Locke, Adam E, Masca, Nicholas GD, Ng, Maggie CY, Mudgal, Poorva, Rivas, Manuel A, Vedantam, Sailaja, Mahajan, Anubha, Guo, Xiuqing, Abecasis, Goncalo, Aben, Katja K, Adair, Linda S, Alam, Dewan S, Albrecht, Eva, Allin, Kristine H, Allison, Matthew, Amouyel, Philippe, Appel, Emil V, Arveiler, Dominique, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Banas, Bernhard, Bang, Lia E, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bonnycastle, Lori L, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Carey, David J, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Galbany, Jordi Corominas, Cox, Amanda J, Cuellar-Partida, Gabriel, Danesh, John, Davies, Gail, de Bakker, Paul IW, de Borst, Gert J, de Denus, Simon, de Groot, Mark CH, de Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, den Hollander, Anneke I, Dennis, Joe G, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dunning, Alison M, Easton, Douglas F, Ebeling, Tapani, Edwards, Todd L, Ellinor, Patrick T, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, and Faul, Jessica D

Subjects
Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, ADAMTS Proteins, Adult, Alleles, Body Height, Cell Adhesion Molecules, Female, Gene Frequency, Genetic Variation, Genome, Human, Glycoproteins, Glycosaminoglycans, Hedgehog Proteins, Humans, Intercellular Signaling Peptides and Proteins, Interferon Regulatory Factors, Interleukin-11 Receptor alpha Subunit, Male, Multifactorial Inheritance, NADPH Oxidase 4, NADPH Oxidases, Phenotype, Pregnancy-Associated Plasma Protein-A, Procollagen N-Endopeptidase, Proteoglycans, Proteolysis, Receptors, Androgen, Somatomedins, EPIC-InterAct Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium, MAGIC Investigators, General Science & Technology
Abstract

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Published
2017

5. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Author

Liu, Chunyu, Kraja, Aldi T, Smith, Jennifer A, Brody, Jennifer A, Franceschini, Nora, Bis, Joshua C, Rice, Kenneth, Morrison, Alanna C, Lu, Yingchang, Weiss, Stefan, Guo, Xiuqing, Palmas, Walter, Martin, Lisa W, Chen, Yii-Der Ida, Surendran, Praveen, Drenos, Fotios, Cook, James P, Auer, Paul L, Chu, Audrey Y, Giri, Ayush, Zhao, Wei, Jakobsdottir, Johanna, Lin, Li-An, Stafford, Jeanette M, Amin, Najaf, Mei, Hao, Yao, Jie, Voorman, Arend, Larson, Martin G, Grove, Megan L, Smith, Albert V, Hwang, Shih-Jen, Chen, Han, Huan, Tianxiao, Kosova, Gulum, Stitziel, Nathan O, Kathiresan, Sekar, Samani, Nilesh, Schunkert, Heribert, Deloukas, Panos, Li, Man, Fuchsberger, Christian, Pattaro, Cristian, Gorski, Mathias, Kooperberg, Charles, Papanicolaou, George J, Rossouw, Jacques E, Faul, Jessica D, Kardia, Sharon LR, Bouchard, Claude, Raffel, Leslie J, Uitterlinden, André G, Franco, Oscar H, Vasan, Ramachandran S, O'Donnell, Christopher J, Taylor, Kent D, Liu, Kiang, Bottinger, Erwin P, Gottesman, Omri, Daw, E Warwick, Giulianini, Franco, Ganesh, Santhi, Salfati, Elias, Harris, Tamara B, Launer, Lenore J, Dörr, Marcus, Felix, Stephan B, Rettig, Rainer, Völzke, Henry, Kim, Eric, Lee, Wen-Jane, Lee, I-Te, Sheu, Wayne H-H, Tsosie, Krystal S, Edwards, Digna R Velez, Liu, Yongmei, Correa, Adolfo, Weir, David R, Völker, Uwe, Ridker, Paul M, Boerwinkle, Eric, Gudnason, Vilmundur, Reiner, Alexander P, van Duijn, Cornelia M, Borecki, Ingrid B, Edwards, Todd L, Chakravarti, Aravinda, Rotter, Jerome I, Psaty, Bruce M, Loos, Ruth JF, Fornage, Myriam, Ehret, Georg B, Newton-Cheh, Christopher, Levy, Daniel, and Chasman, Daniel I

Subjects
Biological Sciences, Genetics, Cardiovascular, Hypertension, Prevention, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Blood Pressure, Exome, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, CHD Exome+ Consortium, ExomeBP Consortium, GoT2DGenes Consortium, T2D-GENES Consortium, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia, CKDGen Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Published
2016

6. A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data.

Author

Kim, Young Jin, Lee, Juyoung, Kim, Bong-Jo, T2D-Genes Consortium, and Park, Taesung

Subjects
T2D-Genes Consortium, Oligonucleotide Array Sequence Analysis, Genotype, Polymorphism, Single Nucleotide, High-Throughput Nucleotide Sequencing, Exome, Combined approach, Exome chip, Imputation, Rare variant, Polymorphism, Single Nucleotide, Biological Sciences, Information and Computing Sciences, Medical and Health Sciences, Bioinformatics
Abstract

BackgroundRare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants.ResultsIn this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF < 1 %), compared to imputation using the SNP chip alone. Also, we investigated the systematic effect of reference panels on imputation quality using five reference panels and three genotype panels. The best performing approach was the combination of the study specific reference panel and the genotype panel of combined data.ConclusionsOur study demonstrates that combined datasets, including SNP chips and exome chips, enhances both the imputation quality and genomic coverage of rare variants.

Published
2015

7. Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes

Author

Majithia, Amit R, Flannick, Jason, Shahinian, Peter, Guo, Michael, Bray, Mark-Anthony, Fontanillas, Pierre, Gabriel, Stacey B, Rosen, Evan D, Altshuler, David, Manning, Alisa K, Hartl, Christopher, Agarwala, Vineeta, Green, Todd, Banks, Eric, DePristo, Mark, Poplin, Ryan, Shakir, Khalid, Fennell, Timothy, Njølstad, Pål R, Burtt, Noël, Gabriel, Stacey, Fuchsberger, Christian, Kang, Hun Min, Sim, Xueling, Ma, Clement, Locke, Adam, Blackwell, Thomas, Jackson, Anne, Teslovich, Tanya M, Stringham, Heather, Chines, Peter, Kwan, Phoenix, Huyghe, Jeroen, Tan, Adrian, Jun, Goo, Stitzel, Michael, Bergman, Richard N, Bonnycastle, Lori, Tuomilehto, Jaakko, Collins, Francis S, Scott, Laura, Mohlke, Karen, Abecasis, Gonçalo, Boehnke, Michael, Strom, Tim, Gieger, Christian, Nurasyid, Martina Müller, Grallert, Harald, Kriebel, Jennifer, Ried, Janina, de Angelis, Martin Hrabé, Huth, Cornelia, Meisinger, Christa, Peters, Annette, Rathmann, Wolfgang, Strauch, Konstantin, Meitinger, Thomas, Kravic, Jasmina, Algren, Peter, Ladenvall, Claes, Toumi, Tiinamaija, Isomaa, Bo, Groop, Leif, Gaulton, Kyle, Moutsianas, Loukas, Rivas, Manny, Pearson, Richard, Mahajan, Anubha, Prokopenko, Inga, Kumar, Ashish, Perry, John, Howie, Bryan, van de Bunt, Martijn, Small, Kerrin, Lindgren, Cecilia, Lunter, Gerton, Robertson, Neil, Rayner, William, Morris, Andrew, Buck, David, Hattersley, Andrew, Spector, Tim, McVean, Gil, Frayling, Tim, Donnelly, Peter, McCarthy, Mark, Gupta, Namrata, Taylor, Herman, Fox, Ervin, Cheh, Christopher Newton, Wilson, James G, O'Donnell, Christopher J, Kathiresan, Sekar, Hirschhorn, Joel, Seidman, JG, and Seidman, Christine

Subjects
Genetics, Biotechnology, Human Genome, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adipocytes, Adult, Aged, Aged, 80 and over, Case-Control Studies, Cell Differentiation, Diabetes Mellitus, Type 2, Ethnicity, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, PPAR gamma, Polymorphism, Single Nucleotide, Risk Factors, Sequence Analysis, DNA, GoT2D Consortium, NHGRI JHS/FHS Allelic Spectrum Project, SIGMA T2D Consortium, T2D-GENES Consortium
Abstract

Peroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and a canonical target of antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy and insulin resistance; in the general population, the common P12A variant is associated with a decreased risk of type 2 diabetes (T2D). Whether and how rare variants in PPARG and defects in adipocyte differentiation influence risk of T2D in the general population remains undetermined. By sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, we identified 49 previously unidentified, nonsynonymous PPARG variants (MAF < 0.5%). Considered in aggregate (with or without computational prediction of functional consequence), these rare variants showed no association with T2D (OR = 1.35; P = 0.17). The function of the 49 variants was experimentally tested in a novel high-throughput human adipocyte differentiation assay, and nine were found to have reduced activity in the assay. Carrying any of these nine LOF variants was associated with a substantial increase in risk of T2D (OR = 7.22; P = 0.005). The combination of large-scale DNA sequencing and functional testing in the laboratory reveals that approximately 1 in 1,000 individuals carries a variant in PPARG that reduces function in a human adipocyte differentiation assay and is associated with a substantial risk of T2D.

Published
2014

8. A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes

Author

Christopher Hartl, Katherine Tooley, Laura Riba, David Torrents, Ulises Alvirde, Olimpia Arellano-Campos, Ralph A. DeFronzo, Taru Tukiainen, Geoffrey A. Walford, Noël P. Burtt, Donna M. Lehman, Amy L. Williams, Alicia Huerta-Chagoya, Pierre Fontanillas, Richa Saxena, Stacey Gabriel, Michael Boehnke, Carlos A. Aguilar-Salinas, Stephan Ripke, Yayoi Segura-Kato, Steven A. McCarroll, Jacqueline M. Lane, Brian E. Henderson, Ravindranath Duggirala, Sobha Puppala, Ignasi Moran, Humberto García-Ortiz, Lizz Caulkins, María Elena González-Villalpando, Vineeta Agarwala, Maria L. Cortes, Jorge Ferrer, Cristina Revilla-Monsalve, Graeme I. Bell, Jason Flannick, Francisco Barajas-Olmos, María Luisa Ordóñez-Sánchez, Angélica Martínez-Hernández, Robert L. Hanson, Jose C. Florez, Broad Genomics Platform, Clicerio González-Villalpando, Ivette Cruz-Bautista, Rosario Rodríguez-Guillén, Sílvia Bonàs-Guarch, Rachel G. Liao, Lorena Orozco, Kathleen A. Jablonski, Daniel G. MacArthur, Elvia Mendoza-Caamal, Emilio J. Cordova, Karol Estrada, Hortensia Moreno-Macías, Leslie J. Baier, Avery Davis Bell, Hanna E. Abboud, Suzanne B.R. Jacobs, Maribel Rodriguez-Torres, Xavier Soberón, William C. Knowler, David Altshuler, Zachary Dymek, Christopher A. Haiman, Josep M. Mercader, Donaji V. Gómez-Velasco, Liliana Muñoz-Hernandez, Joanne E. Curran, Loic Le Marchand, Maegan Harden, Lynne R. Wilkens, John Blangero, Teresa Tusié-Luna, Federico Centeno-Cruz, Ling Chen, Craig L. Hanis, Carlos Zerrweck, Sergio Islas-Andrade, Cecilia Contreras-Cubas, Christopher P. Jenkinson, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, and Medical Research Council (MRC)

Subjects
0301 basic medicine, endocrine system diseases, Endocrinology, Diabetes and Metabolism, LOCI, Adipose tissue, Disease, SUSCEPTIBILITY, TRIGLYCERIDE LEVELS, DISEASE, chemistry.chemical_compound, Mexican Americans, Protein Isoforms, RNA-SEQ, 11 Medical and Health Sciences, Broad Genomics Platform, Genetics, education.field_of_study, Stem Cells, GROWTH-FACTOR-II, 3. Good health, Adipose Tissue, Liver, Life Sciences & Biomedicine, Gene isoform, Genotype, European Continental Ancestry Group, Population, Biology, GENETIC ARCHITECTURE, Cell Line, Endocrinology & Metabolism, 03 medical and health sciences, QUALITY-CONTROL, Insulin-Like Growth Factor II, Genetic variation, Internal Medicine, Humans, GENOME-WIDE ASSOCIATION, Allele, education, Mexico, Allele frequency, Science & Technology, nutritional and metabolic diseases, Genetic Variation, T2D-GENES Consortium, Diabetes Prevention Program Research Group, SIGMA T2D Genetics Consortium, 030104 developmental biology, Diabetes Mellitus, Type 2, Gene Expression Regulation, chemistry, RNA Splice Sites, Glycated hemoglobin, MEXICAN-AMERICANS
Abstract

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage–dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.

Published
2017

9. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center

Subjects
0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Published
2018

10. Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

Author

Horikoshi, Momoko, Pasquali, Lorenzo, Wiltshire, Steven, Huyghe, Jeroen R., Mahajan, Anubha, Asimit, Jennifer L., Ferreira, Teresa, Locke, Adam E., Robertson, Neil R., Wang, Xu, Sim, Xueling, Fujita, Hayato, Hara, Kazuo, Young, Robin, Zhang, Weihua, Choi, Sungkyoung, Chen, Han, Kaur, Ismeet, Takeuchi, Fumihiko, Fontanillas, Pierre, Thuillier, Dorothée, Yengo, Loic, Below, Jennifer E., Tam, Claudia H.T., Wu, Ying, Abecasis, Gonçalo, Altshuler, David, Bell, Graeme I., Blangero, John, Burtt, Noél P., Duggirala, Ravindranath, Florez, Jose C., Hanis, Craig L., Seielstad, Mark, Atzmon, Gil, Chan, Juliana C.N., Ma, Ronald C.W., Froguel, Philippe, Wilson, James G., Bharadwaj, Dwaipayan, Dupuis, Josee, Meigs, James B., Cho, Yoon Shin, Park, Taesung, Kooner, Jaspal S., Chambers, John C., Saleheen, Danish, Kadowaki, Takashi, Tai, E. Shyong, Mohlke, Karen L., Cox, Nancy J., Ferrer, Jorge, Zeggini, Eleftheria, Kato, Norihiro, Teo, Yik Ying, Boehnke, Michael, McCarthy, Mark I., and Morris, Andrew P.

Subjects
Male, Genetics & Heredity, tRNA Methyltransferases, Association Studies Articles, Chromosome Mapping, RNA-Binding Proteins, 11 Medical And Health Sciences, 06 Biological Sciences, Polymorphism, Single Nucleotide, T2D-GENES Consortium, Linkage Disequilibrium, White People, Black or African American, Asian People, Diabetes Mellitus, Type 2, KCNQ1 Potassium Channel, Cyclin-Dependent Kinase Inhibitor p18, Humans, Female, Genetic Predisposition to Disease, Regulatory Elements, Transcriptional, Alleles, Cyclin-Dependent Kinase Inhibitor p16, Genetic Association Studies
Abstract

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

Published
2016
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11. A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Author

Anna Gloyn, Eric Gamazon, Benjamin Glaser, Adam Locke, E Shyong Tai, Jennifer Asimit, Inga Prokopenko, John Blangero, Dan Nicolae, Christian Fuchsberger, Jennifer Below, Mark Seielstad, Mark McCarthy, Cecilia Lindgren, Xueling Sim, Mohammad Kamran Ikram, and Other departments

Subjects
Genotype, Bioinformatics, LOCI, Computational biology, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, DNA sequencing, 03 medical and health sciences, CODING VARIANTS, Missing heritability problem, Genetics, SNP, Exome, GENOME-WIDE ASSOCIATION, COMMON, Genotyping, Exome sequencing, Imputation, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetics & Heredity, AFRICAN-AMERICANS, 08 Information And Computing Sciences, 0303 health sciences, Science & Technology, Methodology Article, 030305 genetics & heredity, Rare variant, GENETIC-VARIATION, High-Throughput Nucleotide Sequencing, T2D-Genes Consortium, 11 Medical And Health Sciences, 06 Biological Sciences, Exome chip, SNP genotyping, Biotechnology & Applied Microbiology, DISEASES, POPULATIONS, Life Sciences & Biomedicine, Combined approach, PROJECT, Imputation (genetics), Biotechnology
Abstract

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF

Published
2015

12. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Author

Surendran, P., Drenos, F., Young, R., Warren, H., Cook, J.P., Manning, A.K., Grarup, N., Sim, X., Barnes, D.R., Witkowska, K., Staley, J.R., Tragante, V., Tukiainen, T., Yaghootkar, H., Masca, N., Freitag, D.F., Ferreira, T., Giannakopoulou, O., Tinker, A., Harakalova, M., Mihailov, E., Liu, C., Kraja, A.T., Nielsen, S.F., Rasheed, A., Samue, M., Zhao, W., Bonnycastle, L.L., Jackson, A.U., Narisu, N., Swift, A.J., Southam, L., Marten, J., Huyghe, J.R., Stancakova, A., Fava, C., Ohlsson, T., Matchan, A., Stirrups, K.E., Bork-Jensen, J., Gjesing, A.P., Kontto, J., Perola, M., Shaw-Hawkins, S., Havulinna, A.S., Zhang, H., Donnelly, L.A., Groves, C.J., Rayner, N.W., Neville, M.J., Robertson, N.R., Yiorkas, A.M., Herzig, K.H., Kajantie, E., Zhang, W., Willems, S.M., Lannfelt, L., Malerba, G., Soranzo, N., Trabetti, E., Verweij, N., Evangelou, E., Moayyeri, A., Vergnaud, A.C., Nelson, C.P., Poveda, A., Varga, T.V., Caslake, M., Craen, A.J.M. de, Trompet, S., Luan, J., Scott, R.A., Harris, S.E., Liewald, D.C.M., Marioni, R., Menni, C., Farmaki, A.E., Hallmans, G., Renstrom, F., Huffman, J.E., Hassinen, M., Burgess, S., Vasan, R.S., Felix, J.F., Uria-Nickelsen, M., Malarstign, A., Reilly, D.F., Hoek, M., Vogt, T.F., Lin, H.H., Lieb, W., Traylor, M., Markus, H.S., Highland, H.M., Justice, A.E., Marouli, E., Lindstrom, J., Uusitupa, M., Komulainen, P., Lakka, T.A., Rauramaa, R., Polasek, O., Rudan, I., Rolandsson, O., Franks, P.W., Dedoussis, G., Spector, T.D., Jousilahti, P., Mannisto, S., Deary, I.J., Starr, J.M., Langenberg, C., Wareham, N.J., Brown, M.J., Dominiczak, A.F., Connell, J.M., Jukema, J.W., Sattar, N., Ford, I., Packard, C.J., Esko, T., Magi, R., Metspalu, A., Boer, R.A. de, Meer, P. van der, Harst, P. van der, Gambaro, G., Ingelsson, E., Lind, L., Bakker, P.I.W. de, Numans, M.E., Brandslund, I., Christensen, C., Petersen, E.R.B., Korpi-Hyovalti, E., Oksa, H., Chambers, J.C., Kooner, J.S., Blakemore, A.I.F., Franks, S., Jarvelin, M.R., Husemoen, L.L., Linneberg, A., Skaaby, T., Thuesen, B., Karpe, F., Tuomilehto, J., Doney, A.S.F., Morris, A.D., Palmer, C.N.A., Holmen, O.L., Hveem, K., Willer, C.J., Tuomi, T., Groop, L., Karajamaki, A., Palotie, A., Ripatti, S., Salomaa, V., Alam, D.S., Majmnder, A.A.S., Angelantonio, E. di, Chowdhury, R., McCarthy, M.I., Poulter, N., Stanton, A.V., Sever, P., Amouyel, P., Arveiler, D., Blankenberg, S., Ferrieres, J., Kee, F., Kuulasmaa, K., Muller-Nurasyid, M., Veronesi, G., Virtamo, J., Deloukas, P., Elliott, P., Zeggini, E., Kathiresan, S., Melander, O., Kuusisto, J., Laakso, M., Padmanabhan, S., Porteous, D.J., Hayward, C., Scotland, G., Collins, F.S., Mohlke, K.L., Hansen, T., Pedersen, O., Boehnke, M., Stringham, H.M., Frossard, P., Newton-Cheh, C., Tobin, M.D., Nordestgaard, B.G., Caulfield, M.J., Mahajan, A., Morris, A.P., Tomaszewski, M., Samani, N.J., Saleheen, D., Asselbergs, F.W., Lindgren, C.M., Danesh, J., Wain, L.V., Butterworth, A.S., Howson, J.M.M., Munroe, P.B., CHARGE Heart Failure Consortiumm, EchoGen Consortiumm, Metastroke Consortiumm, Giant Consortiumm, EPIC-InterAct Consortium, Lifelines Cohort Study, Wellcome Trust Case Control Consor, Understanding Soc Sci Grp, EPIC-CVD Consortium, CHARGE Exome Chip Blood Pressure C, T2D-GENES Consortium, GoT2DGenes Consortium, ExomeBP Consortium, CHD Exome Consortium, Erasmus MC other, Epidemiology, Internal Medicine, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Surendran, Praveen [0000-0002-4911-6077], Barnes, Daniel [0000-0002-3781-7570], Marten, Jonathan [0000-0001-6916-2014], Johnson, Kathleen [0000-0002-6823-3252], Soranzo, Nicole [0000-0003-1095-3852], Luan, Jian'an [0000-0003-3137-6337], Burgess, Stephen [0000-0001-5365-8760], Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Di Angelantonio, Emanuele [0000-0001-8776-6719], Chowdhury, Rajiv [0000-0003-4881-5690], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Apollo - University of Cambridge Repository, British Heart Foundation, Home Office, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, and Action on Hearing Loss

Subjects
0301 basic medicine, EchoGen Consortium, Population genetics, LOCI, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, 0302 clinical medicine, Settore MED/14 - NEFROLOGIA, Missense mutation, GENE-CENTRIC ARRAY, GoT2DGenes Consortium, AGING RESEARCH, Genetics, education.field_of_study, CHD Exome+ Consortium, CHARGE-Heart Failure Consortium, 11 Medical And Health Sciences, 3. Good health, CARDIOVASCULAR-DISEASE, Hypertension, Medical genetics, HEART, Wellcome Trust Case Control Consortium, EPIC-InterAct Consortium, ExomeBP Consortium, CHARGE, Understanding Society Scientific Group, medicine.medical_specialty, Genotype, Population, Biology, CHARGE+ Exome Chip Blood Pressure Consortium, EPIC-CVD Consortium, Article, 03 medical and health sciences, Lifelines Cohort Study, genome-wide association studies, hypertension, population genetics, Genetic variation, GIANT Consortium, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, education, PLASMA-LEVELS, IDENTIFICATION, Genetic Variation, 06 Biological Sciences, medicine.disease, METASTROKE Consortium, T2D-GENES Consortium, 030104 developmental biology, Blood pressure, Pathophysiology of hypertension, RISK-FACTORS, Developmental Biology, Genome-Wide Association Study, blood pressure, gene
Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ~155,063 samples for independent replication. We identified 30 new blood pressure– or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention. N.P. has received financial support from several pharmaceutical companies that manufacture either blood pressure -lowering or lipid-lowering agents, or both, and consultancy fees. S.K. has received research grants from Merck, Bayer and Aegerion, is on the SAB of Catabasis, Regeneron Genetics Center, Merck and Celera, has equity in San Therapeutics and Catabasis, and performs consulting for Novartis, Aegerion, Bristol Myers Squibb, Sanofi, AstraZeneca and Alnylam. P. Sever has received research awards from Pfizer. A. Malarstig and M.U.-N. are full-time employees of Pfizer. D.F.R. and M. Hoek are full-time employees of Merck. M.J.C. is Chief Scientist for Genomics England, a UK government company. The authors declare no other competing financial interests.

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13. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Author

Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Angelantonio, Emanuele Di, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T, Hayward, Caroline, Heid, Iris M, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jarvik, Gail P, Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M, Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kovacs, Peter, Krämer, Bernhard K, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas GD, McCarthy, Mark I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Ntalla, Ioanna, O'Connell, Jeffrey R, Owen, Katharine R, Pedersen, Oluf, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T, Rasheed, Asif, Raulerson, Chelsea K, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Ridker, Paul M, Rivas, Manuel A, Robertson, Neil R, Robino, Antonietta, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Blair H, Smith, Jennifer A, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin MA, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van Duijn, Cornelia M, Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M Carola, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CH, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Rivadeneira, Fernando, Borecki, Ingrid B, Pospisilik, J Andrew, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, Mohlke, Karen L, Rotter, Jerome I, Kutalik, Zoltán, Hirschhorn, Joel N, Cupples, L Adrienne, Loos, Ruth JF, North, Kari E, Lindgren, Cecilia M, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Institute for Molecular Medicine Finland, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, Young, Kristin L [0000-0003-0070-6145], Mahajan, Anubha [0000-0001-5585-3420], Winkler, Thomas W [0000-0003-0292-5421], Locke, Adam E [0000-0001-6227-198X], Medina-Gomez, Carolina [0000-0001-7999-5538], Giri, Ayush [0000-0002-7786-4670], Ng, Maggie CY [0000-0002-4133-2007], Heard-Costa, Nancy L [0000-0001-9730-0306], Manning, Alisa K [0000-0003-0247-902X], Alam, Dewan S [0000-0002-2051-3837], Amouyel, Philippe [0000-0001-9088-234X], Bergmann, Sven [0000-0002-6785-9034], Boehnke, Michael [0000-0002-6442-7754], Butterworth, Adam S [0000-0002-6915-9015], Caulfield, Mark J [0000-0001-9295-3594], Collins, Francis S [0000-0002-1023-7410], de Bakker, Paul IW [0000-0001-7735-7858], Dennis, Joe G [0000-0003-4591-1214], Easton, Douglas F [0000-0003-2444-3247], Elliott, Paul [0000-0002-7511-5684], Evangelou, Evangelos [0000-0002-5488-2999], Giedraitis, Vilmantas [0000-0003-3423-2021], Girotto, Giorgia [0000-0003-4507-6589], Grarup, Niels [0000-0001-5526-1070], Gustafsson, Stefan [0000-0001-5894-0351], Hansen, Torben [0000-0001-8748-3831], Hayward, Caroline [0000-0002-9405-9550], Howson, Joanna MM [0000-0001-7618-0050], Ikram, M Arfan [0000-0003-0372-8585], Jackson, Anne U [0000-0002-9672-2547], Justesen, Johanne M [0000-0002-0484-8522], Kovacs, Peter [0000-0002-0290-5423], Kuulasmaa, Kari [0000-0003-2165-1411], Langenberg, Claudia [0000-0002-5017-7344], Lin, Li-An [0000-0003-2731-1346], Linneberg, Allan [0000-0002-0994-0184], Liu, Ching-Ti [0000-0002-0703-0742], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], MacGregor, Stuart [0000-0001-6731-8142], McCarthy, Mark I [0000-0002-4393-0510], Morgan, Anna [0000-0001-6290-445X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Munroe, Patricia B [0000-0002-4176-2947], Narisu, Narisu [0000-0002-8483-1156], Neville, Matt [0000-0002-6004-5433], Reilly, Dermot F [0000-0002-9456-1364], Rudan, Igor [0000-0001-6993-6884], Saleheen, Danish [0000-0001-6193-020X], Salomaa, Veikko [0000-0001-7563-5324], Sim, Xueling [0000-0002-1233-7642], Small, Kerrin S [0000-0003-4566-0005], Smith, Blair H [0000-0002-5362-9430], Smith, Jennifer A [0000-0002-3575-5468], Southam, Lorraine [0000-0002-7546-9650], Stefansson, Kari [0000-0003-1676-864X], Stirrups, Kathleen E [0000-0002-6823-3252], Stringham, Heather M [0000-0002-2991-6392], Teumer, Alexander [0000-0002-8309-094X], Thompson, Deborah J [0000-0003-1465-5799], Vestergaard, Henrik [0000-0003-3090-269X], Vitart, Veronique [0000-0002-4991-3797], Wang, Carol A [0000-0002-4301-3974], Wessel, Jennifer [0000-0002-7031-0085], Willer, Cristen J [0000-0001-5645-4966], Zeggini, Eleftheria [0000-0003-4238-659X], Rivadeneira, Fernando [0000-0001-9435-9441], Pospisilik, J Andrew [0000-0002-9745-0977], Deloukas, Panos [0000-0001-9251-070X], Mohlke, Karen L [0000-0001-6721-153X], Kutalik, Zoltán [0000-0001-8285-7523], Loos, Ruth JF [0000-0002-8532-5087], Lindgren, Cecilia M [0000-0002-4903-9374], Apollo - University of Cambridge Repository, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Medical and Clinical Psychology, Justice, Anne E., Karaderi, Tugce, Highland, Heather M., Young, Kristin L., Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L., Fine, Rebecca S., Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W., Locke, Adam E., Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie C. Y., Heard-Costa, Nancy L., Feitosa, Mary F., Manning, Alisa K., Willems, Sara M., Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S., Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Mark J., Cesana, Giancarlo, Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele Di, Dörr, Marcu, Drenos, Fotio, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Fornage, Myriam, Fox, Caroline S., Franks, Paul W., Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Girotto, Giorgia, Gorski, Mathia, Grallert, Harald, Grarup, Niel, Grove, Megan L., Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T., Hayward, Caroline, Heid, Iris M., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jarvik, Gail P., Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M., Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kovacs, Peter, Krämer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian’An, Lyytikäinen, Leo-Pekka, Macgregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas G. D., Mccarthy, Mark I., Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, O’Connell, Jeffrey R., Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T., Rasheed, Asif, Raulerson, Chelsea K., Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Ridker, Paul M., Rivas, Manuel A., Robertson, Neil R., Robino, Antonietta, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Blair H., Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin M. A., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, van Duijn, Cornelia M., Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M. Carola, Rivadeneira, Fernando, Borecki, Ingrid B., Pospisilik, J. Andrew, Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, Mohlke, Karen L., Rotter, Jerome I., Kutalik, Zoltán, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., Lindgren, Cecilia M., APH - Societal Participation & Health, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, Epidemiology and Data Science, and VU University medical center

Subjects
Exome/genetics, Male, ReproGen Consortium, Adipose tissue, Genome-wide association study, Type 2 diabetes, White adipose tissue, Body Mass Index, Animals, Body Fat Distribution, Case-Control Studies, Drosophila, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeostasis, Humans, Lipids, Proteins, Risk Factors, Waist-Hip Ratio, 0302 clinical medicine, Hyperlipidemia, Body fat distribution, 2. Zero hunger, Genetics, 0303 health sciences, INSULIN-RESISTANCE, ADIPOCYTE DIFFERENTIATION, CHD Exome+ Consortium, Genetic Predisposition to Disease/genetics, Drosophila/genetics, RS11209026 POLYMORPHISM, KINASE 7, 1184 Genetics, developmental biology, physiology, T2D-Genes Consortium, 11 Medical And Health Sciences, Body Fat Distribution/methods, RECEPTOR ALK7, ADIPOSE-TISSUE, Gene Frequency/genetics, Genetic Variation/genetics, InterAct, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], genetic association study, RNA splicing, Proteins/genetics, Genome-Wide Association Study/methods, Lipid particle, ExomeBP Consortium, WAIST CIRCUMFERENCE, Waist-Hip Ratio/methods, Biology, EPIC-CVD Consortium, Article, MAGIC Investigators, 03 medical and health sciences, Homeostasis/genetics, Lipids/genetics, All institutes and research themes of the Radboud University Medical Center, medicine, Global Lipids Genetic Consortium, Risk factor, GENOME-WIDE ASSOCIATION, ABDOMINAL ADIPOSITY, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Gene, 030304 developmental biology, 06 Biological Sciences, medicine.disease, Minor allele frequency, GoT2D Genes Consortium, genetics research, TYPE-2 DIABETES SUSCEPTIBILITY, 3111 Biomedicine, Body mass index, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Body fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥ 5%) and 9 low frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology, and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants., Editorial summary: A trans-ethnic exome-wide association study for body fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.

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