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2. Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

Author

Yin, Xianyong, Bose, Debraj, Kwon, Annie, Hanks, Sarah C, Jackson, Anne U, Stringham, Heather M, Welch, Ryan, Oravilahti, Anniina, Fernandes Silva, Lilian, FinnGen, Locke, Adam E, Fuchsberger, Christian, Service, Susan K, Erdos, Michael R, Bonnycastle, Lori L, Kuusisto, Johanna, Stitziel, Nathan O, Hall, Ira M, Morrison, Jean, Ripatti, Samuli, Palotie, Aarno, Freimer, Nelson B, Collins, Francis S, Mohlke, Karen L, Scott, Laura J, Fauman, Eric B, Burant, Charles, Boehnke, Michael, Laakso, Markku, and Wen, Xiaoquan

Subjects
Male, Quantitative Trait Loci, Glycerophospholipids, Medical and Health Sciences, colocalizataion, transcriptomics, Carnitine, Genetics, Humans, Metabolomics, 2.1 Biological and endogenous factors, Aetiology, Solute Carrier Family 22 Member 5, Nutrition, Genetics & Heredity, genome-wide association study, Human Genome, Bilirubin, Biological Sciences, metabolomics, transcriptome-wide association study, FinnGen, Good Health and Well Being, Transcriptome, Genome-Wide Association Study, Biotechnology
Abstract

Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite levels were more likely to influence gene expression and disease risk compared to the ones that do not. Integrating transcriptomics with metabolomics results prioritized 397 genes for 521 metabolites, including 496 previously identified gene-metabolite pairs with strong functional connections and suggested 33.3% of such gene-metabolite pairs shared the same causal variants with genetic associations of gene expression. Integrating transcriptomics and metabolomics individually with FinnGen GWAS results identified 1,597 genes for 790 disease traits. Integrating transcriptomics and metabolomics jointly with FinnGen GWAS results helped pinpoint metabolic pathways from genes to diseases. We identified putative causal effects of UGT1A1/UGT1A4 expression on gallbladder disorders through regulating plasma (E,E)-bilirubin levels, of SLC22A5 expression on nasal polyps and plasma carnitine levels through distinct pathways, and of LIPC expression on age-related macular degeneration through glycerophospholipid metabolic pathways. Our study highlights the power of integrating multiple sets of molecular traits and GWAS results to deepen understanding of disease pathophysiology.

Published
2022

3. Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Author

Yin, Xianyong, Chan, Lap Sum, Bose, Debraj, Jackson, Anne U, VandeHaar, Peter, Locke, Adam E, Fuchsberger, Christian, Stringham, Heather M, Welch, Ryan, Yu, Ketian, Fernandes Silva, Lilian, Service, Susan K, Zhang, Daiwei, Hector, Emily C, Young, Erica, Ganel, Liron, Das, Indraniel, Abel, Haley, Erdos, Michael R, Bonnycastle, Lori L, Kuusisto, Johanna, Stitziel, Nathan O, Hall, Ira M, Wagner, Gregory R, FinnGen, Kang, Jian, Morrison, Jean, Burant, Charles F, Collins, Francis S, Ripatti, Samuli, Palotie, Aarno, Freimer, Nelson B, Mohlke, Karen L, Scott, Laura J, Wen, Xiaoquan, Fauman, Eric B, Laakso, Markku, and Boehnke, Michael

Subjects
Male, Human Genome, Single Nucleotide, FinnGen, Phenotype, Gene Frequency, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Alleles, Finland, Genome-Wide Association Study
Abstract

Few studies have explored the impact of rare variants (minor allele frequency

Published
2022

4. Exome sequencing of Finnish isolates enhances rare-variant association power

Author

Locke, Adam E, Steinberg, Karyn Meltz, Chiang, Charleston WK, Service, Susan K, Havulinna, Aki S, Stell, Laurel, Pirinen, Matti, Abel, Haley J, Chiang, Colby C, Fulton, Robert S, Jackson, Anne U, Kang, Chul Joo, Kanchi, Krishna L, Koboldt, Daniel C, Larson, David E, Nelson, Joanne, Nicholas, Thomas J, Pietilä, Arto, Ramensky, Vasily, Ray, Debashree, Scott, Laura J, Stringham, Heather M, Vangipurapu, Jagadish, Welch, Ryan, Yajnik, Pranav, Yin, Xianyong, Eriksson, Johan G, Ala-Korpela, Mika, Järvelin, Marjo-Riitta, Männikkö, Minna, Laivuori, Hannele, FinnGen Project, Dutcher, Susan K, Stitziel, Nathan O, Wilson, Richard K, Hall, Ira M, Sabatti, Chiara, Palotie, Aarno, Salomaa, Veikko, Laakso, Markku, Ripatti, Samuli, Boehnke, Michael, and Freimer, Nelson B

Subjects
Multifactorial Inheritance, HDL, Endpoint Determination, General Science & Technology, Quantitative Trait Loci, Human Genome, Reproducibility of Results, Genetic Variation, Geographic Mapping, Whole Exome Sequencing, Cholesterol, Exome Sequencing, Genetics, Humans, Cluster Analysis, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, FinnGen Project, Aetiology, Alleles, Finland, Genetic Association Studies
Abstract

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exomesequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

Published
2019

5. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

Author

Flannick, Jason, Mercader, Josep M, Fuchsberger, Christian, Udler, Miriam S, Mahajan, Anubha, Wessel, Jennifer, Teslovich, Tanya M, Caulkins, Lizz, Koesterer, Ryan, Barajas-Olmos, Francisco, Blackwell, Thomas W, Boerwinkle, Eric, Brody, Jennifer A, Centeno-Cruz, Federico, Chen, Ling, Chen, Siying, Contreras-Cubas, Cecilia, Córdova, Emilio, Correa, Adolfo, Cortes, Maria, DeFronzo, Ralph A, Dolan, Lawrence, Drews, Kimberly L, Elliott, Amanda, Floyd, James S, Gabriel, Stacey, Garay-Sevilla, Maria Eugenia, García-Ortiz, Humberto, Gross, Myron, Han, Sohee, Heard-Costa, Nancy L, Jackson, Anne U, Jørgensen, Marit E, Kang, Hyun Min, Kelsey, Megan, Kim, Bong-Jo, Koistinen, Heikki A, Kuusisto, Johanna, Leader, Joseph B, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Lyssenko, Valeriya, Manning, Alisa K, Marcketta, Anthony, Malacara-Hernandez, Juan Manuel, Martínez-Hernández, Angélica, Matsuo, Karen, Mayer-Davis, Elizabeth, Mendoza-Caamal, Elvia, Mohlke, Karen L, Morrison, Alanna C, Ndungu, Anne, Ng, Maggie CY, O'Dushlaine, Colm, Payne, Anthony J, Pihoker, Catherine, Broad Genomics Platform, Post, Wendy S, Preuss, Michael, Psaty, Bruce M, Vasan, Ramachandran S, Rayner, N William, Reiner, Alexander P, Revilla-Monsalve, Cristina, Robertson, Neil R, Santoro, Nicola, Schurmann, Claudia, So, Wing Yee, Soberón, Xavier, Stringham, Heather M, Strom, Tim M, Tam, Claudia HT, Thameem, Farook, Tomlinson, Brian, Torres, Jason M, Tracy, Russell P, van Dam, Rob M, Vujkovic, Marijana, Wang, Shuai, Welch, Ryan P, Witte, Daniel R, Wong, Tien-Yin, Atzmon, Gil, Barzilai, Nir, Blangero, John, Bonnycastle, Lori L, Bowden, Donald W, Chambers, John C, Chan, Edmund, Cheng, Ching-Yu, Cho, Yoon Shin, Collins, Francis S, de Vries, Paul S, Duggirala, Ravindranath, Glaser, Benjamin, Gonzalez, Clicerio, Gonzalez, Ma Elena, Groop, Leif, and Kooner, Jaspal Singh

Subjects
Male, General Science & Technology, Knockout, LuCamp, Whole Exome Sequencing, Decision Support Techniques, Mice, T2D-GENES, Gene Frequency, Exome Sequencing, Diabetes Mellitus, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, AMP-T2D-GENES, Exome, Aetiology, ESP, Metabolic and endocrine, Broad Genomics Platform, Prevention, Diabetes, Human Genome, ProDiGY, Case-Control Studies, DiscovEHR Collaboration, SIGMA-T2D, Female, CHARGE, Type 2, GoT2D, Genome-Wide Association Study, Biotechnology
Abstract

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791individuals with type 2 diabetes (T2D) and 24,440non-diabetic control participants from 5ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4genes at exome-wide significance, including a series of more than 30SLC30A8 alleles that conveys protection against T2D, and in 12gene sets, including those corresponding to T2D drug targets (P=6.1×10-3) and candidate genes from knockout mice (P=5.2×10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

Published
2019

6. Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls

Author

Flannick, Jason, Fuchsberger, Christian, Mahajan, Anubha, Teslovich, Tanya M, Agarwala, Vineeta, Gaulton, Kyle J, Caulkins, Lizz, Koesterer, Ryan, Ma, Clement, Moutsianas, Loukas, McCarthy, Davis J, Rivas, Manuel A, Perry, John RB, Sim, Xueling, Blackwell, Thomas W, Robertson, Neil R, Rayner, N William, Cingolani, Pablo, Locke, Adam E, Tajes, Juan Fernandez, Highland, Heather M, Dupuis, Josee, Chines, Peter S, Lindgren, Cecilia M, Hartl, Christopher, Jackson, Anne U, Chen, Han, Huyghe, Jeroen R, van de Bunt, Martijn, Pearson, Richard D, Kumar, Ashish, Müller-Nurasyid, Martina, Grarup, Niels, Stringham, Heather M, Gamazon, Eric R, Lee, Jaehoon, Chen, Yuhui, Scott, Robert A, Below, Jennifer E, Chen, Peng, Huang, Jinyan, Go, Min Jin, Stitzel, Michael L, Pasko, Dorota, Parker, Stephen CJ, Varga, Tibor V, Green, Todd, Beer, Nicola L, Day-Williams, Aaron G, Ferreira, Teresa, Fingerlin, Tasha, Horikoshi, Momoko, Hu, Cheng, Huh, Iksoo, Ikram, Mohammad Kamran, Kim, Bong-Jo, Kim, Yongkang, Kim, Young Jin, Kwon, Min-Seok, Lee, Juyoung, Lee, Selyeong, Lin, Keng-Han, Maxwell, Taylor J, Nagai, Yoshihiko, Wang, Xu, Welch, Ryan P, Yoon, Joon, Zhang, Weihua, Barzilai, Nir, Voight, Benjamin F, Han, Bok-Ghee, Jenkinson, Christopher P, Kuulasmaa, Teemu, Kuusisto, Johanna, Manning, Alisa, Ng, Maggie CY, Palmer, Nicholette D, Balkau, Beverley, Stančáková, Alena, Abboud, Hanna E, Boeing, Heiner, Giedraitis, Vilmantas, Prabhakaran, Dorairaj, Gottesman, Omri, Scott, James, Carey, Jason, Kwan, Phoenix, Grant, George, Smith, Joshua D, Neale, Benjamin M, Purcell, Shaun, Butterworth, Adam S, Howson, Joanna MM, Lee, Heung Man, Lu, Yingchang, Kwak, Soo-Heon, Zhao, Wei, Danesh, John, and Lam, Vincent KL

Abstract

This corrects the article DOI: 10.1038/sdata.2017.179.

Published
2018

7. Sequence data and association statistics from 12,940 type 2 diabetes cases and controls

Author

Flannick, Jason, Fuchsberger, Christian, Mahajan, Anubha, Teslovich, Tanya M, Agarwala, Vineeta, Gaulton, Kyle J, Caulkins, Lizz, Koesterer, Ryan, Ma, Clement, Moutsianas, Loukas, McCarthy, Davis J, Rivas, Manuel A, Perry, John RB, Sim, Xueling, Blackwell, Thomas W, Robertson, Neil R, Rayner, N William, Cingolani, Pablo, Locke, Adam E, Tajes, Juan Fernandez, Highland, Heather M, Dupuis, Josee, Chines, Peter S, Lindgren, Cecilia M, Hartl, Christopher, Jackson, Anne U, Chen, Han, Huyghe, Jeroen R, van de Bunt, Martijn, Pearson, Richard D, Kumar, Ashish, Müller-Nurasyid, Martina, Grarup, Niels, Stringham, Heather M, Gamazon, Eric R, Lee, Jaehoon, Chen, Yuhui, Scott, Robert A, Below, Jennifer E, Chen, Peng, Huang, Jinyan, Go, Min Jin, Stitzel, Michael L, Pasko, Dorota, Parker, Stephen CJ, Varga, Tibor V, Green, Todd, Beer, Nicola L, Day-Williams, Aaron G, Ferreira, Teresa, Fingerlin, Tasha, Horikoshi, Momoko, Hu, Cheng, Huh, Iksoo, Ikram, Mohammad Kamran, Kim, Bong-Jo, Kim, Yongkang, Kim, Young Jin, Kwon, Min-Seok, Lee, Juyoung, Lee, Selyeong, Lin, Keng-Han, Maxwell, Taylor J, Nagai, Yoshihiko, Wang, Xu, Welch, Ryan P, Yoon, Joon, Zhang, Weihua, Barzilai, Nir, Voight, Benjamin F, Han, Bok-Ghee, Jenkinson, Christopher P, Kuulasmaa, Teemu, Kuusisto, Johanna, Manning, Alisa, Ng, Maggie CY, Palmer, Nicholette D, Balkau, Beverley, Stančáková, Alena, Abboud, Hanna E, Boeing, Heiner, Giedraitis, Vilmantas, Prabhakaran, Dorairaj, Gottesman, Omri, Scott, James, Carey, Jason, Kwan, Phoenix, Grant, George, Smith, Joshua D, Neale, Benjamin M, Purcell, Shaun, Butterworth, Adam S, Howson, Joanna MM, Lee, Heung Man, Lu, Yingchang, Kwak, Soo-Heon, Zhao, Wei, Danesh, John, and Lam, Vincent KL

Subjects
European Continental Ancestry Group, Diabetes, Human Genome, Diabetes Mellitus, Genetics, Humans, Genetic Variation, 2.1 Biological and endogenous factors, Aetiology, White People, Type 2, Metabolic and endocrine
Abstract

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

Published
2017

8. Analysis of the effects of Marine Corps M1A1 Abram’s tank age on operational availability

Author

Scruggs, Andrew M., Welch, Ryan P., Naegle, Brad, Kang Keebom, and Graduate School of Business & Public Policy (GSBPP)

Subjects
Materiel Maintenance, Operational Availability, Depot-Level Maintenance, M1A1 Abrams MBT, Reliability Centered Maintenance (RCM), Anniston Army Depot
Abstract

The M1A1 Abram’s Main Battle Tank (MBT) is expected to remain a key piece of USMC equipment beyond 2025. Because the majority of equipment life-cycle costs occur in the operations and support phase, it is imperative that program managers incorporate effective and efficient product support strategies, balancing costs and reliability to create value for the government. The purpose of this project is to determine the effects of age, as measured by the time since the last depot-level rebuild, on equipment operational availability for the M1A1 MBT in the Marine Corps. Our study includes an overview of the history of M1A1 development, Department of Defense materiel maintenance policy, M1A1 rebuild strategy, and prior M1A1 reliability studies. We reviewed depot- and unit-level maintenance records within the USMC’s System Operational Effectiveness database to establish a correlation between years since last rebuild and operational availability (Ao). The objective of our research is to quantify the age-related effects on Ao to better inform the decision-making process of USMC leadership in determining materiel maintenance strategies. http://archive.org/details/analysisofeffect1094542724 Captain, United States Army;Captain, United States Army Approved for public release; distribution is unlimited.

Published
2014

9. Analysis of the Effects of Marine Corps M1A1 Abrams Tanks' Age on Operational Availability

Author

Scruggs, Andrew M., Welch, Ryan P., Naval Postgraduate School Acquisition Research Program, Naegle, Brad, and Kang, Keebom

Abstract

Annual Acquisition Research Symposium The purpose of this project is to determine the effects of age, as measured by the time since the last depot-level rebuild, on equipment operational availability for the M1A1 Main Battle Tank (MBT) in the Marine Corps. Naval Postgraduate School Naval Postgraduate School Acquisition Research Program

Published
2014

10. A genome-wide association search for type 2 diabetes genes in African Americans

Author

Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, DIAGRAM Consortium, MAGIC Investigators, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie CY, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex SF, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul RV, Jørgensen, Torben, Kao, Wen HL, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, and Kronenberg, Florian

Subjects
Adult, Male, endocrine system diseases, Genotype, General Science & Technology, DIAGRAM Consortium, Validation Studies as Topic, Cohort Studies, MAGIC Investigators, Meta-Analysis as Topic, Clinical Research, Diabetes Mellitus, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Metabolic and endocrine, Aged, African Americans, Diabetes, Human Genome, nutritional and metabolic diseases, Single Nucleotide, Middle Aged, Black or African American, Case-Control Studies, Female, Type 2, Genome-Wide Association Study
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Published
2012

11. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals

Author

Dastani, Zari, Hivert, Marie-France, Timpson, Nicholas, Perry, John RB, Yuan, Xin, Scott, Robert A, Henneman, Peter, Heid, Iris M, Kizer, Jorge R, Lyytikäinen, Leo-Pekka, Fuchsberger, Christian, Tanaka, Toshiko, Morris, Andrew P, Small, Kerrin, Isaacs, Aaron, Beekman, Marian, Coassin, Stefan, Lohman, Kurt, Qi, Lu, Kanoni, Stavroula, Pankow, James S, Uh, Hae-Won, Wu, Ying, Bidulescu, Aurelian, Rasmussen-Torvik, Laura J, Greenwood, Celia MT, Ladouceur, Martin, Grimsby, Jonna, Manning, Alisa K, Liu, Ching-Ti, Kooner, Jaspal, Mooser, Vincent E, Vollenweider, Peter, Kapur, Karen A, Chambers, John, Wareham, Nicholas J, Langenberg, Claudia, Frants, Rune, Willems-Vandijk, Ko, Oostra, Ben A, Willems, Sara M, Lamina, Claudia, Winkler, Thomas W, Psaty, Bruce M, Tracy, Russell P, Brody, Jennifer, Chen, Ida, Viikari, Jorma, Kähönen, Mika, Pramstaller, Peter P, Evans, David M, St Pourcain, Beate, Sattar, Naveed, Wood, Andrew R, Bandinelli, Stefania, Carlson, Olga D, Egan, Josephine M, Böhringer, Stefan, Van Heemst, Diana, Kedenko, Lyudmyla, Kristiansson, Kati, Nuotio, Marja-Liisa, Loo, Britt-Marie, Harris, Tamara, Garcia, Melissa, Kanaya, Alka, Haun, Margot, Klopp, Norman, Wichmann, H-Erich, Deloukas, Panos, Katsareli, Efi, Couper, David J, Duncan, Bruce B, Kloppenburg, Margreet, Adair, Linda S, Borja, Judith B, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, Wilson, James G, Musani, Solomon, Guo, Xiuqing, Johnson, Toby, Semple, Robert, Teslovich, Tanya M, Allison, Matthew A, Redline, Susan, Buxbaum, Sarah G, Mohlke, Karen L, Meulenbelt, Ingrid, Ballantyne, Christie M, Dedoussis, George V, Hu, Frank B, Liu, Yongmei, Paulweber, Bernhard, Spector, Timothy D, Slagboom, P Eline, Ferrucci, Luigi, Jula, Antti, Perola, Markus, Raitakari, Olli, Florez, Jose C, Salomaa, Veikko, Eriksson, Johan G, Frayling, Timothy M, Hicks, Andrew A, Lehtimäki, Terho, Smith, George Davey, Siscovick, David S, Kronenberg, Florian, Van Duijn, Cornelia, Loos, Ruth JF, Waterworth, Dawn M, Meigs, James B, Dupuis, Josee, Richards, J Brent, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Hofmann, Oliver M, Segrè, Ayellet V, Van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Crawford, Gabe, Doney, Alex SF, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul RV, Jørgensen, Torben, Kao, Wen HL, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, Van Dam, Rob M, Van Haeften, Timon W, Van Herpt, Thijs, Van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Morris, Andrew D, Palmer, Colin NA, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Pedersen, Oluf, Barroso, Inês, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, Van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Elliott, Paul, Rybin, Denis, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Lajunen, Taina, Doney, Alex, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan JM, Cooper, Matthew N, Crisponi, Laura, Day, Ian NM, De Geus, Eco JC, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Pfeiffer, Andreas FH, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sigurðsson, Gunnar, Sijbrands, Eric JG, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tönjes, Anke, Uitterlinden, André G, Van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline CM, Yarnell, John WG, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Borecki, Ingrid B, Meneton, Pierre, Magnusson, Patrik KE, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, WH Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Procardis Consortium, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Penninx, Brenda WJH, Boomsma, Dorret I, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, MAGIC Investigators, GLGC Consortium, Musunuru, Kiran, Smith, Albert V, Edmondson, Andrew C, Stylianou, Ioannis M, Koseki, Masahiro, Pirruccello, James P, Chasman, Daniel I, Johansen, Christopher T, Fouchier, Sigrid W, Peloso, Gina M, Barbalic, Maja, Ricketts, Sally L, Bis, Joshua C, Feitosa, Mary F, Orho-Melander, Marju, Melander, Olle, Li, Xiaohui, Li, Mingyao, Cho, Yoon Shin, Go, Min Jin, Kim, Young Jin, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Ong, Rick Twee-Hee, Croteau-Chonka, Damien C, Lange, Leslie A, Smith, Joshua D, Ziegler, Andreas, Zhang, Weihua, Zee, Robert YL, Whitfield, John B, Thompson, John R, Surakka, Ida, Spector, Tim D, Smit, Johannes H, Sinisalo, Juha, Scott, James, Saharinen, Juha, Sabatti, Chiara, Rose, Lynda M, Roberts, Robert, Rieder, Mark, Parker, Alex N, Pare, Guillaume, O'Donnell, Christopher J, Nieminen, Markku S, Nickerson, Deborah A, Montgomery, Grant W, McArdle, Wendy, Masson, David, Martin, Nicholas G, Marroni, Fabio, Lucas, Gavin, Luben, Robert, Lokki, Marja-Liisa, Lettre, Guillaume, Launer, Lenore J, Lakatta, Edward G, Laaksonen, Reijo, Kyvik, Kirsten O, König, Inke R, Khaw, Kay-Tee, Kaplan, Lee M, Johansson, Åsa, Janssens, A Cecile JW, Igl, Wilmar, Hovingh, G Kees, Hengstenberg, Christian, Havulinna, Aki S, Hastie, Nicholas D, Harris, Tamara B, Haritunians, Talin, Hall, Alistair S, Groop, Leif C, Gonzalez, Elena, Freimer, Nelson B, Erdmann, Jeanette, Ejebe, Kenechi G, Döring, Angela, Dominiczak, Anna F, Demissie, Serkalem, Deloukas, Panagiotis, De Faire, Ulf, Crawford, Gabriel, Chen, Yii-Der I, Caulfield, Mark J, Boekholdt, S Matthijs, Assimes, Themistocles L, Quertermous, Thomas, Seielstad, Mark, Wong, Tien Y, Tai, E-Shyong, Feranil, Alan B, Kuzawa, Christopher W, Taylor, Herman A, Gabriel, Stacey B, Holm, Hilma, Gudnason, Vilmundur, Krauss, Ronald M, Ordovas, Jose M, Munroe, Patricia B, Kooner, Jaspal S, Tall, Alan R, Hegele, Robert A, Kastelein, John JP, Schadt, Eric E, Strachan, David P, Reilly, Muredach P, Samani, Nilesh J, Schunkert, Heribert, Cupples, L Adrienne, Sandhu, Manjinder S, Ridker, Paul M, Rader, Daniel J, and Kathiresan, Sekar

Subjects
2. Zero hunger, Male, Waist-Hip Ratio, Cholesterol, HDL, Gene Expression, Glucose Tolerance Test, Polymorphism, Single Nucleotide, White People, 3. Good health, Black or African American, Asian People, Diabetes Mellitus, Type 2, Humans, Female, Genetic Predisposition to Disease, Adiponectin, Insulin Resistance, Metabolic Networks and Pathways, Genome-Wide Association Study
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

12. Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study

Author

Teslovich, Tanya M, Kim, Daniel Seung, Yin, Xianyong, Stancáková, Alena, Jackson, Anne U, Wielscher, Matthias, Naj, Adam, Perry, John RB, Huyghe, Jeroen R, Stringham, Heather M, Davis, James P, Raulerson, Chelsea K, Welch, Ryan P, Fuchsberger, Christian, Locke, Adam E, Sim, Xueling, Chines, Peter S, Narisu, Narisu, Kangas, Antti J, Soininen, Pasi, Genetics Of Obesity-Related Liver Disease Consortium (GOLD), The Alzheimer's Disease Genetics Consortium (ADGC), The DIAbetes Genetics Replication And Meta-Analysis (DIAGRAM), Ala-Korpela, Mika, Gudnason, Vilmundur, Musani, Solomon K, Jarvelin, Marjo-Riitta, Schellenberg, Gerard D, Speliotes, Elizabeth K, Kuusisto, Johanna, Collins, Francis S, Boehnke, Michael, Laakso, Markku, and Mohlke, Karen L

Subjects
3. Good health
Abstract

Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6 million genotyped and imputed variants in 8545 non-diabetic Finnish men from the METabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966). We identified five novel loci associated with amino acid levels (P = < 5×10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10-26); ZFHX3 (chr16:73326579, minor allele frequency (MAF) = 0.42%, P = 3.6×10-9), LIPC (rs10468017, P = 1.5×10-8), and WWOX (rs9937914, P = 3.8×10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10-9). Gene-based tests identified two novel genes harboring missense variants of MAF

13. Sequence data and association statistics from 12,940 type 2 diabetes cases and controls

Author

Flannick, Jason, Fuchsberger, Christian, Mahajan, Anubha, Teslovich, Tanya M, Agarwala, Vineeta, Gaulton, Kyle J, Caulkins, Lizz, Koesterer, Ryan, Ma, Clement, Moutsianas, Loukas, McCarthy, Davis J, Rivas, Manuel A, Perry, John RB, Sim, Xueling, Blackwell, Thomas W, Robertson, Neil R, Rayner, N William, Cingolani, Pablo, Locke, Adam E, Tajes, Juan Fernandez, Highland, Heather M, Dupuis, Josee, Chines, Peter S, Lindgren, Cecilia M, Hartl, Christopher, Jackson, Anne U, Chen, Han, Huyghe, Jeroen R, Van De Bunt, Martijn, Pearson, Richard D, Kumar, Ashish, Müller-Nurasyid, Martina, Grarup, Niels, Stringham, Heather M, Gamazon, Eric R, Lee, Jaehoon, Chen, Yuhui, Scott, Robert A, Below, Jennifer E, Chen, Peng, Huang, Jinyan, Go, Min Jin, Stitzel, Michael L, Pasko, Dorota, Parker, Stephen CJ, Varga, Tibor V, Green, Todd, Beer, Nicola L, Day-Williams, Aaron G, Ferreira, Teresa, Fingerlin, Tasha, Horikoshi, Momoko, Hu, Cheng, Huh, Iksoo, Ikram, Mohammad Kamran, Kim, Bong-Jo, Kim, Yongkang, Kim, Young Jin, Kwon, Min-Seok, Lee, Juyoung, Lee, Selyeong, Lin, Keng-Han, Maxwell, Taylor J, Nagai, Yoshihiko, Wang, Xu, Welch, Ryan P, Yoon, Joon, Zhang, Weihua, Barzilai, Nir, Voight, Benjamin F, Han, Bok-Ghee, Jenkinson, Christopher P, Kuulasmaa, Teemu, Kuusisto, Johanna, Manning, Alisa, Ng, Maggie CY, Palmer, Nicholette D, Balkau, Beverley, Stančáková, Alena, Abboud, Hanna E, Boeing, Heiner, Giedraitis, Vilmantas, Prabhakaran, Dorairaj, Gottesman, Omri, Scott, James, Carey, Jason, Kwan, Phoenix, Grant, George, Smith, Joshua D, Neale, Benjamin M, Purcell, Shaun, Butterworth, Adam S, Howson, Joanna MM, Lee, Heung Man, Lu, Yingchang, Kwak, Soo-Heon, Zhao, Wei, Danesh, John, Lam, Vincent KL, Park, Kyong Soo, Saleheen, Danish, So, Wing Yee, Tam, Claudia HT, Afzal, Uzma, Aguilar, David, Arya, Rector, Aung, Tin, Chan, Edmund, Navarro, Carmen, Cheng, Ching-Yu, Palli, Domenico, Correa, Adolfo, Curran, Joanne E, Rybin, Dennis, Farook, Vidya S, Fowler, Sharon P, Freedman, Barry I, Griswold, Michael, Hale, Daniel Esten, Hicks, Pamela J, Khor, Chiea-Chuen, Kumar, Satish, Lehne, Benjamin, Thuillier, Dorothée, Lim, Wei Yen, Liu, Jianjun, Loh, Marie, Musani, Solomon K, Puppala, Sobha, Scott, William R, Yengo, Loïc, Tan, Sian-Tsung, Taylor, Herman A, Thameem, Farook, Wilson, Gregory, Wong, Tien Yin, Njølstad, Pål Rasmus, Levy, Jonathan C, Mangino, Massimo, Bonnycastle, Lori L, Schwarzmayr, Thomas, Fadista, João, Surdulescu, Gabriela L, Herder, Christian, Groves, Christopher J, Wieland, Thomas, Bork-Jensen, Jette, Brandslund, Ivan, Christensen, Cramer, Koistinen, Heikki A, Doney, Alex SF, Kinnunen, Leena, Esko, Tõnu, Farmer, Andrew J, Hakaste, Liisa, Hodgkiss, Dylan, Kravic, Jasmina, Lyssenko, Valeri, Hollensted, Mette, Jørgensen, Marit E, Jørgensen, Torben, Ladenvall, Claes, Justesen, Johanne Marie, Käräjämäki, Annemari, Kriebel, Jennifer, Rathmann, Wolfgang, Lannfelt, Lars, Lauritzen, Torsten, Narisu, Narisu, Linneberg, Allan, Melander, Olle, Milani, Lili, Neville, Matt, Orho-Melander, Marju, Qi, Lu, Qi, Qibin, Roden, Michael, Rolandsson, Olov, Swift, Amy, Rosengren, Anders H, Stirrups, Kathleen, Wood, Andrew R, Mihailov, Evelin, Blancher, Christine, Carneiro, Mauricio O, Maguire, Jared, Poplin, Ryan, Shakir, Khalid, Fennell, Timothy, DePristo, Mark, De Angelis, Martin Hrabé, Deloukas, Panos, Gjesing, Anette P, Jun, Goo, Nilsson, Peter, Murphy, Jacquelyn, Onofrio, Robert, Thorand, Barbara, Hansen, Torben, Meisinger, Christa, Hu, Frank B, Isomaa, Bo, Karpe, Fredrik, Liang, Liming, Peters, Annette, Huth, Cornelia, O'Rahilly, Stephen P, Palmer, Colin NA, Pedersen, Oluf, Rauramaa, Rainer, Tuomilehto, Jaakko, Salomaa, Veikko, Watanabe, Richard M, Syvänen, Ann-Christine, Bergman, Richard N, Bharadwaj, Dwaipayan, Bottinger, Erwin P, Cho, Yoon Shin, Chandak, Giriraj R, Chan, Juliana Cn, Chia, Kee Seng, Daly, Mark J, Ebrahim, Shah B, Langenberg, Claudia, Elliott, Paul, Jablonski, Kathleen A, Lehman, Donna M, Jia, Weiping, Ma, Ronald CW, Pollin, Toni I, Sandhu, Manjinder, Tandon, Nikhil, Froguel, Philippe, Barroso, Inês, Teo, Yik Ying, Zeggini, Eleftheria, Loos, Ruth JF, Small, Kerrin S, Ried, Janina S, DeFronzo, Ralph A, Grallert, Harald, Glaser, Benjamin, Metspalu, Andres, Wareham, Nicholas J, Walker, Mark, Banks, Eric, Gieger, Christian, Ingelsson, Erik, Im, Hae Kyung, Illig, Thomas, Franks, Paul W, Buck, Gemma, Trakalo, Joseph, Buck, David, Prokopenko, Inga, Mägi, Reedik, Lind, Lars, Farjoun, Yossi, Owen, Katharine R, Gloyn, Anna L, Strauch, Konstantin, Tuomi, Tiinamaija, Kooner, Jaspal Singh, Lee, Jong-Young, Park, Taesung, Donnelly, Peter, Morris, Andrew D, Hattersley, Andrew T, Bowden, Donald W, Collins, Francis S, Atzmon, Gil, Chambers, John C, Spector, Timothy D, Laakso, Markku, Strom, Tim M, Bell, Graeme I, Blangero, John, Duggirala, Ravindranath, Tai, E Shyong, McVean, Gilean, Hanis, Craig L, Wilson, James G, Seielstad, Mark, Frayling, Timothy M, Meigs, James B, Cox, Nancy J, Sladek, Rob, Lander, Eric S, Gabriel, Stacey, Mohlke, Karen L, Meitinger, Thomas, Groop, Leif, Abecasis, Goncalo, Scott, Laura J, Morris, Andrew P, Kang, Hyun Min, Altshuler, David, Burtt, Noël P, Florez, Jose C, Boehnke, Michael, and McCarthy, Mark I

Subjects
Diabetes Mellitus, Type 2, Genetic Variation, Humans, White People, 3. Good health
Abstract

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

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