Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Wessel, Jennifer; Chu, Audrey Y.; Willems, Sara M.; Wang, Shuai; Yaghootkar, Hanieh; Brody, Jennifer A.; Dauriz, Marco; Hivert, Marie-France; Raghavan, Sridharan; Lipovich, Leonard; Hidalgo, Bertha; Fox, Keolu; Huffman, Jennifer E.; An, Ping; Lu, Yingchang; Rasmussen-Torvik, Laura J.; Grarup, Niels; Ehm, Margaret G.; Li, Li; Baldridge, Abigail S.; Stančáková, Alena; Abrol, Ravinder; Besse, Céline; Boland, Anne; Bork-Jensen, Jette; Fornage, Myriam; Freitag, Daniel F.; Garcia, Melissa E.; Guo, Xiuqing; Hara, Kazuo; Isaacs, Aaron; Jakobsdottir, Johanna; Lange, Leslie A.; Layton, Jill C.; Li, Man; Hua Zhao, Jing; Meidtner, Karina; Morrison, Alanna C.; Nalls, Mike A.; Peters, Marjolein J.; Sabater-Lleal, Maria; Schurmann, Claudia; Silveira, Angela; Smith, Albert V.; Southam, Lorraine; Stoiber, Marcus H.; Strawbridge, Rona J.; Taylor, Kent D.; Varga, Tibor V.; Allin, Kristine H.; Amin, Najaf; Aponte, Jennifer L.; Aung, Tin; Barbieri, Caterina; Bihlmeyer, Nathan A.; Boehnke, Michael; Bombieri, Cristina; Bowden, Donald W.; Burns, Sean M.; Chen, Yuning; Chen, Yii-DerI; Cheng, Ching-Yu; Correa, Adolfo; Czajkowski, Jacek; Dehghan, Abbas; Ehret, Georg B.; Eiriksdottir, Gudny; Escher, Stefan A.; Farmaki, Aliki-Eleni; Frånberg, Mattias; Gambaro, Giovanni; Giulianini, Franco; Goddard, William A.; Goel, Anuj; Gottesman, Omri; Grove, Megan L.; Gustafsson, Stefan; Hai, Yang; Hallmans, Göran; Heo, Jiyoung; Hoffmann, Per; Ikram, Mohammad K.; Jensen, Richard A.; Jørgensen, Marit E.; Jørgensen, Torben; Karaleftheri, Maria; Khor, Chiea C.; Kirkpatrick, Andrea; Kraja, Aldi T.; Kuusisto, Johanna; Lange, Ethan M.; Lee, I. T.; Lee, Wen-Jane; Leong, Aaron; Liao, Jiemin; Liu, Chunyu; Liu, Yongmei; Lindgren, Cecilia M.; Linneberg, Allan; Malerba, Giovanni; Mamakou, Vasiliki; Marouli, Eirini; Maruthur, Nisa M.; Matchan, Angela; McKean-Cowdin, Roberta; McLeod, Olga; Metcalf, Ginger A.; Mohlke, Karen L.; Muzny, Donna M.; Ntalla, Ioanna; Palmer, Nicholette D.; Pasko, Dorota; Peter, Andreas; Rayner, Nigel W.; Renström, Frida; Rice, Ken; Sala, Cinzia F.; Sennblad, Bengt; Serafetinidis, Ioannis; Smith, Jennifer A.; Soranzo, Nicole; Speliotes, Elizabeth K.; Stahl, Eli A.; Stirrups, Kathleen; Tentolouris, Nikos; Thanopoulou, Anastasia; Torres, Mina; Traglia, Michela; Tsafantakis, Emmanouil; Javad, Sundas; Yanek, Lisa R.; Zengini, Eleni; Becker, Diane M.; Bis, Joshua C.; Brown, James B.; Adrienne Cupples, L.; Hansen, Torben; Ingelsson, Erik; Karter, Andrew J.; Lorenzo, Carlos; Mathias, Rasika A.; Norris, Jill M.; Peloso, Gina M.; Sheu, Wayne H.-H.; Toniolo, Daniela; Vaidya, Dhananjay; Varma, Rohit; Wagenknecht, Lynne E.; Boeing, Heiner; Bottinger, Erwin P.; Dedoussis, George; Deloukas, Panos; Ferrannini, Ele; Franco, Oscar H.; Franks, Paul W.; Gibbs, Richard A.; Gudnason, Vilmundur; Hamsten, Anders; Harris, Tamara B.; Hattersley, Andrew T.; Hayward, Caroline; Hofman, Albert; Jansson, Jan-Håkan; Langenberg, Claudia; Launer, Lenore J.; Levy, Daniel; Oostra, Ben A.; O’Donnell, Christopher J.; O’Rahilly, Stephen; Padmanabhan, Sandosh; Pankow, James S.; Polasek, Ozren; Province, Michael A.; Rich, Stephen S.; Ridker, Paul M.; Rudan, Igor; Schulze, Matthias B.; Smith, Blair H.; Uitterlinden, André G.; Walker, Mark; Watkins, Hugh; Wong, Tien Y.; Zeggini, Eleftheria; Laakso, Markku; Borecki, Ingrid B.; Chasman, Daniel I.; Pedersen, Oluf; Psaty, Bruce M.; Shyong Tai, E.; van Duijn, Cornelia M.; Wareham, Nicholas J.; Waterworth, Dawn M.; Boerwinkle, Eric; Linda Kao, W. H.; Florez, Jose C.; Loos, Ruth J.F.; Wilson, James G.; Frayling, Timothy M.; Siscovick, David S.; Dupuis, Josée; Rotter, Jerome I.; Meigs, James B.; Scott, Robert A.; Goodarzi, Mark O.

doi:10.1038/ncomms6897

Title: Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Journal Article · Thu Jan 29 00:00:00 EST 2015 · Nature Communications

DOI:https://doi.org/10.1038/ncomms6897· OSTI ID:1623962

Wessel, Jennifer; Chu, Audrey Y.; Willems, Sara M.; Wang, Shuai; Yaghootkar, Hanieh; Brody, Jennifer A.; Dauriz, Marco; Hivert, Marie-France; Raghavan, Sridharan; Lipovich, Leonard; Hidalgo, Bertha; Fox, Keolu; Huffman, Jennifer E.; An, Ping; Lu, Yingchang; Rasmussen-Torvik, Laura J.; Grarup, Niels; Ehm, Margaret G.; Li, Li; Baldridge, Abigail S. more »

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l^-1, P=3.4 × 10^-12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmol_insulin mmol_glucose^-1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l^-1, P=4.3 × 10^-4). We identify a gene-based association with FG at G6PC2 (p_SKAT=6.8 × 10^-6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l^-1, P=1.3 × 10^-8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

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Research Organization:: Lawrence Berkeley National Lab (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); American Recovery and Reinvestment Act (ARRA); Atherosclerosis Risk in Communities (ARIC) Study; Baylor Genome Center; National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI)

Contributing Organization:: The EPIC-InterAct Consortium

Grant/Contract Number:: AC02-05CH11231; 5RC2HL102419; U54 HG003273; HL120393; HL105756

OSTI ID:: 1623962

Journal Information:: Nature Communications, Vol. 6, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (77)

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways Scott, Robert A.; Lagou, Vasiliki; Welch, Ryan P. Nature Genetics, Vol. 44, Issue 9 https://doi.org/10.1038/ng.2385	journal	August 2012
An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People Nelson, Matthew R.; Wegmann, Daniel; Ehm, Margaret G. Science, Vol. 337, Issue 6090 https://doi.org/10.1126/science.1217876	journal	May 2012
Recent Explosive Human Population Growth Has Resulted in an Excess of Rare Genetic Variants Keinan, A.; Clark, A. G. Science, Vol. 336, Issue 6082 https://doi.org/10.1126/science.1217283	journal	May 2012
Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes Tennessen, Jacob A.; Bigham, Abigail W.; O’Connor, Timothy D. Science, Vol. 337, Issue 6090 https://doi.org/10.1126/science.1219240	journal	May 2012
Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants Fu, Wenqing; O’Connor, Timothy D.; Jun, Goo Nature, Vol. 493, Issue 7431 https://doi.org/10.1038/nature11690	journal	November 2012
Whole-genome sequence???based analysis of high-density lipoprotein cholesterol Consortium, Charge Nature Genetics, Vol. 45, Issue 8, p. 899-901 https://doi.org/10.1038/ng.2671	journal	January 2013
Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks Peloso, Gina M.; Auer, Paul L.; Bis, Joshua C. The American Journal of Human Genetics, Vol. 94, Issue 2 https://doi.org/10.1016/j.ajhg.2014.01.009	journal	February 2014
Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion Huyghe, Jeroen R.; Jackson, Anne U.; Fogarty, Marie P. Nature Genetics, Vol. 45, Issue 2 https://doi.org/10.1038/ng.2507	journal	December 2012
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes Flannick, Jason; Thorleifsson, Gudmar; Beer, Nicola L. Nature Genetics, Vol. 46, Issue 4 https://doi.org/10.1038/ng.2915	journal	March 2014
Searching for missing heritability: Designing rare variant association studies Zuk, O.; Schaffner, S. F.; Samocha, K. Proceedings of the National Academy of Sciences, Vol. 111, Issue 4 https://doi.org/10.1073/pnas.1322563111	journal	January 2014
Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts Psaty, Bruce M.; O'Donnell, Christopher J.; Gudnason, Vilmundur Circulation: Cardiovascular Genetics, Vol. 2, Issue 1 https://doi.org/10.1161/CIRCGENETICS.108.829747	journal	February 2009
Best Practices and Joint Calling of the HumanExome BeadChip: The CHARGE Consortium Grove, Megan L.; Yu, Bing; Cochran, Barbara J. PLoS ONE, Vol. 8, Issue 7 https://doi.org/10.1371/journal.pone.0068095	journal	July 2013
An integrated encyclopedia of DNA elements in the human genome Nature, Vol. 489, Issue 7414, p. 57-74 https://doi.org/10.1038/nature11247	journal	September 2012
ENCODE Data in the UCSC Genome Browser: year 5 update Rosenbloom, Kate R.; Sloan, Cricket A.; Malladi, Venkat S. Nucleic Acids Research, Vol. 41, Issue D1 https://doi.org/10.1093/nar/gks1172	journal	November 2012
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes Drucker, Daniel J.; Nauck, Michael A. The Lancet, Vol. 368, Issue 9548 https://doi.org/10.1016/S0140-6736(06)69705-5	journal	November 2006
Insulin Secretion in Response to Glycemic Stimulus: Relation of Delayed Initial Release to Carbohydrate intolerance in Mild Diabetes Mellitus* Seltzer, Holbrooke S.; Allen, E. William; Herron, Arthur L. Journal of Clinical Investigation, Vol. 46, Issue 3 https://doi.org/10.1172/JCI105534	journal	March 1967
Glucagon-like peptide 1 and appetite Dailey, Megan J.; Moran, Timothy H. Trends in Endocrinology & Metabolism, Vol. 24, Issue 2 https://doi.org/10.1016/j.tem.2012.11.008	journal	February 2013
Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide Astrup, A.; Carraro, R.; Finer, N. International Journal of Obesity, Vol. 36, Issue 6 https://doi.org/10.1038/ijo.2011.158	journal	August 2011
Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor Kirkpatrick, A.; Heo, J.; Abrol, R. Proceedings of the National Academy of Sciences, Vol. 109, Issue 49 https://doi.org/10.1073/pnas.1218051109	journal	November 2012
Polymorphism and recombination events at the ABO locus: a major challenge for genomic ABO blood grouping strategies Olsson, M. L.; Chester, M. A. Transfusion Medicine, Vol. 11, Issue 4 https://doi.org/10.1046/j.1365-3148.2001.00320.x	journal	August 2001
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease Schunkert, Heribert; König, Inke R.; Kathiresan, Sekar Nature Genetics, Vol. 43, Issue 4 https://doi.org/10.1038/ng.784	journal	March 2011
Biological, clinical and population relevance of 95 loci for blood lipids Teslovich, Tanya M.; Musunuru, Kiran; Smith, Albert V. Nature, Vol. 466, Issue 7307 https://doi.org/10.1038/nature09270	journal	August 2010
Mouse Glucose Transporter 9 Splice Variants Are Expressed in Adult Liver and Kidney and Are Up-Regulated in Diabetes Keembiyehetty, Chithra; Augustin, Robert; Carayannopoulos, Mary O. Molecular Endocrinology, Vol. 20, Issue 3 https://doi.org/10.1210/me.2005-0010	journal	March 2006
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga Nature Genetics, Vol. 42, Issue 2 https://doi.org/10.1038/ng.520	journal	January 2010
Re-sequencing Expands Our Understanding of the Phenotypic Impact of Variants at GWAS Loci Service, Susan K.; Teslovich, Tanya M.; Fuchsberger, Christian PLoS Genetics, Vol. 10, Issue 1 https://doi.org/10.1371/journal.pgen.1004147	journal	January 2014
Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels Baerenwald, D. A.; Bonnefond, A.; Bouatia-Naji, N. Diabetologia, Vol. 56, Issue 6 https://doi.org/10.1007/s00125-013-2875-3	journal	March 2013
dbNSFP v2.0: A Database of Human Non-synonymous SNVs and Their Functional Predictions and Annotations Liu, Xiaoming; Jian, Xueqiu; Boerwinkle, Eric Human Mutation, Vol. 34, Issue 9 https://doi.org/10.1002/humu.22376	journal	July 2013
A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance Manning, Alisa K.; Hivert, Marie-France; Scott, Robert A. Nature Genetics, Vol. 44, Issue 6 https://doi.org/10.1038/ng.2274	journal	May 2012
Human growth factor receptor bound 14 binds the activated insulin receptor and alters the insulin-stimulated tyrosine phosphorylation levels of multiple proteins Hemming, Richard; Agatep, Ronald; Badiani, Ketan Biochemistry and Cell Biology, Vol. 79, Issue 1 https://doi.org/10.1139/o00-090	journal	January 2001
Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes Morris, Andrew P.; Voight, Benjamin F. Nature Genetics, Vol. 44, Issue 9, p. 981-990 https://doi.org/10.1038/ng.2383	journal	August 2012
A Common Functional Regulatory Variant at a Type 2 Diabetes Locus Upregulates ARAP1 Expression in the Pancreatic Beta Cell Kulzer, Jennifer R.; Stitzel, Michael L.; Morken, Mario A. The American Journal of Human Genetics, Vol. 94, Issue 2 https://doi.org/10.1016/j.ajhg.2013.12.011	journal	February 2014
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis Voight, Benjamin F.; Scott, Laura J.; Steinthorsdottir, Valgerdur Nature Genetics, Vol. 42, Issue 7 https://doi.org/10.1038/ng.609	journal	June 2010
Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations Orho-Melander, M.; Melander, O.; Guiducci, C. Diabetes, Vol. 57, Issue 11 https://doi.org/10.2337/db08-0516	journal	August 2008
Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk Rees, M. G.; Wincovitch, S.; Schultz, J. Diabetologia, Vol. 55, Issue 1 https://doi.org/10.1007/s00125-011-2348-5	journal	October 2011
The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver Beer, Nicola L.; Tribble, Nicholas D.; McCulloch, Laura J. Human Molecular Genetics, Vol. 18, Issue 21 https://doi.org/10.1093/hmg/ddp357	journal	July 2009
Pharmacological Characterization of Human Incretin Receptor Missense Variants Fortin, Jean-Philippe; Schroeder, Jonathan C.; Zhu, Yuantee Journal of Pharmacology and Experimental Therapeutics, Vol. 332, Issue 1 https://doi.org/10.1124/jpet.109.160531	journal	October 2009
Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation Koole, Cassandra; Wootten, Denise; Simms, John Molecular Pharmacology, Vol. 80, Issue 3 https://doi.org/10.1124/mol.111.072884	journal	May 2011
Glucose intolerance but normal satiety in mice with a null mutation in the glucagon–like peptide 1 receptor gene Scrocchi, L. A.; Brown, T. J.; Maclusky, N. Nature Medicine, Vol. 2, Issue 11 https://doi.org/10.1038/nm1196-1254	journal	November 1996
Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism Gozu, Hulya Iliksu; Lublinghoff, Julia; Bircan, Rifat Molecular and Cellular Endocrinology, Vol. 322, Issue 1-2 https://doi.org/10.1016/j.mce.2010.02.001	journal	June 2010
G protein-coupled receptors: mutations and endocrine diseases Vassart, Gilbert; Costagliola, Sabine Nature Reviews Endocrinology, Vol. 7, Issue 6 https://doi.org/10.1038/nrendo.2011.20	journal	February 2011
zCall: a rare variant caller for array-based genotyping Goldstein, Jacqueline I.; Crenshaw, Andrew; Carey, Jason Bioinformatics, Vol. 28, Issue 19 https://doi.org/10.1093/bioinformatics/bts479	journal	July 2012
Fast and accurate short read alignment with Burrows-Wheeler transform Li, H.; Durbin, R. Bioinformatics, Vol. 25, Issue 14 https://doi.org/10.1093/bioinformatics/btp324	journal	May 2009
The Sequence Alignment/Map format and SAMtools Li, H.; Handsaker, B.; Wysoker, A. Bioinformatics, Vol. 25, Issue 16 https://doi.org/10.1093/bioinformatics/btp352	journal	June 2009
NARWHAL, a primary analysis pipeline for NGS data Brouwer, R. W. W.; van den Hout, M. C. G. N.; Grosveld, F. G. Bioinformatics, Vol. 28, Issue 2 https://doi.org/10.1093/bioinformatics/btr613	journal	November 2011
SOAP: short oligonucleotide alignment program Li, R.; Li, Y.; Kristiansen, K. Bioinformatics, Vol. 24, Issue 5 https://doi.org/10.1093/bioinformatics/btn025	journal	January 2008
A framework for variation discovery and genotyping using next-generation DNA sequencing data DePristo, Mark A.; Banks, Eric; Poplin, Ryan Nature Genetics, Vol. 43, Issue 5 https://doi.org/10.1038/ng.806	journal	April 2011
An integrative variant analysis suite for whole exome next-generation sequencing data Challis, Danny; Yu, Jin; Evani, Uday S. BMC Bioinformatics, Vol. 13, Issue 1 https://doi.org/10.1186/1471-2105-13-8	journal	January 2012
The variant call format and VCFtools Danecek, P.; Auton, A.; Abecasis, G. Bioinformatics, Vol. 27, Issue 15 https://doi.org/10.1093/bioinformatics/btr330	journal	June 2011
SNP detection for massively parallel whole-genome resequencing Li, R.; Li, Y.; Fang, X. Genome Research, Vol. 19, Issue 6 https://doi.org/10.1101/gr.088013.108	journal	May 2009
Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol Lange, Leslie A.; Hu, Youna; Zhang, He The American Journal of Human Genetics, Vol. 94, Issue 2 https://doi.org/10.1016/j.ajhg.2014.01.010	journal	February 2014
Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge Saxena, Richa; Hivert, Marie-France; Langenberg, Claudia Nature Genetics, Vol. 42, Issue 2 https://doi.org/10.1038/ng.521	journal	January 2010
Analysis of serial measurements in medical research. Matthews, J. N.; Altman, D. G.; Campbell, M. J. BMJ, Vol. 300, Issue 6719 https://doi.org/10.1136/bmj.300.6719.230	journal	January 1990
Association between birth weight and visceral fat in adults De Lucia Rolfe, Emanuella; Loos, Ruth JF; Druet, Céline The American Journal of Clinical Nutrition, Vol. 92, Issue 2 https://doi.org/10.3945/ajcn.2010.29247	journal	June 2010
Incidence of Type 2 diabetes in England and its association with baseline impaired fasting glucose: The Ely study 1990-2000 Forouhi, N. G.; Luan, J.; Hennings, S. Diabetic Medicine, Vol. 24, Issue 2 https://doi.org/10.1111/j.1464-5491.2007.02068.x	journal	February 2007
The EGIR-RISC STUDY (The European group for the study of insulin resistance: relationship between insulin sensitivity and cardiovascular disease risk): I. Methodology and Objectives Hills, S. A.; Balkau, B.; Coppack, S. W. Diabetologia, Vol. 47, Issue 3 https://doi.org/10.1007/s00125-004-1335-5	journal	March 2004
Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk Holmen, Oddgeir L.; Zhang, He; Fan, Yanbo Nature Genetics, Vol. 46, Issue 4 https://doi.org/10.1038/ng.2926	journal	March 2014
Testing Association of Statistically Inferred Haplotypes with Discrete and Continuous Traits in Samples of Unrelated Individuals Zaykin, Dmitri V.; Westfall, Peter H.; Young, S. Stanley Human Heredity, Vol. 53, Issue 2 https://doi.org/10.1159/000057986	journal	January 2002
The Synthesis of Regression Slopes in Meta-Analysis Becker, Betsy Jane; Wu, Meng-Jia Statistical Science, Vol. 22, Issue 3 https://doi.org/10.1214/07-STS243	journal	August 2007
Common Inherited Variation in Mitochondrial Genes Is Not Enriched for Associations with Type 2 Diabetes or Related Glycemic Traits Segrè, Ayellet V.; Groop, Leif; Mootha, Vamsi K. PLoS Genetics, Vol. 6, Issue 8 https://doi.org/10.1371/journal.pgen.1001058	journal	August 2010
CHARMM: The biomolecular simulation program Brooks, B. R.; Brooks, C. L.; Mackerell, A. D. Journal of Computational Chemistry, Vol. 30, Issue 10 https://doi.org/10.1002/jcc.21287	journal	July 2009
Scalable molecular dynamics with NAMD Phillips, James C.; Braun, Rosemary; Wang, Wei Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802 https://doi.org/10.1002/jcc.20289	journal	January 2005
Ancestry deconvolution and partial polygenic score can improve susceptibility predictions in recently admixed individuals Marnetto, Davide; Pärna, Katri; Läll, Kristi Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-15464-w	journal	April 2020
Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion Xueling, Sim,; J., Daly, Mark; Johanna, Kuusisto, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/63sx-0c91	text	January 2013
An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People G., Ehm, M.; R., Nelson, M.; Y., Li, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/d45t-vz73	text	January 2012
A Common Functional Regulatory Variant at a Type 2 Diabetes Locus Upregulates ARAP1 Expression in the Pancreatic Beta Cell L., Mohlke, Karen; Christian, Fuchsberger,; Johanna, Kuusisto, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/gfrr-b738	text	January 2014
Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways Emil, Rehnberg,; V., Smith, Albert; Stefan, Gustafsson, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/qy4d-rv77	text	January 2012
Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes Libraries, The University of North Carolina at Chapel Hill University The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/sa0w-h884	text	January 2012
An integrated encyclopedia of DNA elements in the human genome Libraries, The University of North Carolina at Chapel Hill University The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/wcvb-k036	text	January 2012
CHARMM: the biomolecular simulation program Brooks, B. R.; Brooks, C. L.; Mackerell, A. D. Wiley-Blackwell https://doi.org/10.5167/uzh-19245	text	January 2009
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk Consrotium, Global BPgen; Ulla, Sovio,; R., Shuldiner, Alan The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/qp7m-ew12	text	January 2010
Erratum: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga Nature Genetics, Vol. 42, Issue 5 https://doi.org/10.1038/ng0510-464a	journal	May 2010
Large-Scale Association Analysis Identifies 13 New Susceptibility Loci for Coronary Artery Disease Mehta, Nehal N. Circulation: Cardiovascular Genetics, Vol. 4, Issue 3 https://doi.org/10.1161/circgenetics.111.960443	journal	June 2011
The Synthesis of Regression Slopes in Meta-Analysis Becker, Betsy Jane; Wu, Meng-Jia arXiv https://doi.org/10.48550/arxiv.0801.4442	text	January 2008
Somatic and germline mutations of the TSH receptor gene in thyroid diseases Van Sande, J. Journal of Clinical Endocrinology & Metabolism, Vol. 80, Issue 9 https://doi.org/10.1210/jc.80.9.2577	journal	September 1995
Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia. Tonacchera, M.; Van Sande, J.; Cetani, F. The Journal of Clinical Endocrinology & Metabolism, Vol. 81, Issue 2 https://doi.org/10.1210/jcem.81.2.8636266	journal	February 1996
Whole Genome Sequence-Based Analysis of a Model Complex Trait, High Density Lipoprotein Cholesterol Adrienne, Cupples, L.; Alexander, Li,; Richard, Gibbs, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/f0v2-k177	text	January 2013
Incretin Therapy – Present and Future Garber, Alan J. The Review of Diabetic Studies, Vol. 8, Issue 3 https://doi.org/10.1900/rds.2011.8.307	journal	January 2011

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Detection and interpretation of shared genetic influences on 42 human traits Pickrell, Joseph K.; Berisa, Tomaz; Liu, Jimmy Z. Nature Genetics, Vol. 48, Issue 7 https://doi.org/10.1038/ng.3570	journal	May 2016
TCF1 links GIPR signaling to the control of beta cell function and survival Campbell, Jonathan E.; Ussher, John R.; Mulvihill, Erin E. Nature Medicine, Vol. 22, Issue 1 https://doi.org/10.1038/nm.3997	journal	December 2015
Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes Flannick, Jason; Johansson, Stefan; Njølstad, Pål R. Nature Reviews Endocrinology, Vol. 12, Issue 7 https://doi.org/10.1038/nrendo.2016.50	journal	April 2016
Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes Bonàs-Guarch, Sílvia; Guindo-Martínez, Marta; Miguel-Escalada, Irene Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-017-02380-9	journal	January 2018
Exome-wide analyses identify low-frequency variant in CYP26B1 and additional coding variants associated with esophageal squamous cell carcinoma Chang, Jiang; Zhong, Rong; Tian, Jianbo Nature Genetics, Vol. 50, Issue 3 https://doi.org/10.1038/s41588-018-0045-8	journal	January 2018
Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population Suzuki, Ken; Akiyama, Masato; Ishigaki, Kazuyoshi Nature Genetics, Vol. 51, Issue 3 https://doi.org/10.1038/s41588-018-0332-4	journal	February 2019
Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes Jäger, Susanne; Wahl, Simone; Kröger, Janine Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-06158-3	journal	July 2017
Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity Pigeyre, Marie; Yazdi, Fereshteh T.; Kaur, Yuvreet Clinical Science, Vol. 130, Issue 12 https://doi.org/10.1042/cs20160136	journal	May 2016
Cohort Profile: The Framingham Heart Study (FHS): overview of milestones in cardiovascular epidemiology Tsao, Connie W.; Vasan, Ramachandran S. International Journal of Epidemiology, Vol. 44, Issue 6 https://doi.org/10.1093/ije/dyv337	journal	December 2015
Advantages of genotype imputation with ethnically matched reference panel for rare variant association analyses Kals, Mart; Nikopensius, Tiit; Läll, Kristi BioRxiv https://doi.org/10.1101/579201	posted_content	April 2019
Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation Ng, Natasha H. J.; Willems, Sara M.; Fernandez, Juan BioRxiv https://doi.org/10.1101/790618	posted_content	October 2019
On Efficient and Accurate Calculation of Significance P -Values for Sequence Kernel Association Testing of Variant Set: P -Value Calculation for SKAT and SKAT-O Wu, Baolin; Guan, Weihua; Pankow, James S. Annals of Human Genetics, Vol. 80, Issue 2 https://doi.org/10.1111/ahg.12144	journal	January 2016
On Sample Size and Power Calculation for Variant Set-Based Association Tests: Sample Size and Power Calculation for SKAT Wu, Baolin; Pankow, James S. Annals of Human Genetics, Vol. 80, Issue 2 https://doi.org/10.1111/ahg.12147	journal	February 2016
Gene-based evaluation of low-frequency variation and genetically-predicted gene expression impacting risk of keloid formation Hellwege, Jacklyn N.; Russell, Shirley B.; Williams, Scott M. Annals of Human Genetics, Vol. 82, Issue 4 https://doi.org/10.1111/ahg.12245	journal	February 2018
A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease Scott, Robert A.; Freitag, Daniel F.; Li, Li Science Translational Medicine, Vol. 8, Issue 341 https://doi.org/10.1126/scitranslmed.aad3744	journal	June 2016
Impact of rare and low-frequency sequence variants on reliability of genomic prediction in dairy cattle Zhang, Qianqian; Sahana, Goutam; Su, Guosheng Genetics Selection Evolution, Vol. 50, Issue 1 https://doi.org/10.1186/s12711-018-0432-8	journal	November 2018
Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection Al-Daghri, Nasser M.; Pontremoli, Chiara; Cagliani, Rachele BMC Evolutionary Biology, Vol. 17, Issue 1 https://doi.org/10.1186/s12862-017-0897-z	journal	February 2017
Gene-gene interactions lead to higher risk for development of type 2 diabetes in a Chinese Han population: a prospective nested case-control study Zhou, Wen; Li, Yuqian; Zhang, Lulu Lipids in Health and Disease, Vol. 17, Issue 1 https://doi.org/10.1186/s12944-018-0813-6	journal	July 2018
Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey Spracklen, Cassandra N.; Shi, Jinxiu; Vadlamudi, Swarooparani PLOS Genetics, Vol. 14, Issue 4 https://doi.org/10.1371/journal.pgen.1007275	journal	April 2018
Genes associated with diabetes: potential for novel therapeutic targets? Hara, Kazuo; Kadowaki, Takashi; Odawara, Masato Expert Opinion on Therapeutic Targets, Vol. 20, Issue 3 https://doi.org/10.1517/14728222.2016.1098618	journal	October 2015
Imputation-Aware Tag SNP Selection To Improve Power for Large-Scale, Multi-ethnic Association Studies Wojcik, Genevieve L.; Fuchsberger, Christian; Taliun, Daniel G3 Genes\|Genomes\|Genetics, Vol. 8, Issue 10 https://doi.org/10.1534/g3.118.200502	journal	October 2018
Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine Mannino, Gaia Chiara; Andreozzi, Francesco; Sesti, Giorgio Diabetes/Metabolism Research and Reviews, Vol. 35, Issue 3 https://doi.org/10.1002/dmrr.3109	journal	January 2019
Reversing the tide — diagnosis and prevention of T2DM in populations of African descent Utumatwishima, Jean N.; Chung, Stephanie T.; Bentley, Amy R. Nature Reviews Endocrinology, Vol. 14, Issue 1 https://doi.org/10.1038/nrendo.2017.127	journal	October 2017
Type 2 diabetes: genetic data sharing to advance complex disease research Flannick, Jason; Florez, Jose C. Nature Reviews Genetics, Vol. 17, Issue 9 https://doi.org/10.1038/nrg.2016.56	journal	July 2016
Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls Flannick, Jason; Mercader, Josep M.; Fuchsberger, Christian Nature, Vol. 570, Issue 7759 https://doi.org/10.1038/s41586-019-1231-2	journal	May 2019
Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS Kane, Maureen A.; Chen, Na; Sparks, Susan Biochemical Journal, Vol. 388, Issue 1 https://doi.org/10.1042/BJ20041867	journal	May 2005
The genomic landscape of African populations in health and disease Rotimi, Charles N.; Bentley, Amy R.; Doumatey, Ayo P. Human Molecular Genetics, Vol. 26, Issue R2 https://doi.org/10.1093/hmg/ddx253	journal	June 2017
Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease Hobbs, Brian D.; Parker, Margaret M.; Chen, Han American Journal of Respiratory and Critical Care Medicine, Vol. 194, Issue 1 https://doi.org/10.1164/rccm.201510-2053oc	journal	July 2016
A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans Clapham, Katharine R.; Chu, Audrey Y.; Wessel, Jennifer BMC Endocrine Disorders, Vol. 16, Issue 1 https://doi.org/10.1186/s12902-016-0088-8	journal	January 2016
The impact of rare and low-frequency genetic variants in common disease Bomba, Lorenzo; Walter, Klaudia; Soranzo, Nicole Genome Biology, Vol. 18, Issue 1 https://doi.org/10.1186/s13059-017-1212-4	journal	April 2017
The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases Laakso, Markku; Kuusisto, Johanna; Stančáková, Alena Journal of Lipid Research, Vol. 58, Issue 3 https://doi.org/10.1194/jlr.o072629	journal	March 2017
Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection Clerici, Mario; Al-Daghri, Nasser; Pontremolli, C. Endocrine Abstracts https://doi.org/10.1530/endoabs.49.gp77	journal	May 2017
Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey W., Huang,; J., Luo,; L. A., Lange, Public Library of Science https://doi.org/10.17615/g4bd-r865	text	January 2018
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease Sarah, Taylor,; David, Craig,; Liming, Qu, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/pbds-w495	text	January 2017
A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease Scott, Robert; Freitag, Daniel F.; Li, Li Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.205	text	January 2016
Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes. Bonàs-Guarch, Sílvia; Guindo-Martínez, Marta; Miguel-Escalada, Irene Springer Science and Business Media LLC https://doi.org/10.17863/cam.21898	journalarticle	January 2018
Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6 Prins, Bram P.; Mead, Timothy J.; Brody, Jennifer A. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.25493	collection	January 2018
Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium. Merino, Jordi; Dashti, Hassan S.; Li, Sherly X. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.27719	text	January 2018
Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation Ng, Natasha; Willems, Sara M.; Fernandez, Juan SSRN Electronic Journal https://doi.org/10.2139/ssrn.3469835	journal	January 2019
Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6 Prins, Bram P.; Mead, Timothy J.; Brody, Jennifer A. Genome Biology, Vol. 19, Issue 1 https://doi.org/10.1186/s13059-018-1457-6	journal	July 2018
The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases J., Lusis, Aldons; S., Collins, Francis; L., Mohlke, Karen The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/bd2w-eh24	text	January 2017
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Sims, Rebecca; Van Der Lee, Sven J.; Naj, Adam C. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.21667	text	January 2017
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease Sims, Rebecca; van der Lee, Sven J.; Naj, Adam C. Nature Genetics, Vol. 49, Issue 9 https://doi.org/10.1038/ng.3916	journal	July 2017
Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls T. M., Teslovich,; N. J., Cox,; M., Laakso, Nature Publishing Group https://doi.org/10.17615/ctnf-k559	text	January 2019
Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium Merino, Jordi; Dashti, Hassan S.; Li, Sherly X. Molecular Psychiatry, Vol. 24, Issue 12 https://doi.org/10.1038/s41380-018-0079-4	journal	July 2018
Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes Jäger, Susanne; Wahl, Simone; Kröger, Janine Charité - Universitätsmedizin Berlin https://doi.org/10.17169/refubium-23757	text	January 2017
Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Prins, Bram; Mead, Timothy J.; Brody, Jennifer A. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.27662	text	January 2018

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