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1. Epigenetic analysis in rheumatoid arthritis synoviocytes

Author

Seokjin Ham, Jae-Bum Bae, Suman Lee, Bong-Jo Kim, Bok-Ghee Han, Seung-Ki Kwok, and Tae-Young Roh

Subjects
Medicine, Biochemistry, QD415-436
Abstract

Rheumatoid arthritis: Understanding the regulation of disease-relevant genes Whole genome analysis of synoviocytes, specialized cells in the joint-lubricating synovial fluid, sheds light on the pathogenic mechanisms of rheumatoid arthritis (RA). Around 350 million people worldwide suffer joint pain and stiffness due to RA, but the inheritance pattern of the disease remains unclear. A study led by Tae-Young Roh at Pohang University of Science and Technology, South Korea, reveals a distinct pattern of chemical tags on the DNA of synoviocytes from RA patients. Differences in methyl group tags in over 500 regions of the genome influenced the expression of RA-associated genes and of microRNAs, small RNA molecules that are also involved in the regulation of gene expression. These differentially methylated sites may not only represent potential disease biomarkers, but also offer new insights into the regulation of RA-relevant genes.

Published
2019
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2. Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author

M. Carola Zillikens, Serkalem Demissie, Yi-Hsiang Hsu, Laura M. Yerges-Armstrong, Wen-Chi Chou, Lisette Stolk, Gregory Livshits, Linda Broer, Toby Johnson, Daniel L. Koller, Zoltán Kutalik, Jian’an Luan, Ida Malkin, Janina S. Ried, Albert V. Smith, Gudmar Thorleifsson, Liesbeth Vandenput, Jing Hua Zhao, Weihua Zhang, Ali Aghdassi, Kristina Åkesson, Najaf Amin, Leslie J. Baier, Inês Barroso, David A. Bennett, Lars Bertram, Rainer Biffar, Murielle Bochud, Michael Boehnke, Ingrid B. Borecki, Aron S. Buchman, Liisa Byberg, Harry Campbell, Natalia Campos Obanda, Jane A. Cauley, Peggy M. Cawthon, Henna Cederberg, Zhao Chen, Nam H. Cho, Hyung Jin Choi, Melina Claussnitzer, Francis Collins, Steven R. Cummings, Philip L. De Jager, Ilja Demuth, Rosalie A. M. Dhonukshe-Rutten, Luda Diatchenko, Gudny Eiriksdottir, Anke W. Enneman, Mike Erdos, Johan G. Eriksson, Joel Eriksson, Karol Estrada, Daniel S. Evans, Mary F. Feitosa, Mao Fu, Melissa Garcia, Christian Gieger, Thomas Girke, Nicole L. Glazer, Harald Grallert, Jagvir Grewal, Bok-Ghee Han, Robert L. Hanson, Caroline Hayward, Albert Hofman, Eric P. Hoffman, Georg Homuth, Wen-Chi Hsueh, Monica J. Hubal, Alan Hubbard, Kim M. Huffman, Lise B. Husted, Thomas Illig, Erik Ingelsson, Till Ittermann, John-Olov Jansson, Joanne M. Jordan, Antti Jula, Magnus Karlsson, Kay-Tee Khaw, Tuomas O. Kilpeläinen, Norman Klopp, Jacqueline S. L. Kloth, Heikki A. Koistinen, William E. Kraus, Stephen Kritchevsky, Teemu Kuulasmaa, Johanna Kuusisto, Markku Laakso, Jari Lahti, Thomas Lang, Bente L. Langdahl, Lenore J. Launer, Jong-Young Lee, Markus M. Lerch, Joshua R. Lewis, Lars Lind, Cecilia Lindgren, Yongmei Liu, Tian Liu, Youfang Liu, Östen Ljunggren, Mattias Lorentzon, Robert N. Luben, William Maixner, Fiona E. McGuigan, Carolina Medina-Gomez, Thomas Meitinger, Håkan Melhus, Dan Mellström, Simon Melov, Karl Michaëlsson, Braxton D. Mitchell, Andrew P. Morris, Leif Mosekilde, Anne Newman, Carrie M. Nielson, Jeffrey R. O’Connell, Ben A. Oostra, Eric S. Orwoll, Aarno Palotie, Stephen C. J. Parker, Munro Peacock, Markus Perola, Annette Peters, Ozren Polasek, Richard L. Prince, Katri Räikkönen, Stuart H. Ralston, Samuli Ripatti, John A. Robbins, Jerome I. Rotter, Igor Rudan, Veikko Salomaa, Suzanne Satterfield, Eric E. Schadt, Sabine Schipf, Laura Scott, Joban Sehmi, Jian Shen, Chan Soo Shin, Gunnar Sigurdsson, Shad Smith, Nicole Soranzo, Alena Stančáková, Elisabeth Steinhagen-Thiessen, Elizabeth A. Streeten, Unnur Styrkarsdottir, Karin M. A. Swart, Sian-Tsung Tan, Mark A. Tarnopolsky, Patricia Thompson, Cynthia A. Thomson, Unnur Thorsteinsdottir, Emmi Tikkanen, Gregory J. Tranah, Jaakko Tuomilehto, Natasja M. van Schoor, Arjun Verma, Peter Vollenweider, Henry Völzke, Jean Wactawski-Wende, Mark Walker, Michael N. Weedon, Ryan Welch, H.-Erich Wichmann, Elisabeth Widen, Frances M. K. Williams, James F. Wilson, Nicole C. Wright, Weijia Xie, Lei Yu, Yanhua Zhou, John C. Chambers, Angela Döring, Cornelia M. van Duijn, Michael J. Econs, Vilmundur Gudnason, Jaspal S. Kooner, Bruce M. Psaty, Timothy D. Spector, Kari Stefansson, Fernando Rivadeneira, André G. Uitterlinden, Nicholas J. Wareham, Vicky Ossowski, Dawn Waterworth, Ruth J. F. Loos, David Karasik, Tamara B. Harris, Claes Ohlsson, and Douglas P. Kiel

Subjects
Science
Abstract

A correction to this article has been published and is linked from the HTML version of this article.

Published
2017
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3. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author

M. Carola Zillikens, Serkalem Demissie, Yi-Hsiang Hsu, Laura M. Yerges-Armstrong, Wen-Chi Chou, Lisette Stolk, Gregory Livshits, Linda Broer, Toby Johnson, Daniel L. Koller, Zoltán Kutalik, Jian’an Luan, Ida Malkin, Janina S. Ried, Albert V. Smith, Gudmar Thorleifsson, Liesbeth Vandenput, Jing Hua Zhao, Weihua Zhang, Ali Aghdassi, Kristina Åkesson, Najaf Amin, Leslie J. Baier, Inês Barroso, David A. Bennett, Lars Bertram, Rainer Biffar, Murielle Bochud, Michael Boehnke, Ingrid B. Borecki, Aron S. Buchman, Liisa Byberg, Harry Campbell, Natalia Campos Obanda, Jane A. Cauley, Peggy M. Cawthon, Henna Cederberg, Zhao Chen, Nam H. Cho, Hyung Jin Choi, Melina Claussnitzer, Francis Collins, Steven R. Cummings, Philip L. De Jager, Ilja Demuth, Rosalie A. M. Dhonukshe-Rutten, Luda Diatchenko, Gudny Eiriksdottir, Anke W. Enneman, Mike Erdos, Johan G. Eriksson, Joel Eriksson, Karol Estrada, Daniel S. Evans, Mary F. Feitosa, Mao Fu, Melissa Garcia, Christian Gieger, Thomas Girke, Nicole L. Glazer, Harald Grallert, Jagvir Grewal, Bok-Ghee Han, Robert L. Hanson, Caroline Hayward, Albert Hofman, Eric P. Hoffman, Georg Homuth, Wen-Chi Hsueh, Monica J. Hubal, Alan Hubbard, Kim M. Huffman, Lise B. Husted, Thomas Illig, Erik Ingelsson, Till Ittermann, John-Olov Jansson, Joanne M. Jordan, Antti Jula, Magnus Karlsson, Kay-Tee Khaw, Tuomas O. Kilpeläinen, Norman Klopp, Jacqueline S. L. Kloth, Heikki A. Koistinen, William E. Kraus, Stephen Kritchevsky, Teemu Kuulasmaa, Johanna Kuusisto, Markku Laakso, Jari Lahti, Thomas Lang, Bente L. Langdahl, Lenore J. Launer, Jong-Young Lee, Markus M. Lerch, Joshua R. Lewis, Lars Lind, Cecilia Lindgren, Yongmei Liu, Tian Liu, Youfang Liu, Östen Ljunggren, Mattias Lorentzon, Robert N. Luben, William Maixner, Fiona E. McGuigan, Carolina Medina-Gomez, Thomas Meitinger, Håkan Melhus, Dan Mellström, Simon Melov, Karl Michaëlsson, Braxton D. Mitchell, Andrew P. Morris, Leif Mosekilde, Anne Newman, Carrie M. Nielson, Jeffrey R. O’Connell, Ben A. Oostra, Eric S. Orwoll, Aarno Palotie, Stephen C. J. Parker, Munro Peacock, Markus Perola, Annette Peters, Ozren Polasek, Richard L. Prince, Katri Räikkönen, Stuart H. Ralston, Samuli Ripatti, John A. Robbins, Jerome I. Rotter, Igor Rudan, Veikko Salomaa, Suzanne Satterfield, Eric E. Schadt, Sabine Schipf, Laura Scott, Joban Sehmi, Jian Shen, Chan Soo Shin, Gunnar Sigurdsson, Shad Smith, Nicole Soranzo, Alena Stančáková, Elisabeth Steinhagen-Thiessen, Elizabeth A. Streeten, Unnur Styrkarsdottir, Karin M. A. Swart, Sian-Tsung Tan, Mark A. Tarnopolsky, Patricia Thompson, Cynthia A. Thomson, Unnur Thorsteinsdottir, Emmi Tikkanen, Gregory J. Tranah, Jaakko Tuomilehto, Natasja M. van Schoor, Arjun Verma, Peter Vollenweider, Henry Völzke, Jean Wactawski-Wende, Mark Walker, Michael N. Weedon, Ryan Welch, H.-Erich Wichmann, Elisabeth Widen, Frances M. K. Williams, James F. Wilson, Nicole C. Wright, Weijia Xie, Lei Yu, Yanhua Zhou, John C. Chambers, Angela Döring, Cornelia M. van Duijn, Michael J. Econs, Vilmundur Gudnason, Jaspal S. Kooner, Bruce M. Psaty, Timothy D. Spector, Kari Stefansson, Fernando Rivadeneira, André G. Uitterlinden, Nicholas J. Wareham, Vicky Ossowski, Dawn Waterworth, Ruth J. F. Loos, David Karasik, Tamara B. Harris, Claes Ohlsson, and Douglas P. Kiel

Subjects
Science
Abstract

Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

Published
2017
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4. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Yingchang Lu, Felix R. Day, Stefan Gustafsson, Martin L. Buchkovich, Jianbo Na, Veronique Bataille, Diana L. Cousminer, Zari Dastani, Alexander W. Drong, Tõnu Esko, David M. Evans, Mario Falchi, Mary F. Feitosa, Teresa Ferreira, Åsa K. Hedman, Robin Haring, Pirro G. Hysi, Mark M. Iles, Anne E. Justice, Stavroula Kanoni, Vasiliki Lagou, Rui Li, Xin Li, Adam Locke, Chen Lu, Reedik Mägi, John R. B. Perry, Tune H. Pers, Qibin Qi, Marianna Sanna, Ellen M. Schmidt, William R. Scott, Dmitry Shungin, Alexander Teumer, Anna A. E. Vinkhuyzen, Ryan W. Walker, Harm-Jan Westra, Mingfeng Zhang, Weihua Zhang, Jing Hua Zhao, Zhihong Zhu, Uzma Afzal, Tarunveer Singh Ahluwalia, Stephan J. L. Bakker, Claire Bellis, Amélie Bonnefond, Katja Borodulin, Aron S. Buchman, Tommy Cederholm, Audrey C. Choh, Hyung Jin Choi, Joanne E. Curran, Lisette C. P. G. M. de Groot, Philip L. De Jager, Rosalie A. M. Dhonukshe-Rutten, Anke W. Enneman, Elodie Eury, Daniel S. Evans, Tom Forsen, Nele Friedrich, Frédéric Fumeron, Melissa E. Garcia, Simone Gärtner, Bok-Ghee Han, Aki S. Havulinna, Caroline Hayward, Dena Hernandez, Hans Hillege, Till Ittermann, Jack W. Kent, Ivana Kolcic, Tiina Laatikainen, Jari Lahti, Irene Mateo Leach, Christine G. Lee, Jong-Young Lee, Tian Liu, Youfang Liu, Stéphane Lobbens, Marie Loh, Leo-Pekka Lyytikäinen, Carolina Medina-Gomez, Karl Michaëlsson, Mike A. Nalls, Carrie M. Nielson, Laticia Oozageer, Laura Pascoe, Lavinia Paternoster, Ozren Polašek, Samuli Ripatti, Mark A. Sarzynski, Chan Soo Shin, Nina Smolej Narančić, Dominik Spira, Priya Srikanth, Elisabeth Steinhagen-Thiessen, Yun Ju Sung, Karin M. A. Swart, Leena Taittonen, Toshiko Tanaka, Emmi Tikkanen, Nathalie van der Velde, Natasja M. van Schoor, Niek Verweij, Alan F. Wright, Lei Yu, Joseph M. Zmuda, Niina Eklund, Terrence Forrester, Niels Grarup, Anne U. Jackson, Kati Kristiansson, Teemu Kuulasmaa, Johanna Kuusisto, Peter Lichtner, Jian'an Luan, Anubha Mahajan, Satu Männistö, Cameron D. Palmer, Janina S. Ried, Robert A. Scott, Alena Stancáková, Peter J. Wagner, Ayse Demirkan, Angela Döring, Vilmundur Gudnason, Douglas P. Kiel, Brigitte Kühnel, Massimo Mangino, Barbara Mcknight, Cristina Menni, Jeffrey R. O'Connell, Ben A. Oostra, Alan R. Shuldiner, Kijoung Song, Liesbeth Vandenput, Cornelia M. van Duijn, Peter Vollenweider, Charles C. White, Michael Boehnke, Yvonne Boettcher, Richard S. Cooper, Nita G. Forouhi, Christian Gieger, Harald Grallert, Aroon Hingorani, Torben Jørgensen, Pekka Jousilahti, Mika Kivimaki, Meena Kumari, Markku Laakso, Claudia Langenberg, Allan Linneberg, Amy Luke, Colin A. Mckenzie, Aarno Palotie, Oluf Pedersen, Annette Peters, Konstantin Strauch, Bamidele O. Tayo, Nicholas J. Wareham, David A. Bennett, Lars Bertram, John Blangero, Matthias Blüher, Claude Bouchard, Harry Campbell, Nam H. Cho, Steven R. Cummings, Stefan A. Czerwinski, Ilja Demuth, Rahel Eckardt, Johan G. Eriksson, Luigi Ferrucci, Oscar H. Franco, Philippe Froguel, Ron T. Gansevoort, Torben Hansen, Tamara B. Harris, Nicholas Hastie, Markku Heliövaara, Albert Hofman, Joanne M. Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Paul B. Knekt, Seppo Koskinen, Peter Kovacs, Terho Lehtimäki, Lars Lind, Yongmei Liu, Eric S. Orwoll, Clive Osmond, Markus Perola, Louis Pérusse, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Treva K. Rice, Fernando Rivadeneira, Igor Rudan, Veikko Salomaa, Thorkild I. A. Sørensen, Michael Stumvoll, Anke Tönjes, Bradford Towne, Gregory J. Tranah, Angelo Tremblay, André G. Uitterlinden, Pim van der Harst, Erkki Vartiainen, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Henry Völzke, Mark Walker, Henri Wallaschofski, Sarah Wild, James F. Wilson, Loïc Yengo, D. Timothy Bishop, Ingrid B. Borecki, John C. Chambers, L. Adrienne Cupples, Abbas Dehghan, Panos Deloukas, Ghazaleh Fatemifar, Caroline Fox, Terrence S. Furey, Lude Franke, Jiali Han, David J. Hunter, Juha Karjalainen, Fredrik Karpe, Robert C. Kaplan, Jaspal S. Kooner, Mark I. McCarthy, Joanne M. Murabito, Andrew P. Morris, Julia A. N. Bishop, Kari E. North, Claes Ohlsson, Ken K. Ong, Inga Prokopenko, J. Brent Richards, Eric E. Schadt, Tim D. Spector, Elisabeth Widén, Cristen J. Willer, Jian Yang, Erik Ingelsson, Karen L. Mohlke, Joel N. Hirschhorn, John Andrew Pospisilik, M. Carola Zillikens, Cecilia Lindgren, Tuomas Oskari Kilpeläinen, and Ruth J. F. Loos

Subjects
Science
Abstract

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Published
2016
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5. Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population

Author

Min Jin Go, Joo-Yeon Hwang, Tae-Joon Park, Young Jin Kim, Ji Hee Oh, Yeon-Jung Kim, Bok-Ghee Han, and Bong-Jo Kim

Subjects
Genome-wide association study, Glycemic trait, Sex-specific, Type 2 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

BackgroundUntil recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population.MethodsWe performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively.ResultsA combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study.ConclusionOur study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.

Published
2014
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6. Differential DNA methylation of MSI2 and its correlation with diabetic traits.

Author

Jae-Pil Jeon, In-Uk Koh, Nak-Hyun Choi, Bong-Jo Kim, Bok-Ghee Han, and Suman Lee

Subjects
Medicine, Science
Abstract

Differential DNA methylation with hyperglycemia is significantly associated with Type 2 Diabetes (T2D). Longtime extended exposure to high blood glucose levels can affect the epigenetic signatures in all organs. However, the relevance of the differential DNA methylation changes with hyperglycemia in blood with pancreatic islets remains unclear. We investigated differential DNA methylation in relation to glucose homeostasis based on the Oral Glucose Tolerance Test (OGTT) in a population-based cohort. We found a total of 382 differential methylation sites from blood DNA in hyperglycemia and type 2 diabetes subgroups using a longitudinal and cross-sectional approach. Among them, three CpG sites were overlapped; they were mapped to the MSI2 and CXXC4 genes. In a DNA methylation replication study done by pyrosequencing (n = 440), the CpG site of MSI2 were shown to have strong associations with the T2D group (p value = 2.20E-16). The differential methylation of MSI2 at chr17:55484635 was associated with diabetes-related traits, in particular with insulin sensitivity (QUICKI, p value = 2.20E-16) and resistance (HOMA-IR, p value = 1.177E-07). In human pancreatic islets, at the single-base resolution (using whole-genome bisulfite sequencing), the 292 CpG sites in the ±5kb at chr17:55484635 were found to be significantly hypo-methylated in donors with T2D (average decrease = 13.91%, 95% confidence interval (CI) = 4.18~ 17.06) as compared to controls, and methylation patterns differed by sex (-9.57%, CI = -16.76~ -6.89) and age (0.12%, CI = -11.17~ 3.77). Differential methylation of the MSI2 gene (chr17:55484635) in blood and islet cells is strongly related to hyperglycemia. Our findings suggest that epigenetic perturbation on the target site of MSI2 gene in circulating blood and pancreatic islets should represent or affect hyperglycemia.

Published
2017
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7. Replication of genome-wide association studies on asthma and allergic diseases in Korean adult population

Author

Dankyu Yoon, Hyo-Jeong Ban, Young Jin Kim, Eun-Jin Kim, Hyung-Cheol Kim, Bok-Ghee Han, Jung-Won Park, Soo-Jong Hong, Sang-Heon Cho, Kiejung Park, and Joo-Shil Lee

Subjects
Allergic diseases, Asthma, GWAS replication, Korean, Biology (General), QH301-705.5, Biochemistry, QD415-436
Abstract

Allergic diseases such as asthma, allergic rhinitis, and atopicdermatitis are heterogeneous diseases characterized by multiplesymptoms and phenotypes. Recent advancements in geneticstudy enabled us to identify disease associated genetic factors.Numerous genome-wide association studies (GWAS) have revealedmultiple associated loci for allergic diseases. However,the majority of previous studies have been conducted in populationsof European ancestry. Moreover, the associations of singlenucleotide polymorphisms (SNPs) with allergic diseaseshave not been studied amongst the large-scale general Koreanpopulation. Herein, we performed the replication study to validatethe previous variants, known to be associated with allergicdiseases, in the Korean population. In this study, we categorizedthree allergic related phenotypes, one allergy and two asthmarelated phenotypes, based on self-reports of physician diagnosisand their symptoms from 8,842 samples. As a result, we foundnominally significant associations of 6 SNPs with at least one allergicrelated phenotype in the Korean population. [BMB reports2012; 45(5): 305-310]

Published
2012
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8. Prediction of breast cancer survival using clinical and genetic markers by tumor subtypes.

Author

Nan Song, Ji-Yeob Choi, Hyuna Sung, Sujee Jeon, Seokang Chung, Sue K Park, Wonshik Han, Jong Won Lee, Mi Kyung Kim, Ji-Young Lee, Keun-Young Yoo, Bok-Ghee Han, Sei-Hyun Ahn, Dong-Young Noh, and Daehee Kang

Subjects
Medicine, Science
Abstract

PURPOSE:To identify the genetic variants associated with breast cancer survival, a genome-wide association study (GWAS) was conducted of Korean breast cancer patients. METHODS:From the Seoul Breast Cancer Study (SEBCS), 3,226 patients with breast cancer (1,732 in the discovery and 1,494 in the replication set) were included in a two-stage GWAS on disease-free survival (DFS) by tumor subtypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). The associations of the re-classified combined prognostic markers through recursive partitioning analysis (RPA) of DFS for breast cancer were assessed with the Cox proportional hazard model. The prognostic predictive values of the clinical and genetic models were evaluated by Harrell's C. RESULTS:In the two-stage GWAS stratified by tumor subtypes, rs166870 and rs10825036 were consistently associated with DFS in the HR+ HER2- and HR- HER2- breast cancer subtypes, respectively (Prs166870 = 2.88 × 10(-7) and Prs10825036 = 3.54 × 10(-7) in the combined set). When patients were classified by the RPA in each subtype, genetic factors contributed significantly to differentiating the high risk group associated with DFS inbreast cancer, specifically the HR+ HER2- (P discovery=1.18 × 10(-8) and P replication = 2.08 × 10(-5)) and HR- HRE2- subtypes (P discovery = 2.35 × 10(-4) and P replication = 2.60 × 10(-2)). The inclusion of the SNPs tended to improve the performance of the prognostic models consisting of age, TNM stage and tumor subtypes based on ER, PR, and HER2 status. CONCLUSION:Combined prognostic markers that include clinical and genetic factors by tumor subtypes could improve the prediction of survival in breast cancer.

Published
2015
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9. Ubiquitous polygenicity of human complex traits: genome-wide analysis of 49 traits in Koreans.

Author

Jian Yang, Taeheon Lee, Jaemin Kim, Myeong-Chan Cho, Bok-Ghee Han, Jong-Young Lee, Hyun-Jeong Lee, Seoae Cho, and Heebal Kim

Subjects
Genetics, QH426-470
Abstract

Recent studies in population of European ancestry have shown that 30% ~ 50% of heritability for human complex traits such as height and body mass index, and common diseases such as schizophrenia and rheumatoid arthritis, can be captured by common SNPs and that genetic variation attributed to chromosomes are in proportion to their length. Using genome-wide estimation and partitioning approaches, we analysed 49 human quantitative traits, many of which are relevant to human diseases, in 7,170 unrelated Korean individuals genotyped on 326,262 SNPs. For 43 of the 49 traits, we estimated a nominally significant (P

Published
2013
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10. Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.

Author

Jirong Long, Qiuyin Cai, Hyuna Sung, Jiajun Shi, Ben Zhang, Ji-Yeob Choi, Wanqing Wen, Ryan J Delahanty, Wei Lu, Yu-Tang Gao, Hongbing Shen, Sue K Park, Kexin Chen, Chen-Yang Shen, Zefang Ren, Christopher A Haiman, Keitaro Matsuo, Mi Kyung Kim, Ui Soon Khoo, Motoki Iwasaki, Ying Zheng, Yong-Bing Xiang, Kai Gu, Nathaniel Rothman, Wenjing Wang, Zhibin Hu, Yao Liu, Keun-Young Yoo, Dong-Young Noh, Bok-Ghee Han, Min Hyuk Lee, Hong Zheng, Lina Zhang, Pei-Ei Wu, Ya-Lan Shieh, Sum Yin Chan, Shenming Wang, Xiaoming Xie, Sung-Won Kim, Brian E Henderson, Loic Le Marchand, Hidemi Ito, Yoshio Kasuga, Sei-Hyun Ahn, Han Sung Kang, Kelvin Y K Chan, Hiroji Iwata, Shoichiro Tsugane, Chun Li, Xiao-Ou Shu, Dae-Hee Kang, and Wei Zheng

Subjects
Genetics, QH426-470
Abstract

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.

Published
2012
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11. Carriage of the V279F null allele within the gene encoding Lp-PLA₂ is protective from coronary artery disease in South Korean males.

Author

Yangsoo Jang, Dawn Waterworth, Jong-Eun Lee, Kijoung Song, Sujin Kim, Hyo-Soo Kim, Kyung Woo Park, Hyun-Jai Cho, Il-Young Oh, Jeong Euy Park, Bok-Soo Lee, Hyo Jeong Ku, Dong-Jik Shin, Jong Ho Lee, Sun Ha Jee, Bok-Ghee Han, Hye-Yoon Jang, Eun-Young Cho, Patrick Vallance, John Whittaker, Lon Cardon, and Vincent Mooser

Subjects
Medicine, Science
Abstract

The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA₂) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA₂ in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted.PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66-0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69-0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA₂ activity and CAD risk.Natural deficiency in Lp-PLA₂ activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA₂ and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.

Published
2011
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12. A network-based approach to prioritize results from genome-wide association studies.

Author

Nirmala Akula, Ancha Baranova, Donald Seto, Jeffrey Solka, Michael A Nalls, Andrew Singleton, Luigi Ferrucci, Toshiko Tanaka, Stefania Bandinelli, Yoon Shin Cho, Young Jin Kim, Jong-Young Lee, Bok-Ghee Han, Bipolar Disorder Genome Study (BiGS) Consortium, Wellcome Trust Case-Control Consortium, and Francis J McMahon

Subjects
Medicine, Science
Abstract

Genome-wide association studies (GWAS) are a valuable approach to understanding the genetic basis of complex traits. One of the challenges of GWAS is the translation of genetic association results into biological hypotheses suitable for further investigation in the laboratory. To address this challenge, we introduce Network Interface Miner for Multigenic Interactions (NIMMI), a network-based method that combines GWAS data with human protein-protein interaction data (PPI). NIMMI builds biological networks weighted by connectivity, which is estimated by use of a modification of the Google PageRank algorithm. These weights are then combined with genetic association p-values derived from GWAS, producing what we call 'trait prioritized sub-networks.' As a proof of principle, NIMMI was tested on three GWAS datasets previously analyzed for height, a classical polygenic trait. Despite differences in sample size and ancestry, NIMMI captured 95% of the known height associated genes within the top 20% of ranked sub-networks, far better than what could be achieved by a single-locus approach. The top 2% of NIMMI height-prioritized sub-networks were significantly enriched for genes involved in transcription, signal transduction, transport, and gene expression, as well as nucleic acid, phosphate, protein, and zinc metabolism. All of these sub-networks were ranked near the top across all three height GWAS datasets we tested. We also tested NIMMI on a categorical phenotype, Crohn's disease. NIMMI prioritized sub-networks involved in B- and T-cell receptor, chemokine, interleukin, and other pathways consistent with the known autoimmune nature of Crohn's disease. NIMMI is a simple, user-friendly, open-source software tool that efficiently combines genetic association data with biological networks, translating GWAS findings into biological hypotheses.

Published
2011
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13. Identification of new genetic risk variants for type 2 diabetes.

Author

Xiao Ou Shu, Jirong Long, Qiuyin Cai, Lu Qi, Yong-Bing Xiang, Yoon Shin Cho, E Shyong Tai, Xiangyang Li, Xu Lin, Wong-Ho Chow, Min Jin Go, Mark Seielstad, Wei Bao, Huaixing Li, Marilyn C Cornelis, Kai Yu, Wanqing Wen, Jiajun Shi, Bok-Ghee Han, Xue Ling Sim, Liegang Liu, Qibin Qi, Hyung-Lae Kim, Daniel P K Ng, Jong-Young Lee, Young Jin Kim, Chun Li, Yu-Tang Gao, Wei Zheng, and Frank B Hu

Subjects
Genetics, QH426-470
Abstract

Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r(2)

Published
2010
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14. Associations of variants in CHRNA5/A3/B4 gene cluster with smoking behaviors in a Korean population.

Author

Ming D Li, Dankyu Yoon, Jong-Young Lee, Bok-Ghee Han, Tianhua Niu, Thomas J Payne, Jennie Z Ma, and Taesung Park

Subjects
Medicine, Science
Abstract

Multiple genome-wide and targeted association studies reveal a significant association of variants in the CHRNA5-CHRNA3-CHRNB4 (CHRNA5/A3/B4) gene cluster on chromosome 15 with nicotine dependence. The subjects examined in most of these studies had a European origin. However, considering the distinct linkage disequilibrium patterns in European and other ethnic populations, it would be of tremendous interest to determine whether such associations could be replicated in populations of other ethnicities, such as Asians. In this study, we performed comprehensive association and interaction analyses for 32 single-nucleotide polymorphisms (SNPs) in CHRNA5/A3/B4 with smoking initiation (SI), smoking quantity (SQ), and smoking cessation (SC) in a Korean sample (N = 8,842). We found nominally significant associations of 7 SNPs with at least one smoking-related phenotype in the total sample (SI: P = 0.015 approximately 0.023; SQ: P = 0.008 approximately 0.028; SC: P = 0.018 approximately 0.047) and the male sample (SI: P = 0.001 approximately 0.023; SQ: P = 0.001 approximately 0.046; SC: P = 0.01). A spectrum of haplotypes formed by three consecutive SNPs located between rs16969948 in CHRNA5 and rs6495316 in the intergenic region downstream from the 5' end of CHRNB4 was associated with these three smoking-related phenotypes in both the total and the male sample. Notably, associations of these variants and haplotypes with SC appear to be much weaker than those with SI and SQ. In addition, we performed an interaction analysis of SNPs within the cluster using the generalized multifactor dimensionality reduction method and found a significant interaction of SNPs rs7163730 in LOC123688, rs6495308 in CHRNA3, and rs7166158, rs8043123, and rs11072793 in the intergenic region downstream from the 5' end of CHRNB4 to be influencing SI in the male sample. Considering that fewer than 5% of the female participants were smokers, we did not perform any analysis on female subjects specifically. Together, our detected associations of variants in the CHRNA5/A3/B4 cluster with SI, SQ, and SC in the Korean smoker samples provide strong evidence for the contribution of this cluster to the etiology of SI, ND, and SC in this Asian population.

Published
2010
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15. Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection

Author

David Adlam, Timothy M. Olson, Nicolas Combaret, Jason C. Kovacic, Siiri E. Iismaa, Abtehale Al-Hussaini, Megan M. O'Byrne, Sara Bouajila, Adrien Georges, Ketan Mishra, Peter S. Braund, Valentina d’Escamard, Siying Huang, Marios Margaritis, Christopher P. Nelson, Mariza de Andrade, Daniella Kadian-Dodov, Catherine A. Welch, Stephani Mazurkiewicz, Xavier Jeunemaitre, Claire Mei Yi Wong, Eleni Giannoulatou, Michael Sweeting, David Muller, Alice Wood, Lucy McGrath-Cadell, Diane Fatkin, Sally L. Dunwoodie, Richard Harvey, Cameron Holloway, Jean-Philippe Empana, Xavier Jouven, Jeffrey W. Olin, Rajiv Gulati, Marysia S. Tweet, Sharonne N. Hayes, Nilesh J. Samani, Robert M. Graham, Pascal Motreff, Nabila Bouatia-Naji, Loïc Belle, Patrick Dupouy, Pierre Barnay, Nicolas Meneveau, Martine Gilard, Gilles Rioufol, Grégoire Range, Philippe Brunel, Nicolas Delarche, Emmanuelle Filippi, Louis Le Bivic, Brahim Harbaoui, Hakim Benamer, Guillaume Cayla, Olivier Varenne, Stephane Peggy Manzo-Silberman, Johanne Silvain, Christian Spaulding, Christophe Caussin, Edouard Gerbaud, Yann Valy, René Koning, Thibault Lhermusier, Stanislas Champin, Emmanuel Salengro, Arnaud Fluttaz, Amer Zabalawi, Yves Cottin, Emmanuel Teiger, Christophe Saint-Etienne, Grégory Ducrocq, Stéphanie Marliere, Emmanuel Boiffard, Pierre Aubry, Jean Louis Georges, Didier Bresson, Fabien De Poli, Gaëtan Karrillon, Vincent Roule, Laurent Bali, Mathieu Valla, Antoine Gerbay, David Houpe, Olivier Dubreuil, Arsène Monnier, Norbert Mayaud, Aurélie Manchuelle, Philippe Commeau, Marc Bedossa, Majid Nikpay, Anuj Goel, Hong-Hee Won, Leanne M. Hall, Christina Willenborg, Stavroula Kanoni, Danish Saleheen, Theodosios Kyriakou, Jemma C. Hopewell, Thomas R. Webb, Lingyao Zeng, Abbas Dehghan, Maris Alver, Sebastian M. Armasu, Kirsi Auro, Andrew Bjonnes, Daniel I. Chasman, Shufeng Chen, Ian Ford, Nora Franceschini, Christian Gieger, Christopher Grace, Stefan Gustafsson, Jie Huang, Shih-Jen Hwang, Yun Kyoung Kim, Marcus E. Kleber, King Wai Lau, Xiangfeng Lu, Yingchang Lu, Leo P. Lyytikäinen, Evelin Mihailov, Alanna Morrison, Natalia Pervjakova, Liming Qu, Lynda M. Rose, Elias Salfati, Richa Saxena, Markus Scholz, Albert V. Smith, Emmi Tikkanen, Andre Uitterlinden, Xueli Yang, Weihua Zhang, Wei Zhao, Paul S. de Vries, Natalie R. van Zuydam, Sonia S. Anand, Lars Bertram, Frank Beutner, George Dedoussis, Philippe Frossard, Dominique Gauguier, Alison H. Goodall, Omri Gottesman, Marc Haber, Bok-Ghee Han, Jianfeng Huang, Shapour Jalilzadeh, Thorsten Kessler, Inke R. König, Lars Lannfelt, Wolfgang Lieb, Lars Lind, Cecilia M. Lindgren, Maisa Lokki, Patrik K. Magnusson, Nadeem H. Mallick, Narinder Mehra, Thomas Meitinger, Fazal-ur-Rehman Memon, Andrew P. Morris, Markku S. Nieminen, Nancy L. Pedersen, Annette Peters, Loukianos S. Rallidis, Asif Rasheed, Maria Samuel, Svati H. Shah, Juha Sinisalo, Kathleen E. Stirrups, Stella Trompet, Laiyuan Wang, Khan S. Zaman, Diego Ardissino, Eric Boerwinkle, Ingrid B. Borecki, Erwin P. Bottinger, Julie E. Buring, John C. Chambers, Rory Collins, L Adrienne Cupples, John Danesh, Ilja Demuth, Roberto Elosua, Stephen E. Epstein, Tõnu Esko, Mary F. Feitosa, Oscar H. Franco, Maria Grazia Franzosi, Christopher B. Granger, Dongfeng Gu, Vilmundur Gudnason, Alistair S. Hall, Anders Hamsten, Tamara B. Harris, Stanley L. Hazen, Christian Hengstenberg, Albert Hofman, Erik Ingelsson, Carlos Iribarren, J Wouter Jukema, Pekka J. Karhunen, Bong-Jo Kim, Jaspal S. Kooner, Iftikhar J. Kullo, Terho Lehtimäki, Ruth J. Loos, Olle Melander, Andres Metspalu, Winfried März, Colin N. Palmer, Markus Perola, Thomas Quertermous, Daniel J. Rader, Paul M. Ridker, Samuli Ripatti, Robert Roberts, Veikko Salomaa, Dharambir K. Sanghera, Stephen M. Schwartz, Udo Seedorf, Alexandre F. Stewart, David J. Stott, Joachim Thiery, Pierre A. Zalloua, Christopher J. O'Donnell, Muredach P. Reilly, Themistocles L. Assimes, John R. Thompson, Jeanette Erdmann, Robert Clarke, Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Panos Deloukas, Heribert Schunkert, Martin Farrall, Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, Mayo Clinic [Rochester], Service de Cardiologie Maladies Vasculaires [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Victor Chang Cardiac Research Institute, University of New South Wales [Sydney] (UNSW), St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Department of Cardiovascular Medicine, Mayo Clinic, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), and Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)

Subjects
Adult, Male, medicine.medical_specialty, Myocardial infarction, Coronary Vessel Anomalies, Fibromuscular dysplasia, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Prevalence, Fibromuscular Dysplasia, Humans, 030212 general & internal medicine, Vascular Diseases, Artery dissection, MESH: Australia, United Kingdom, USA, Coronary Vessel Anomalies / epidemiology, Endothelin-1 / genetics, Microfilament proteins / genetics, Genetic association, Aged, Endothelin-1, business.industry, Microfilament Proteins, Australia, Cardiovascular disease in women, Middle Aged, medicine.disease, R1, United States, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Case-Control Studies, Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, France, Cardiology and Cardiovascular Medicine, Scad, business
Abstract

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Published
2019

16. Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Author

Alan B. Feranil, Cassandra N. Spracklen, Sing-Hui Lim, Cathy S.J. Fann, Tin Aung, Yii-Der Ida Chen, Yonghong Zhang, Li-Hsin Chien, Jirong Long, Xiuqing Guo, Chien-Hsiun Chen, Jyh-Ming Jimmy Juang, Fumihiko Takeuchi, Xueling Sim, Norihiro Kato, Wen-Harn Pan, Masato Isono, Tzung-Dau Wang, Jer-Yuarn Wu, Dongfeng Gu, Xu Wang, Xuhong Hou, Peng Chen, Wen-Jane Lee, Kae-Woei Liang, Sun-Ju Lee, Chao A. Hsiung, Meian He, Lee-Ming Chuang, Devin Absher, Chii-Min Hwu, Tangchun Wu, Li-Ching Chang, Sanghoon Moon, Mi Yeong Hwang, Chew-Kiat Heng, Sun Ha Jee, Feijie Wang, Yik Ying Teo, Kent D. Taylor, Shufa Du, Wen Bin Wei, Ching-Yu Cheng, I-Te Lee, Elias Salfati, Jie Wang, Cheng Hu, Chiea Chuen Khor, Qiuyin Cai, James E. Hixson, Toru Nabika, Wayne Huey-Herng Sheu, Qiao Fan, Woon-Puay Koh, Linda S. Adair, Jianjun Liu, Pok Chien Tan, Penny Gordon-Larsen, Yechiel Friedlander, Bok-Ghee Han, Keng-Hung Lin, Ying Wu, Hao Peng, E-Shyong Tai, Young-Jin Kim, Koichi Akiyama, Bong-Jo Kim, Rajkumar Dorajoo, Wanting Zhao, Tomohiro Katsuya, Stephen S. Rich, Sue-Anne Toh, Rong Zhang, Shengxu Li, Yuan-Tsong Chen, Ya Xing Wang, Keum Ji Jung, Xu Lin, Zhirong Guo, Wei Zheng, Karen L. Mohlke, Shu-Pei Tan, Rob M. van Dam, Liang Sun, Jiang He, Lixuan Gui, Tatsuhiko Tsunoda, Hui Cai, Aili Wang, Huaixing Li, Wei Huang, Yao Hu, Kevin Sandow, Toshihiro Tanaka, Thomas Quertermous, Themistocles L. Assimes, Jerome I. Rotter, Maren E Cannon, Tamara S. Roman, Yong-Bing Xiang, Yoon Shin Cho, Todd A. Johnson, Shi Jinxiu, Weiping Jia, Tien Yin Wong, Yun Kyoung Kim, Jie Yao, Xiao-Ou Shu, Jian-Min Yuan, Blanche Lim, Michiaki Kubo, Shu-Chun Chuang, Charumathi Sabanayagam, and Jost B. Jonas

Subjects
Adult, Male, 0301 basic medicine, Linkage disequilibrium, Quantitative Trait Loci, Locus (genetics), Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Asian People, Gene Frequency, Ethnicity, Genetics, Humans, Allele, Molecular Biology, Allele frequency, Alleles, Genetic Association Studies, Triglycerides, Genetics (clinical), Genetic association, Cholesterol, Association Studies Articles, General Medicine, Middle Aged, Lipids, Lipoproteins, LDL, 030104 developmental biology, chemistry, Female, Lipoproteins, HDL, Corrigendum, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P

Published
2017

17. A study of transposable element-associated structural variations (TASVs) using a de novo-assembled Korean genome

Author

Seyoung Mun, Bok-Ghee Han, Keunsoo Kang, Thomas J. Meyer, Heui-Soo Kim, Wooseok Lee, Kyudong Han, and Songmi Kim

Subjects
Transposable element, Clinical Biochemistry, Computational biology, Biology, Biochemistry, Genome, DNA sequencing, Article, Mobile elements, Transposition (music), Structural variation, Alu Elements, Databases, Genetic, Republic of Korea, Humans, Molecular Biology, Genome, Human, Comparative genomics, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, Genomics, Sequence Analysis, DNA, Genetics, Population, DNA Transposable Elements, Next-generation sequencing, Molecular Medicine, Human genome, Personal genomics, Reference genome
Abstract

Advances in next-generation sequencing (NGS) technology have made personal genome sequencing possible, and indeed, many individual human genomes have now been sequenced. Comparisons of these individual genomes have revealed substantial genomic differences between human populations as well as between individuals from closely related ethnic groups. Transposable elements (TEs) are known to be one of the major sources of these variations and act through various mechanisms, including de novo insertion, insertion-mediated deletion, and TE–TE recombination-mediated deletion. In this study, we carried out de novo whole-genome sequencing of one Korean individual (KPGP9) via multiple insert-size libraries. The de novo whole-genome assembly resulted in 31,305 scaffolds with a scaffold N50 size of 13.23 Mb. Furthermore, through computational data analysis and experimental verification, we revealed that 182 TE-associated structural variation (TASV) insertions and 89 TASV deletions contributed 64,232 bp in sequence gain and 82,772 bp in sequence loss, respectively, in the KPGP9 genome relative to the hg19 reference genome. We also verified structural differences associated with TASVs by comparative analysis with TASVs in recent genomes (AK1 and TCGA genomes) and reported their details. Here, we constructed a new Korean de novo whole-genome assembly and provide the first study, to our knowledge, focused on the identification of TASVs in an individual Korean genome. Our findings again highlight the role of TEs as a major driver of structural variations in human individual genomes., Genomics: Following the footprints of ‘jumping genes’ A novel strategy for genome analysis offers insights into the distribution and impact on genome variation of transposable elements, DNA sequences that can replicate and relocate themselves at different chromosomal regions. These sequences, also known as ‘jumping genes’, comprise up to 50% of the genome, but it has proven challenging to map them with existing techniques. Seyoung Mun of Dankook University, Cheonan, South Korea, and coworkers have developed a sequencing and computational analysis strategy that allowed them to accurately map transposable elements across the genome of a Korean individual. These data revealed hundreds of insertion and deletion events relative to an existing reference map of the genome, showing significant alterations in the chromosomal structure. The authors speculate that such widespread transposition events could potentially contribute to individual differences in gene expression and risk of disease.

Published
2019

18. Epigenetic analysis in rheumatoid arthritis synoviocytes

Author

Tae-Young Roh, Bok-Ghee Han, Jae-Bum Bae, Seokjin Ham, Seung-Ki Kwok, Suman Lee, and Bong-Jo Kim

Subjects
0301 basic medicine, Clinical Biochemistry, Bisulfite sequencing, lcsh:Medicine, Biology, Biochemistry, Article, Epigenesis, Genetic, Collagen fibril organization, lcsh:Biochemistry, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, microRNA, Humans, lcsh:QD415-436, Gene Regulatory Networks, RNA, Messenger, Molecular Biology, Gene, Transcription factor, Epigenomics, Regulation of gene expression, Gene Expression Profiling, lcsh:R, Genetic Variation, DNA Methylation, Synoviocytes, 3. Good health, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, Molecular Medicine, CpG Islands
Abstract

Rheumatoid arthritis (RA) is a complex chronic systematic disease with progressive destruction of the joints by invasive synoviocytes. To characterize the key regulators involved in the development of RA, we obtained multilayer epigenomics data including DNA methylation by whole-genome bisulfite sequencing, miRNA profiles, genetic variations by whole-exome sequencing, and mRNA profiles from synoviocytes of RA and osteoarthritis (OA) patients. The overall DNA methylation patterns were not much different between RA and OA, but 523 low-methylated regions (LMRs) were specific to RA. The LMRs were preferentially localized at the 5′ introns and overlapped with transcription factor binding motifs for GLI1, RUNX2, and TFAP2A/C. Single base-scale differentially methylated CpGs were linked with several networks related to wound response, tissue development, collagen fibril organization, and the TGF-β receptor signaling pathway. Further, the DNA methylation of 201 CpGs was significantly correlated with 27 expressed miRNA genes. Our interpretation of epigenomic data of the synoviocytes from RA and OA patients is an informative resource to further investigate regulatory elements and biomarkers responsible for the pathophysiology of RA and OA., Rheumatoid arthritis: Understanding the regulation of disease-relevant genes Whole genome analysis of synoviocytes, specialized cells in the joint-lubricating synovial fluid, sheds light on the pathogenic mechanisms of rheumatoid arthritis (RA). Around 350 million people worldwide suffer joint pain and stiffness due to RA, but the inheritance pattern of the disease remains unclear. A study led by Tae-Young Roh at Pohang University of Science and Technology, South Korea, reveals a distinct pattern of chemical tags on the DNA of synoviocytes from RA patients. Differences in methyl group tags in over 500 regions of the genome influenced the expression of RA-associated genes and of microRNAs, small RNA molecules that are also involved in the regulation of gene expression. These differentially methylated sites may not only represent potential disease biomarkers, but also offer new insights into the regulation of RA-relevant genes.

Published
2019

19. The genetic architecture of type 2 diabetes

Author

Clement Ma, Liisa Hakaste, Claes Ladenvall, Massimo Mangino, Lars Lind, Aaron G. Day-Williams, Ryan Poplin, Thomas Schwarzmayr, Annette Peters, Thomas Meitinger, Satish Kumar, Kyong Soo Park, Ching-Yu Cheng, Farook Thameem, Kyle J. Gaulton, Olov Rolandsson, Yossi Farjoun, Neil Robertson, Mauricio O. Carneiro, Mark A. DePristo, Pierre Fontanillas, Ruth J. F. Loos, Heather M. Highland, Vilmantas Giedraitis, Gemma Buck, Fredrik Karpe, Mohammad Kamran Ikram, Alex S. F. Doney, Hae Kyung Im, Eric S. Lander, Johanna Kuusisto, Dorothée Thuillier, Denis Rybin, Jacquelyn Murphy, Benjamin M. Neale, Martina Müller-Nurasyid, Eric R. Gamazon, Johanne Marie Justesen, Tin Aung, Vincent K. L. Lam, John Danesh, Donna M. Lehman, Goo Jun, Marit E. Jørgensen, Christian Herder, Edmund Chan, Pamela J. Hicks, Todd Green, Claudia Langenberg, Yoon Shin Cho, James G. Wilson, Daniel E. Hale, Rector Arya, Giriraj R. Chandak, Juan Fernandez Tajes, Jaakko Tuomilehto, Christopher P. Jenkinson, Anders Rosengren, Torsten Lauritzen, Michael Griswold, Karen L. Mohlke, Amy J. Swift, Alena Stančáková, Christian Fuchsberger, Iksoo Huh, Nikhil Tandon, João Fadista, Christa Meisinger, Gonçalo R. Abecasis, Pål R. Njølstad, Dwaipayan Bharadwaj, Richard M. Watanabe, Shaun Purcell, Veikko Salomaa, Tim D. Spector, Paul W. Franks, Adam E. Locke, Sharon P. Fowler, Panos Deloukas, Reedik Mägi, Solomon K. Musani, Kee Seng Chia, Barbara Thorand, Soo Heon Kwak, Annemari Käräjämäki, Evelin Mihailov, John Blangero, Thomas Wieland, Christian Gieger, E. Shyong Tai, Jianjun Liu, James B. Meigs, Teemu Kuulasmaa, Martin Hrabé de Angelis, Francis S. Collins, Tim M. Strom, Tibor V. Varga, Juyoung Lee, Mark I. McCarthy, Domenico Palli, Jong-Young Lee, Benjamin Glaser, Tasha E. Fingerlin, Stephen O'Rahilly, Andrew T. Hattersley, Gil Atzmon, Manuel A. Rivas, Noël P. Burtt, Ivan Brandslund, Young-Jin Kim, Dorairaj Prabhakaran, Xu Wang, Taylor J. Maxwell, Valeriya Lyssenko, Frank B. Hu, Adolfo Correa, Khalid Shakir, Kathleen A. Jablonski, Yingchang Lu, Wei-Yen Lim, Min Jin Go, William R. Scott, Hanna E. Abboud, Leena Kinnunen, Inês Barroso, Gabriela L. Surdulescu, Peng Chen, Robert Sladek, Marju Orho-Melander, Xueling Sim, Robert A. Scott, Joanna M. M. Howson, Markku Laakso, David Altshuler, Vidya S. Farook, Harald Grallert, Janina S. Ried, Vineeta Agarwala, Philippe Froguel, Nicholas J. Wareham, Tiinamaija Tuomi, Joon Yoon, Heikki A. Koistinen, Toni I. Pollin, Heiner Boeing, Marie Loh, Nicola L. Beer, Joanne E. Curran, Lars Lannfelt, Dorota Pasko, Taesung Park, David Buck, Nir Barzilai, Stephen C. J. Parker, Michael Roden, Bok-Ghee Han, David Aguilar, Timothy Fennell, Sian-Tsung Tan, Gregory P. Wilson, Momoko Horikoshi, Cramer Christensen, Craig L. Hanis, Gilean McVean, Benjamin F. Voight, Wolfgang Rathmann, Jared Maguire, Ashok Kumar, Donald W. Bowden, Michael L. Stitzel, Yongkang Kim, Christine Blancher, Jason Carey, Min-Seok Kwon, Nicholette D. Palmer, Oluf Pedersen, Niels Grarup, Peter S. Chines, Cornelia Huth, James Scott, Torben Hansen, Konstantin Strauch, Erwin P. Bottinger, Andrew D. Morris, Anette P. Gjesing, Erik Ingelsson, Colin N. A. Palmer, Claudia H. T. Tam, Stacey Gabriel, Pablo Cingolani, Beverley Balkau, Michael Boehnke, Peter M. Nilsson, Wing-Yee So, Andrew R. Wood, Lili Milani, Ravindranath Duggirala, Qibin Qi, Mark Walker, Weiping Jia, Mark Seielstad, Narisu Narisu, Tien Yin Wong, Martijn van de Bunt, Anubha Mahajan, Davis J. McCarthy, Ann-Christine Syvänen, Jennifer Kriebel, N. William Rayner, Han Chen, Jinyan Huang, Chiea Chuen Khor, Richard N. Bergman, Shah Ebrahim, Dylan Hodgkiss, Weihua Zhang, Manjinder S. Sandhu, Richard D. Pearson, Juliana C.N. Chan, Rainer Rauramaa, Ralph A. DeFronzo, Andrew Farmer, Yoshihiko Nagai, Allan Linneberg, Herman A. Taylor, Jose C. Florez, Jaspal S. Kooner, Lori L. Bonnycastle, Jeroen R. Huyghe, Leif Groop, Joseph Trakalo, Sobha Puppala, Bong-Jo Kim, Kathleen Stirrups, Kerrin S. Small, Cecilia M. Lindgren, Jennifer E. Below, Heung Man Lee, Inga Prokopenko, Liming Liang, Timothy M. Frayling, Uzma Afzal, Mark J. Daly, Yik Ying Teo, Andrew P. Morris, Phoenix Kwan, Yvonne T. van der Schouw, Cheng Hu, Katharine R. Owen, Alisa K. Manning, Christopher J. Groves, Josée Dupuis, Ryan P. Welch, Loukas Moutsianas, Joshua D. Smith, Tanya M. Teslovich, Robert C. Onofrio, Maggie C.Y. Ng, Peter Donnelly, Tõnu Esko, Matt Neville, Bo Isomaa, Anne U. Jackson, Jette Bork-Jensen, Barry I. Freedman, Yi Chen, Danish Saleheen, Lu Qi, Laura J. Scott, Jasmina Kravic, Paul Elliott, Mette Hollensted, Carmen Navarro, Selyeong Lee, Benjamin Lehne, Thomas Illig, Nancy J. Cox, Jonathan C. Levy, George B. Grant, John C. Chambers, Adam S. Butterworth, Ronald C.W. Ma, Teresa Ferreira, John R. B. Perry, Eleftheria Zeggini, Hyun Min Kang, Loic Yengo, Eric Banks, Jae-Hoon Lee, Anna L. Gloyn, Christopher Hartl, Wei Zhao, Andres Metspalu, Keng-Han Lin, Graeme I. Bell, Jason Flannick, Torben Jørgensen, Thomas W. Blackwell, Heather M. Stringham, Olle Melander, Omri Gottesman, Other departments, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, Internal Medicine, Perry, John [0000-0001-6483-3771], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Danesh, John [0000-0003-1158-6791], Johnson, Kathleen [0000-0002-6823-3252], O'Rahilly, Stephen [0000-0003-2199-4449], Langenberg, Claudia [0000-0002-5017-7344], Sandhu, Manjinder [0000-0002-2725-142X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, PROTEIN INTERACTION NETWORKS, SUSCEPTIBILITY LOCI, Genotyping Techniques, General Science & Technology, DNA Mutational Analysis, SEQUENCING ASSOCIATION, 030209 endocrinology & metabolism, Genome-wide association study, Biology, Research Support, N.I.H, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Genetic predisposition, Journal Article, Humans, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Non-U.S. Gov't, Exome sequencing, Alleles, Genetic association, Genetics, RISK, Multidisciplinary, HERITABILITY, Research Support, Non-U.S. Gov't, COMPLEX TRAITS, Extramural, Genetic Variation, Genetic architecture, HUMAN-DISEASE, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, RARE VARIANTS, Sample Size, LOW-FREQUENCY, Imputation (genetics), Common disease-common variant, Genome-Wide Association Study
Abstract

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Published
2016

20. Impact of Whole-Blood Processing Conditions on Plasma and Serum Concentrations of Cytokines

Author

Jae-Eun Lee, Bok-Ghee Han, Jong-Wan Kim, and So-Youn Shin

Subjects
Serum, 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, Plasma, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Macrophage, Centrifugation, Whole blood, Receiver operating characteristic, Chemistry, Interleukin, Cell Biology, General Medicine, Serum concentration, 030104 developmental biology, Endocrinology, Cytokine, 030220 oncology & carcinogenesis, Immunology, Cytokines
Abstract

Pre-analytical variations in plasma and serum samples can occur because of variability in whole-blood processing procedures. The aim of this study was to determine the impact of delayed separation of whole blood on the plasma and serum concentrations of cytokines. The concentrations of 16 cytokines were measured in plasma and serum samples when the centrifugation of whole blood at room temperature was delayed for 4, 6, 24, or 48 h, and the values were compared with those observed after separation within 2 h of whole-blood collection. Receiver operating characteristic (ROC) curve analysis was also performed for cytokines to determine whether cytokine levels in plasma and serum samples can be used to assess delayed separation of whole blood. Plasma concentrations of interleukin (IL)-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and soluble CD40 ligand (sCD40L) and serum concentrations of IL-1β, IL-6, IL-8, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β increased significantly (2-fold) when separation was delayed at room temperature for 24 h. The concentrations of 6 of these cytokines (all except serum IL-1β and IL-6) demonstrated high diagnostic performance (area under the ROC curve0.8) for delayed separation of whole blood. Furthermore, these cytokine concentrations typically exhibited high sensitivity and specificity at each optimal cutoff point. Conversely, IL-17A was stable in both plasma and serum samples, even when whole-blood centrifugation was delayed at room temperature for 48 h. This study shows that certain cytokines (IL-1β, GM-CSF, sCD40L, IL-8, MIP-1α, and MIP-1β) could be used for assessing the quality of plasma or serum samples.

Published
2016

21. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

Author

Xana Kim-Howard, Takayuki Sumida, Celi Sun, Hong Zhang, Bok Ghee Han, Chang Hee Suh, Yong Beom Park, So Young Bang, Swapan K. Nath, Kwangwoo Kim, Nan Shen, Young Mo Kang, Kek Heng Chua, Yukinori Okada, Jonathan D. Wren, Yuan-yuan Qi, Julio E. Molineros, Akari Suzuki, Xu-jie Zhou, Seung Cheol Shim, Loren L. Looger, Sang Cheol Bae, Michiaki Kubo, John B. Harley, Adam Adler, Jung Yoon Choe, Hye Soon Lee, Young-Jin Kim, Kazuhiko Yamamoto, Prasenjeet Motghare, Yuta Kochi, Won Tae Chung, Kenneth M. Kaufman, Mikhail G. Dozmorov, Shin-Seok Lee, Tae-Hwan Kim, Jianyang Ma, and Krishna Bhattarai

Subjects
0301 basic medicine, Male, Genotype, Genotyping Techniques, CD226, Gene Expression, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Genetics, medicine, Humans, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, Genotyping, Lupus erythematosus, medicine.disease, Genetic architecture, 3. Good health, 030104 developmental biology, Female, Genome-Wide Association Study
Abstract

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

Published
2016

22. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Author

Ching-Ti Liu, Michael Boehnke, George Dedoussis, Sophie V. Eastwood, Ruth J. F. Loos, Keng-Hung Lin, Denis Rybin, Fredrik Karpe, Martina Müller-Nurasyid, Michael A. Province, Alison D. Murray, Bo Isomaa, Eirini Marouli, Konstantin Strauch, Michael Preuss, Paul M. Ridker, Jette Bork-Jensen, Albert V. Smith, Hugoline G. de Haan, Wayne Huey-Herng Sheu, Barbara Thorand, Wolfgang Rathmann, Lawrence F. Bielak, Peter Kovacs, Marit E. Jørgensen, Jennifer Wessel, Danish Saleheen, Jung-Jin Lee, James B. Meigs, Veikko Salomaa, Alena Stančáková, Tibor V. Varga, Hidetoshi Kitajima, Inês Barroso, Kent D. Taylor, Claudia Langenberg, Yoon Shin Cho, Joanna M. M. Howson, Andrew T. Hattersley, Marie-France Hivert, Markku Laakso, Kai-Uwe Eckardt, Bram P. Prins, Matthias B. Schulze, Andrew D. Morris, Susanne Jäger, Francis S. Collins, Kristi Läll, Xu Lin, Anette Varbo, Benjamin Lehne, Girish N. Nadkarni, Jonathan Marchini, Daniel I. Chasman, Michael Stumvoll, Mark O. Goodarzi, Cécile Lecoeur, Philippe M. Frossard, Noël P. Burtt, Frank Kee, Jasmina Kravic, Alain G. Bertoni, Ivan Brandslund, Najaf Amin, Lenore J. Launer, Oluf Pedersen, Johanna Kuusisto, Line Rode, Eleftheria Zeggini, Yingchang Lu, Markus Perola, Helen R. Warren, André G. Uitterlinden, Hanieh Yaghootkar, Torben Hansen, Harald Grallert, Annemari Käräjämäki, Abbas Dehghan, Gina M. Peloso, Yii-Der Ida Chen, Man Li, Shaofeng Huo, Lars Lind, Karen L. Mohlke, Adrienne Tin, Yang Hai, Renée de Mutsert, Gudmar Thorleifsson, Marie Moitry, Sune F. Nielsen, Sara M. Willems, Matthias Wuttke, Weihua Zhang, Young-Jin Kim, Giovanni Malerba, Richard A. Jensen, Loic Yengo, Mickaël Canouil, Kurt Lohman, Robert A. Scott, Tamara B. Harris, Ruifang Li-Gao, Florian Kronenberg, Anke Tönjes, Bok-Ghee Han, Krista Fischer, Thomas Meitinger, James S. Pankow, Jaakko Tuomilehto, Adam S. Butterworth, Jerome I. Rotter, Olov Rolandsson, Xiuqing Guo, Cramer Christensen, Marie Loh, Elizabeth Selvin, Bong-Jo Kim, Audrey Y. Chu, Reedik Mägi, Josée Dupuis, Anna Köttgen, Jean Ferrières, Jin Li, Robert Sladek, Leslie A. Lange, Niels Grarup, Roberta McKean-Cowdin, Cristen J. Willer, Jose C. Florez, Valgerdur Steinthorsdottir, Karina Meidtner, Annette Peters, Børge G. Nordestgaard, Rajiv Chowdhury, Ioanna Ntalla, Emma Ahlqvist, Leif Groop, Nicholas J. Wareham, Kerrin S. Small, Tiinamaija Tuomi, Cecilia M. Lindgren, Katharine R. Owen, Giovanni Gambaro, Cornelia M. van Duijn, Dennis O. Mook-Kanamori, Kenneth Rice, Erik Ingelsson, Colin N. A. Palmer, Sharon L.R. Kardia, Neil R. Robertson, Dajiang J. Liu, Sebastian Schönherr, Daniel Taliun, Sekar Kathiresan, James G. Wilson, Ping An, Patricia A. Peyser, Matthias Blüher, Frits R. Rosendaal, John C. Chambers, Caroline Hayward, Shoaib Afzal, Fernando Rivadineira, Marielisa Graff, Pranav Yajnik, Vasiliki Mamakou, Juan Fernandez Tajes, Stefan Gustafsson, Heather M. Highland, Vilmantas Giedraitis, Andrew R. Wood, Saima Afaq, Jaspal S. Kooner, Megan L. Grove, Jennifer A. Brody, Andrew P. Morris, James P. Cook, Praveen Surendran, Jennifer Kriebel, Heikki A. Koistinen, Kari Stefansson, Anders Rosengren, Rainer Rauramaa, Satu Männistö, Oscar H. Franco, Yongmei Liu, N. William Rayner, Blair H. Smith, Erwin P. Bottinger, Ayse Demirkan, Allan Linneberg, Jonathan Marten, Huaixing Li, Sung Soo Kim, Sophie Hackinger, Cristina Bombieri, Lia B. Bang, Jun Liu, Asif Rasheed, Tim D. Spector, Paul W. Franks, Mark I. McCarthy, Heiner Boeing, Anne E. Justice, Vilmundur Gudnason, Sohee Han, Unnur Thorsteinsdottir, Panos Deloukas, Naveed Sattar, Eric Boerwinkle, Martin Ingelsson, John Danesh, Vassily Trubetskoy, Marco M Ferrario, Marju Orho-Melander, Wei Gan, Philippe Froguel, Symen Ligthart, Susan R. Heckbert, Jie Yao, Anne Tybjærg-Hansen, Robin Young, Daniel R. Witte, Anubha Mahajan, Peter Almgren, Timothy M. Frayling, Tanya M. Teslovich, Matt Neville, Philippe Amouyel, Wei Zhao, Andres Metspalu, Yao Hu, Olle Melander, Kari Kuulasmaa, Jason Flannick, Torben Jørgensen, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Rohit Varma, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Male, Inference, Genome-wide association study, Whole Exome Sequencing, 0302 clinical medicine, type 2 diabetes, coding variant associations signals, mechanistic inference, fine mapping, Coding region, Chromosome Mapping/statistics & numerical data, European Continental Ancestry Group/genetics, CONFERS SUSCEPTIBILITY, Exome sequencing, 11 Medical and Health Sciences, Genetics, Genetics & Heredity, 0303 health sciences, MAGIC Consortium, Chromosome Mapping, Whole Exome Sequencing/statistics & numerical data, Identification (information), RARE VARIANTS, LOW-FREQUENCY, Female, ExomeBP Consortium, Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, Posterior probability, European Continental Ancestry Group, 030209 endocrinology & metabolism, Context (language use), Computational biology, Biology, GENOTYPE IMPUTATION, Article, White People, GENETIC ARCHITECTURE, 03 medical and health sciences, SDG 3 - Good Health and Well-being, QUALITY-CONTROL, Exome Sequencing, Genome-Wide Association Study/statistics & numerical data, Journal Article, GIANT Consortium, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Alleles, Genetic association, 030304 developmental biology, FATTY LIVER-DISEASE, Science & Technology, Genetic Variation, 06 Biological Sciences, Genetic architecture, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 2/classification, 030217 neurology & neurosurgery, Coding (social sciences), Genome-Wide Association Study, Developmental Biology
Abstract

Identification of coding variant associations for complex diseases offers a direct route to biological insight, but is dependent on appropriate inference concerning the causal impact of those variants on disease risk. We aggregated coding variant data for 81,412 type 2 diabetes (T2D) cases and 370,832 controls of diverse ancestry, identifying 40 distinct coding variant association signals (at 38 loci) reaching significance (p−7). Of these, 16 represent novel associations mapping outside known genome-wide association study (GWAS) signals. We make two important observations. First, despite a threefold increase in sample size over previous efforts, only five of the 40 signals are driven by variants with minor allele frequency 1.29. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls of European ancestry to fine-map these associated coding variants in their regional context, with and without additional weighting to account for the global enrichment of complex trait association signals in coding exons. At the 37 signals for which we attempted fine-mapping, we demonstrate convincing support (posterior probability >80% under the “annotation-weighted” model) that coding variants are causal for the association at 16 (including novel signals involving POC5 p.His36Arg, ANKH p.Arg187Gln, WSCD2 p.Thr113Ile, PLCB3 p.Ser778Leu, and PNPLA3 p.Ile148Met). However, at 13 of the 37 loci, the associated coding variants represent “false leads” and naïve analysis could have led to an erroneous inference regarding the effector transcript mediating the signal. Accurate identification of validated targets is dependent on correct specification of the contribution of coding and non-coding mediated mechanisms at associated loci.

Published
2018

23. Genome-based exome sequencing analysis identifies GYG1, DIS3L and DDRGK1 are associated with myocardial infarction in Koreans

Author

Bok Ghee Han, Bok Soo Lee, Sang Hak Lee, Yangsoo Jang, Min Young Park, Sanghoon Moon, Yun Kyoung Kim, Jeong Euy Park, and Ji-Young Lee

Subjects
0301 basic medicine, Adult, Male, Genotype, Myocardial Infarction, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Genome, Polymorphism, Single Nucleotide, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Ribonucleases, Asian People, Risk Factors, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic variability, Myocardial infarction, Gene, Exome sequencing, Genetic association, Adaptor Proteins, Signal Transducing, Glycoproteins, Middle Aged, medicine.disease, 030104 developmental biology, Glucosyltransferases, Female, Carrier Proteins, Genome-Wide Association Study
Abstract

Myocardial infarction (MI) is a complex disease caused by combination of genetic and environmental factors. Although genome-wide association studies (GWAS) identified more than 46 risk loci which are associated with coronary artery disease and MI, most of the genetic variability in MI still remains undefined. Here, we screened the susceptibility loci for MI using exome sequencing and validated candidate variants in replication sets. We identified that three genes (GYG1, DIS3L and DDRGK1) were associated with MI at the discovery and replication stages. Further research will be required to determine the functional association of these genes with MI risk, and these associations have to be confirmed in other ethnic populations.

Published
2018

24. MicroRNA-650 in a copy number-variable region regulates the production of interleukin 6 in human osteosarcoma cells

Author

Bok Ghee Han, Youngsoo Kim, Sanghoon Moon, Jun Ho Yun, Mi Yeong Hwang, Jeong Min Kim, Ho Yeong Yu, Heun Sik Lee, Bong Jo Kim, and Yeon Jung Kim

Subjects
Genetics, Cancer Research, Oncogene, business.industry, Interleukin, Articles, Cell cycle, Cell biology, Oncology, Gene expression, microRNA, Medicine, Copy-number variation, business, Enhancer, Gene
Abstract

Copy number variation is a well-known genetic variation. microRNAs (miRNAs/miRs) are non-coding RNAs that mediate gene expression by regulating target mRNAs. In the present study, copy number deletions encompassing miRNA coding regions were investigated to determine the association between the deletion of miRNA and its phenotypic effects. A total of 38 human miRNAs in copy number variants were identified and miR-650, which is functional in the human osteosarcoma MG-63 cell line, was selected. Overexpression of miR-650 decreased the expression of inhibitor of growth family member 4 (ING4) in the MG-63 cells and increased interleukin (IL)6 transcription, as well as IL6 secretion in IL1B-stimulated cells. Furthermore, miR-650 downregulated the amount of nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor α and increased the transcriptional activity of nuclear factor (NF)κB. Downregulation of ING4 also increased the production of IL6, similar to miR-650 overexpression. Taken together, these data indicate that miR-650 plays a significant role in the production of IL6 by regulating ING4 expression and NFκB signaling in IL1B-stimulated MG-63 osteosarcoma cells.

Published
2015

25. Identification of FAM13A gene associated with the ratio of FEV1 to FVC in Korean population by genome-wide association studies including gene–environment interactions

Author

Sun Ha Jee, Jae Woong Sull, Soriul Kim, Hyun Kim, Namhan Cho, Bok Ghee Han, Chol Shin, and Seung Ku Lee

Subjects
Adult, Vital Capacity, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Pulmonary function testing, Cohort Studies, Pulmonary Disease, Chronic Obstructive, FEV1/FVC ratio, Asian People, Gene Frequency, Risk Factors, Forced Expiratory Volume, Republic of Korea, Genetics, medicine, Humans, Genetic Predisposition to Disease, Risk factor, Genetics (clinical), COPD, Base Sequence, GTPase-Activating Proteins, Smoking, Haplotype, Middle Aged, medicine.disease, respiratory tract diseases, Haplotypes, Genetic epidemiology, Multivariate Analysis, Cohort, Linear Models, Gene-Environment Interaction, Genome-Wide Association Study
Abstract

Chronic obstructive pulmonary disease (COPD) is a complex, multifactorial disease. Although smoking is a main risk factor for obstructive impairment, not all smokers develop this critical disease. We conducted a genome-wide association study to identify the association between genetic variants and pulmonary function and also examined how these variants relate to lung impairment in accordance with smoking behaviors. Using two community-based cohorts, the Ansan cohort (n=4319) and the Ansung cohort (n=3674), in the Korean Genome Epidemiology Study, we analyzed the association between genetic variants (single-nucleotide polymorphisms and haplotypes) and the ratio of FEV1 to FVC (FEV1/FVC) using multivariate linear regression models. Similar analyses were conducted after stratification by smoking status. Four genome-wide significant signals in the FAM13A gene (the strongest signal at rs2609264, P=1.76 × 10(-7) in a combined set) were associated with FEV1/FVC. For the association with ratio, the effect size in the CTGA haplotype (risk haplotype) was -0.57% (s.e., 0.11; P=2.10 × 10(-7)) as compared with the TCAG haplotype (reference haplotype) in a combined set. There was also a significant interaction of FAM13A haplotypes with heavy smoking on FEV1/FVC (P for interaction=0.028). We confirmed the previously reported association of FAM13A in 4q22.1 with pulmonary function. The FAM13A haplotypes also interacted with heavy smoking to affect the risk of reduced pulmonary function.

Published
2015

26. A genome-wide association study identifies a LEPR gene as a novel predisposing factor for childhood fasting plasma glucose

Author

Bok-Ghee Han, Bong-Jo Kim, Hye-Ja Lee, Tae Joon Park, Lyong Heo, Han Byul Jang, Kyung Hee Park, Ju Young Lee, Min Jin Go, Jihyun Song, Jae Heon Kang, and Joo-Yeon Hwang

Subjects
Blood Glucose, Male, Genetics, Plasma glucose, Adolescent, Genome, Human, Genome-wide association study, Fasting, Biology, Humans, Receptors, Leptin, Female, Child, Lepr gene, Genome-Wide Association Study
Abstract

• A genome wide association study identifies a LEPR gene as a novel predisposing factor for childhood fasting plasma glucose

Published
2014

27. Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population

Author

Joo-Yeon Hwang, Yeonjung Kim, Bong-Jo Kim, Min Jin Go, Bok-Ghee Han, Taejoon Park, Young-Jin Kim, and Ji Hee Oh

Subjects
Genome-wide association study, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Type 2 diabetes, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, 0302 clinical medicine, medicine, Sex-specific, education, 030304 developmental biology, Glycemic, Genetic association, Genetics, 0303 health sciences, education.field_of_study, lcsh:RC648-665, business.industry, Confounding, medicine.disease, 3. Good health, Glycemic trait, Others, Allelic heterogeneity, Original Article, business
Abstract

Background: Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contri bution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and popula tion-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population. Methods: We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 con trols recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively. Results: A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide sig nificance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study. Conclusion: Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.

Published
2014

28. The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

Author

Sergio Abrignani, David Adams, Melanie de Almeida, ALTUCCI, Lucia, Viren Amin, Ido Amit, Stylianos E, Antonarakis, Samuel Aparicio, Takahiro Arima, Laura Arrigoni, Rob Arts, Vahid Asnafi, Manel Esteller, Jae Bum Bae, Kevin Bassler, Stephan Beck, Benjamin Berkman, Bradley E, Bernstein, Mikhail Bilenky, Adrian Bird, Christoph Bock, Bernhard Boehm, Guillaume Bourque, Charles E, Breeze, Benedikt Brors, David Bujold, Oliver Burren, Marion J, Bussemakers, Adam Butterworth, Elias Campo, Enrique Carrillo de Santa Pau, Lisa Chadwick, Kui Ming Chan, Wei Chen, Tom H, Cheung, Luca Chiapperino, Nak Hyen Choi, Ho Ryun Chung, Laura Clarke, Joseph M, Connors, Philippe Cronet, John Danesh, Manolis Dermitzakis, Gerard Drewes, Pawel Durek, Stephanie Dyke, Tomasz Dylag, Connie J, Eaves, Peter Ebert, Roland Eils, Jürgen Eils, Catherine A, Ennis, Tariq Enver, Elise A, Feingold, Bärbel Felder, Anne Ferguson Smith, Jude Fitzgibbon, Paul Flicek, Roger S, Y, Foo, Peter Fraser, Mattia Frontini, Eileen Furlong, Sitanshu Gakkhar, Nina Gasparoni, Gilles Gasparoni, Daniel H, Geschwind, Petar Glažar, Thomas Graf, Frank Grosveld, Xin Yuan Guan, Roderic Guigo, Ivo G, Gut, Alf Hamann, Bok Ghee Han, R, Alan Harris, Simon Heath, Kristian Helin, Jan G, Hengstler, Alireza Heravi Moussavi, Karl Herrup, Steven Hill, Jason A, Hilton, Benjamin C, Hitz, Bernhard Horsthemke, Ming Hu, Joo Yeon Hwang, Nancy Y, Takashi Ito, Biola Maria Javierre, Sasa Jenko, Thomas Jenuwein, Yann Joly, Steven J, M, Jones, Yae Kanai, Hee Gyung Kang, Aly Karsan, Alexandra K, Kiemer, Song Cheol Kim, Bong Jo Kim, Hyeon Hoe Kim, Hiroshi Kimura, Sarah Kinkley, Filippos Klironomos, In Uk Koh, Myrto Kostadima, Christopher Kressler, Roman Kreuzhuber, Anshul Kundaje, Ralf Küppers, Carolyn Larabell, Paul Lasko, Mark Lathrop, S, Lee, Suman Lee, Hans Lehrach, Elsa Leitão, Thomas Lengauer, Åke Lernmark, David Leslie, Gilberto K, K, Leung, Danny Leung, Markus Loeffler, Yussanne Ma, Antonello Mai, Thomas Manke, Eric R, Marcotte, Marco A, Marra, Joost H, A, Martens, Jose Ignacio Martin Subero, Karen Maschke, Christoph Merten, Aleksandar Milosavljevic, Saverio Minucci, Totai Mitsuyama, Richard A, Moore, Fabian Müller, Andrew J, Mungall, Mihai G, Netea, Karl Nordström, Irene Norstedt, Hiroaki Okae, Vitor Onuchic, Francis Ouellette, Willem Ouwehand, Massimiliano Pagani, Vera Pancaldi, Thomas Pap, Tomi Pastinen, Ronak Patel, Dirk S, Paul, Michael J, Pazin, Pier Giuseppe Pelicci, Anthony G, Phillips, Julia Polansky, Bo Porse, J, Andrew Pospisilik, Shyam Prabhakar, Dena C, Procaccini, Andreas Radbruch, Nikolaus Rajewsky, Vardham Rakyan, Wolf Reik, Bing Ren, David Richardson, Andreas Richter, Daniel Rico, David J, Roberts, Philip Rosenstiel, Mark Rothstein, Abdulrahman Salhab, Hiroyuki Sasaki, John S, Satterlee, Sascha Sauer, Claudia Schacht, Florian Schmidt, Gerd Schmitz, Stefan Schreiber, Christopher Schröder, Dirk Schübeler, Joachim L, Schultze, Ronald P, Schulyer, Marcel Schulz, Martin Seifert, Katsuhiko Shirahige, Reiner Siebert, Thomas Sierocinski, Laura Siminoff, Anupam Sinha, Nicole Soranzo, Salvatore Spicuglia, Mikhail Spivakov, Christian Steidl, Seth Strattan, Michael Stratton, Peter Südbeck, Hao Sun, Narumi Suzuki, Yutaka Suzuki, Amos Tanay, David Torrents, Frederick L, Tyson, Thomas Ulas, Sebastian Ullrich, Toshikazu Ushijima, Alfonso Valencia, Edo Vellenga, Martin Vingron, Chris Wallace, Stefan Wallner, Jörn Walter, Huating Wang, Stephanie Weber, Nina Weiler, Andreas Weller, Andrew Weng, Steven Wilder, Sam M, Wiseman, Angela R, Zhenguo Wu, Jieyi Xiong, Yasuhiro Yamashita, Xinyi Yang, Desmond Y, Yap, Kevin Y, Yip, Stephen Yip, Jae Il Yoo, Daniel Zerbino, Gideon Zipprich, Antonarakis, Stylianos, International Human Epigenome Consortium, [0000-0002-8682-6748], Apollo - University of Cambridge Repository, Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Radboud University Medical Center [Nijmegen], Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Hematology, University of Groningen and University Medical Center Groningen, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universitat de Barcelona, Sergio, Abrignani, David, Adam, Melanie de, Almeida, Altucci, Lucia, Viren, Amin, Ido, Amit, Stylianos, E, Antonarakis, Samuel, Aparicio, Takahiro, Arima, Laura, Arrigoni, Rob, Art, Vahid, Asnafi, Manel, Esteller, Jae Bum, Bae, Kevin, Bassler, Stephan, Beck, Benjamin, Berkman, Bradley, E, Bernstein, Mikhail, Bilenky, Adrian, Bird, Christoph, Bock, Bernhard, Boehm, Guillaume, Bourque, Charles, E, Breeze, Benedikt, Bror, David, Bujold, Oliver, Burren, Marion, J, Bussemakers, Adam, Butterworth, Elias, Campo, Enrique Carrillo de Santa, Pau, Lisa, Chadwick, Kui Ming, Chan, Wei, Chen, Tom, H, Cheung, Luca, Chiapperino, Nak Hyen, Choi, Ho Ryun, Chung, Laura, Clarke, Joseph, M, Connors, Philippe, Cronet, John, Danesh, Manolis, Dermitzaki, Gerard, Drewe, Pawel, Durek, Stephanie, Dyke, Tomasz, Dylag, Connie, J, Eaves, Peter, Ebert, Roland, Eil, Jürgen, Eil, Catherine, A, Ennis, Tariq, Enver, Elise, A, Feingold, Bärbel, Felder, Anne Ferguson, Smith, Jude, Fitzgibbon, Paul, Flicek, Roger, S, Y, Foo, Peter, Fraser, Mattia, Frontini, Eileen, Furlong, Sitanshu, Gakkhar, Nina, Gasparoni, Gilles, Gasparoni, Daniel, H, Geschwind, Petar, Glažar, Thomas, Graf, Frank, Grosveld, Xin Yuan, Guan, Roderic, Guigo, Ivo, G, Gut, Alf, Hamann, Bok Ghee, Han, R, Alan, Harri, Simon, Heath, Kristian, Helin, Jan, G, Hengstler, Alireza Heravi, Moussavi, Karl, Herrup, Steven, Hill, Jason, A, Hilton, Benjamin, C, Hitz, Bernhard, Horsthemke, Ming, Hu, Joo Yeon, Hwang, Nancy, Y, Ip, Takashi, Ito, Biola Maria, Javierre, Sasa, Jenko, Thomas, Jenuwein, Yann, Joly, Steven, J, M, Jone, Yae, Kanai, Hee Gyung, Kang, Aly, Karsan, Alexandra, K, Kiemer, Song Cheol, Kim, Bong Jo, Kim, Hyeon Hoe, Kim, Hiroshi, Kimura, Sarah, Kinkley, Filippos, Klironomo, In Uk, Koh, Myrto, Kostadima, Christopher, Kressler, Roman, Kreuzhuber, Anshul, Kundaje, Ralf, Küpper, Carolyn, Larabell, Paul, Lasko, Mark, Lathrop, S, Lee, Suman, Lee, Hans, Lehrach, Elsa, Leitão, Thomas, Lengauer, Åke, Lernmark, David, Leslie, Gilberto, K, K, Leung, Danny, Leung, Markus, Loeffler, Yussanne, Ma, Antonello, Mai, Thomas, Manke, Eric, R, Marcotte, Marco, A, Marra, Joost, H, A, Marten, Jose Ignacio Martin, Subero, Karen, Maschke, Christoph, Merten, Aleksandar, Milosavljevic, Saverio, Minucci, Totai, Mitsuyama, Richard, A, Moore, Fabian, Müller, Andrew, J, Mungall, Mihai, G, Netea, Karl, Nordström, Irene, Norstedt, Hiroaki, Okae, Vitor, Onuchic, Francis, Ouellette, Willem, Ouwehand, Massimiliano, Pagani, Vera, Pancaldi, Thomas, Pap, Tomi, Pastinen, Ronak, Patel, Dirk, S, Paul, Michael, J, Pazin, Pier Giuseppe, Pelicci, Anthony, G, Phillips, Julia, Polansky, Bo, Porse, J, Andrew, Pospisilik, Shyam, Prabhakar, Dena, C, Procaccini, Andreas, Radbruch, Nikolaus, Rajewsky, Vardham, Rakyan, Wolf, Reik, Bing, Ren, David, Richardson, Andreas, Richter, Daniel, Rico, David, J, Roberts, Philip, Rosenstiel, Mark, Rothstein, Abdulrahman, Salhab, Hiroyuki, Sasaki, John, S, Satterlee, Sascha, Sauer, Claudia, Schacht, Florian, Schmidt, Gerd, Schmitz, Stefan, Schreiber, Christopher, Schröder, Dirk, Schübeler, Joachim, L, Schultze, Ronald, P, Schulyer, Marcel, Schulz, Martin, Seifert, Katsuhiko, Shirahige, Reiner, Siebert, Thomas, Sierocinski, Laura, Siminoff, Anupam, Sinha, Nicole, Soranzo, Salvatore, Spicuglia, Mikhail, Spivakov, Christian, Steidl, Seth, Strattan, Michael, Stratton, Peter, Südbeck, Hao, Sun, Narumi, Suzuki, Yutaka, Suzuki, Amos, Tanay, David, Torrent, Frederick, L, Tyson, Thomas, Ula, Sebastian, Ullrich, Toshikazu, Ushijima, Alfonso, Valencia, Edo, Vellenga, Martin, Vingron, Chris, Wallace, Stefan, Wallner, Jörn, Walter, Huating, Wang, Stephanie, Weber, Nina, Weiler, Andreas, Weller, Andrew, Weng, Steven, Wilder, Sam, M, Wiseman, Angela, R, Wu, Zhenguo, Wu, Jieyi, Xiong, Yasuhiro, Yamashita, Xinyi, Yang, Desmond, Y, Yap, Kevin, Y, Yip, Stephen, Yip, Jae Il, Yoo, Daniel, Zerbino, and Gideon, Zipprich

Subjects
Epigenomics, 0301 basic medicine, [SDV]Life Sciences [q-bio], ADN, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Medizin, Biology, Genoma humà, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, World Wide Web, 03 medical and health sciences, Human health, 0302 clinical medicine, Blueprint, Databases, Genetic, Humans, Disease, ddc:576.5, DNA methylation, databases, genetic, disease, histone code, humans, epigenesis, genetic, epigenomics, genome, human, biochemistry, genetics and molecular biology (all), Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Human genome, Genome, Human, DNA, Epigenome, DNA Methylation, Human cell, Epigenètica, Histone Code, 030104 developmental biology, 030220 oncology & carcinogenesis, Epigenetics
Abstract

Item does not contain fulltext The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic datasets to gain insights in the epigenetic control of cell states relevant for human health and disease. PAPERCLIP.

Published
2016

29. Differential DNA methylation of MSI2 and its correlation with diabetic traits

Author

Bok-Ghee Han, Suman Lee, Bong-Jo Kim, Nak-Hyun Choi, In-Uk Koh, and Jae-Pil Jeon

Subjects
0301 basic medicine, Male, endocrine system diseases, Physiology, Bisulfite sequencing, lcsh:Medicine, Biochemistry, Epigenesis, Genetic, Endocrinology, Medicine and Health Sciences, Glucose homeostasis, Insulin, Homeostasis, Longitudinal Studies, Prospective Studies, lcsh:Science, Multidisciplinary, DNA methylation, RNA-Binding Proteins, Methylation, Middle Aged, Chromatin, Blood Sugar, Body Fluids, Type 2 Diabetes, Nucleic acids, Blood, CpG site, Epigenetics, Female, Anatomy, DNA modification, Chromatin modification, Research Article, Chromosome biology, Adult, medicine.medical_specialty, Cell biology, Endocrine Disorders, Blood sugar, Biology, 03 medical and health sciences, Islets of Langerhans, Internal medicine, medicine, Genetics, Diabetes Mellitus, Humans, Aged, Diabetic Endocrinology, Biology and life sciences, lcsh:R, DNA, Glucose Tolerance Test, Hormones, 030104 developmental biology, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Metabolic Disorders, Hyperglycemia, Case-Control Studies, lcsh:Q, CpG Islands, Gene expression, Physiological Processes, Epigenetics of diabetes Type 2
Abstract

Differential DNA methylation with hyperglycemia is significantly associated with Type 2 Diabetes (T2D). Longtime extended exposure to high blood glucose levels can affect the epigenetic signatures in all organs. However, the relevance of the differential DNA methylation changes with hyperglycemia in blood with pancreatic islets remains unclear. We investigated differential DNA methylation in relation to glucose homeostasis based on the Oral Glucose Tolerance Test (OGTT) in a population-based cohort. We found a total of 382 differential methylation sites from blood DNA in hyperglycemia and type 2 diabetes subgroups using a longitudinal and cross-sectional approach. Among them, three CpG sites were overlapped; they were mapped to the MSI2 and CXXC4 genes. In a DNA methylation replication study done by pyrosequencing (n = 440), the CpG site of MSI2 were shown to have strong associations with the T2D group (p value = 2.20E-16). The differential methylation of MSI2 at chr17:55484635 was associated with diabetes-related traits, in particular with insulin sensitivity (QUICKI, p value = 2.20E-16) and resistance (HOMA-IR, p value = 1.177E-07). In human pancreatic islets, at the single-base resolution (using whole-genome bisulfite sequencing), the 292 CpG sites in the +/- 5kb at chr17: 55484635 were found to be significantly hypo-methylated in donors with T2D (average decrease = 13.91%, 95% confidence interval (CI) = 4.18 similar to 17.06) as compared to controls, and methylation patterns differed by sex (-9.57%, CI = -16.76 similar to -6.89) and age (0.12%, CI = -11.17 similar to 3.77). Differential methylation of the MSI2 gene (chr17: 55484635) in blood and islet cells is strongly related to hyperglycemia. Our findings suggest that epigenetic perturbation on the target site of MSI2 gene in circulating blood and pancreatic islets should represent or affect hyperglycemia.

Published
2017

30. Genome-Wide Association Study Meta-Analysis of Long Term Average Blood Pressure in East Asians

Author

Santhi K. Ganesh, E-Shyong Tai, Chieh Hsiang Lu, Jie Yao, Jia Yu Koh, Dongfeng Gu, Tanika N. Kelly, Tangchun Wu, Jer-Yuarn Wu, Neelam Kumari, DC Rao, Jinying Zhao, Sohee Han, Liang Sun, Xu Lin, Jerome I. Rotter, Ju Young Lee, Yun Kyoung Kim, Yao Hu, Walter Palmas, Meian He, Lixuan Gui, Kae-Woei Liang, Hua Hu, Chien-Hsiun Chen, Bong-Jo Kim, I-Te Lee, Xueling Sim, Rajkumar Dorajoo, Huaixing Li, Kent D. Taylor, Yik-Ying Teo, Jianjun Liu, Sanghoon Moon, Wayne H-H Sheu, Wen-Jane Lee, Bok-Ghee Han, Yingfeng Zheng, Yii-Der Ida Chen, Tien Yin Wong, Ching-Yu Cheng, Jiang He, Changwei Li, James E. Hixson, Yiqin Wang, Yunfeng He, Xiuqing Guo, Jing Chen, Leslie J. Raffel, and Fuu-Jen Tsai

Subjects
0301 basic medicine, Male, Mean arterial pressure, Locus (genetics), Genome-wide association study, Blood Pressure, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Asian People, Genetics, Humans, Gene, Genetics (clinical), Asia, Eastern, 030104 developmental biology, Blood pressure, Phenotype, CYP17A1, Genetic Loci, Meta-analysis, Female, ATP2B1, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background— Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP. Methods and Results— We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P −8 and 2.5×10 − 6 , respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P =5.03×10 − 8 , stage-2 P =8.64×10 − 3 , joint P =2.63×10 − 8 ) and mean arterial pressure (stage-1 P =3.59×10 − 9 , stage-2 P =2.35×10 − 2 , joint P =2.64×10 − 8 ). Three previously reported BP loci ( WBP1L , NT5C2 , and ATP2B1 ) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P =8.55×10 − 6 , stage-2 P =1.62×10 − 5 , joint P =3.28×10 − 9 ) and mean arterial pressure (stage-1 P =9.19×10 − 7 , stage-2 P =9.69×10 − 5 , joint P =2.15×10 − 9 ) phenotypes. Fourteen genes ( TMEM180 , ACTR1A , SUFU , ARL3 , SFXN2 , WBP1L , CYP17A1 , C10orf32 , C10orf32 - ASMT , AS3MT , CNNM2 , and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes ( P =1.27×10 − 4 and 3.30×10 − 4 , respectively). Conclusions— We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.

Published
2017

31. Mitochondrial DNA copy number augments performance of A1C and oral glucose tolerance testing in the prediction of type 2 diabetes

Author

Seong Beom Cho, Jae-Pil Jeon, Hong Kyu Lee, Hye-Young Nam, InSong Koh, and Bok-Ghee Han

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Mitochondrial DNA, DNA Copy Number Variations, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Bioinformatics, DNA, Mitochondrial, Sensitivity and Specificity, Article, Decision Support Techniques, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, medicine, Humans, Glycated Hemoglobin, Glucose tolerance test, Multidisciplinary, medicine.diagnostic_test, Glucose Tolerance Test, Middle Aged, medicine.disease, 030104 developmental biology, Blood pressure, Diabetes Mellitus, Type 2, Biomarker (medicine), Female, Hemoglobin, Body mass index, Follow-Up Studies
Abstract

Here, we tested the performance of the mitochondrial DNA copy number (mtDNA-CN) in predicting future type 2 diabetes (n = 1108). We used the baseline clinical data (age, sex, body mass index, waist-to-hip ratio, systolic and diastolic blood pressure) and the mtDNA-CN, hemoglobin A1c (A1C) levels and results of oral glucose tolerance test (OGTT) including fasting plasma glucose, 1-hour glucose, and 2-hour glucose levels, to predict future diabetes. We built a prediction model using the baseline data and the diabetes status at biannual follow-up of 8 years. The mean area under curve (AUC) for all follow-ups of the full model including all variables was 0.92 ± 0.04 (mean ± standard deviation), while that of the model excluding the mtDNA-CN was 0.90 ± 0.03. The sensitivity of the f4ull model was much greater than that of the model not including mtDNA-CN: the mean sensitivities of the model with and without mtDNA-CN were 0.60 ± 0.06 and 0.53 ± 0.04, respectively. We found that the mtDNA-CN of peripheral leukocytes is a biomarker that augments the predictive power for future diabetes of A1C and OGTT. We believe that these results could provide invaluable information for developing strategies for the management of diabetes.

Published
2017
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32. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author

Jing Hua Zhao, Hyung Jin Choi, Leslie J. Baier, Vilmundur Gudnason, Melina Claussnitzer, Jian Shen, Mary F. Feitosa, Melissa E. Garcia, Douglas P. Kiel, Murielle Bochud, Christian Gieger, L. B. Husted, Kristina Åkesson, Alan Hubbard, John-Olov Jansson, Jacqueline S. L. Kloth, Yanhua Zhou, Richard L. Prince, Angela Döring, H.-Erich Wichmann, Thomas Girke, Monica J. Hubal, Mark A. Tarnopolsky, Laura M. Yerges-Armstrong, Yi-Hsiang Hsu, Patricia A. Thompson, Mattias Lorentzon, Gudmar Thorleifsson, Wen-Chi Chou, Karin M. A. Swart, Tim D. Spector, Braxton D. Mitchell, Kim M. Huffman, Inês Barroso, Igor Rudan, William E. Kraus, Nicholas J. Wareham, Chan Soo Shin, Jaakko Tuomilehto, Gunnar Sigurdsson, Bok Ghee Han, Munro Peacock, Mao Fu, Unnur Thorsteinsdottir, Gregory Livshits, Laura J. Scott, Jane A. Cauley, Heikki A. Koistinen, Arjun Verma, Peggy M. Cawthon, Carrie M. Nielson, Aron S. Buchman, Aarno Palotie, Daniel S. Evans, Elisabeth Widen, Caroline Hayward, Frances M K Williams, Nam H. Cho, Peter Vollenweider, Liisa Byberg, Robert Luben, Veikko Salomaa, Alena Stančáková, Markus M. Lerch, Jian'an Luan, Eric P. Hoffman, Thomas Lang, Jari Lahti, Mike Erdos, Stephen C. J. Parker, Ida Malkin, Jaspal S. Kooner, Francis S. Collins, Claes Ohlsson, James F. Wilson, Ben A. Oostra, Carolina Medina-Gomez, Toby Johnson, Cornelia M. van Duijn, Joel Eriksson, Natalia Campos Obanda, Samuli Ripatti, Kay-Tee Khaw, Ryan P. Welch, Jeffrey R. O'Connell, Karl Michaëlsson, Erik Ingelsson, Elizabeth A. Streeten, Eric E. Schadt, Markus Perola, Albert V. Smith, Henna Cederberg, Ruth J. F. Loos, Michael J. Econs, Thomas Illig, Ingrid B. Borecki, Unnur Styrkarsdottir, Kari Stefansson, Anne B. Newman, Ozren Polasek, Weihua Zhang, Shad B. Smith, Wen Chi Hsueh, Serkalem Demissie, Najaf Amin, Simon Melov, Lenore J. Launer, Harald Grallert, E. Steinhagen-Thiessen, Jean Wactawski-Wende, Stuart H. Ralston, Leif Mosekilde, Liesbeth Vandenput, Zoltán Kutalik, Nicole L. Glazer, Teemu Kuulasmaa, Lisette Stolk, Johanna Kuusisto, Lei Yu, Steven R. Cummings, Cynthia A. Thomson, Harry Campbell, Mark Walker, Lars Lind, André G. Uitterlinden, Albert Hofman, Linda Broer, Vicky Ossowski, John C. Chambers, Jerome I. Rotter, Gregory J. Tranah, Östen Ljunggren, Tamara B. Harris, Ali A. Aghdassi, Nicole Soranzo, Jong-Young Lee, Bruce M. Psaty, Magnus Karlsson, Luda Diatchenko, Nicole C. Wright, A.W. Enneman, Cecilia M. Lindgren, Yongmei Liu, Sabine Schipf, Tian Liu, Annette Peters, Daniel L. Koller, Georg Homuth, Ilja Demuth, Andrew P. Morris, Jagvir Grewal, Katri Räikkönen, Markku Laakso, Tuomas O. Kilpeläinen, Michael Boehnke, Fernando Rivadeneira, David A. Bennett, Joban Sehmi, Gudny Eiriksdottir, Rainer Biffar, Till Ittermann, Natasja M. van Schoor, Michael N. Weedon, Zhao Chen, Norman Klopp, Antti Jula, Bente L. Langdahl, William Maixner, Håkan Melhus, Rosalie A. M. Dhonukshe-Rutten, Dan Mellström, Robert L. Hanson, M. Carola Zillikens, Janina S. Ried, David Karasik, Suzanne Satterfield, Stephen B. Kritchevsky, Henry Völzke, Karol Estrada, Thomas Meitinger, Sian Tsung Tan, John A Robbins, Dawn M. Waterworth, Lars Bertram, Fiona E. McGuigan, Philip L. De Jager, Youfang Liu, Emmi Tikkanen, Eric S. Orwoll, Weijia Xie, Joanne M. Jordan, Johan G. Eriksson, Joshua R. Lewis, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, School of Medicine / Clinical Medicine, Internal Medicine, Epidemiology, Clinical Genetics, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Luben, Robert [0000-0002-5088-6343], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Societal Participation & Health, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, Epidemiology and Data Science, APH - Personalized Medicine, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Department of Medicine, Endokrinologian yksikkö, Medicum, Department of Psychology and Logopedics, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Department of Medical and Clinical Genetics, Quantitative Genetics, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, and Genomic Discoveries and Clinical Translation

Subjects
0301 basic medicine, Medicin och hälsovetenskap, 17-Hydroxysteroid Dehydrogenases, General Physics and Astronomy, Physiology, Genome-wide association study, VARIANTS, Bioinformatics, Medical and Health Sciences, Genome-wide association studies, 0302 clinical medicine, ADAMTS Proteins, Versicans, Regulatory Elements, Transcriptional, GENE-EXPRESSION, INSULIN-RESISTANCE, Extracellular Matrix Proteins, Multidisciplinary, Aldehyde Oxidoreductases, Multidisciplinary Sciences, Phenotype, OBESITY, Body Composition, Science & Technology - Other Topics, Medical genetics, BONE-MINERAL DENSITY, PHYSICAL-DISABILITY, Bioelectrical impedance analysis, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, medicine.medical_specialty, Science, Quantitative Trait Loci, UNITED-STATES, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Biology, Predictive markers, Polymorphism, Single Nucleotide, SARCOPENIA, General Biochemistry, Genetics and Molecular Biology, SKELETAL-MUSCLE MASS, 03 medical and health sciences, Insulin resistance, Thinness, MD Multidisciplinary, Journal Article, medicine, Humans, Life Science, Erfðafræði, Human height, Science & Technology, predictive markers, General Chemistry, Rannsóknir, Líkamsvöxtur, Arfgengi, medicine.disease, Obesity, Onderwijsinstituut, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Sarcopenia, genome-wide association studies, Lean body mass, Insulin Receptor Substrate Proteins, gene expression, Gene expression, HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p, We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland’s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI’s Atherosclerosis Risk in Communities (ARIC) Study, and Iceland’s Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik): has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Old Order Amish (OOA): this work was supported by NIH research grants U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, and U01 HL084756. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488).). L.M.Y.-A. was supported by F32AR059469 from NIH/NIAMS. M.F. was supported by American Heart Association grant 10SDG2690004. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CoLaus: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). We thank Vincent Mooser and Gérard Waeber, Co-PIs of the CoLaus study. Special thanks to Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. Data analysis was supervised by Sven Bergmann and Jacques S. Beckmann. The computations for this paper were performed in part at the Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. The EPIC Study: The EPIC Obesity study is funded by Cancer Research United Kingdom and the Medical Research Council. I.B. acknowledges support from EU FP6 funding (contract no. LSHM-CT-2003-503041) and by the Wellcome Trust (WT098051). Erasmus Rucphen Family (ERF) Study: The study was supported by grants from The Netherlands Organisation for Scientific Research (NWO), Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. We are grateful to all general practitioners for their contributions, to Petra Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and Peter Snijders for his help in data collection. Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF—1333-00124 and Sapere Aude program grant DFF—1331-00730B). Framingham Osteoporosis Study (FOS)/Framingham Heart Study (FHS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and U24AG051129; D.P.K. and R01AR057118; D.K. D.K. was also supported by FP7-PEOPLE-2012-Marie Curie Career Integration Grants (CIG)). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, and the Göteborg Medical Society. We would like to thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015G for access to their grid resources. We also thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands for advice regarding the grid resources. Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG 041517 and M01 RR-00750. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Kora (KORA F3 and KORA F4): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The London Life Sciences Population (LOLIPOP): The study was funded by the British Heart Foundation, Wellcome Trust, the Medical Research Council, and Kidney Research UK. The study also receives support from a National Institute for Health Research (NIHR) programme grant. Rotterdam Study (RSI, RSII & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, PhD, for the creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Karol Estrada, Dr Fernando Rivadeneira, Dr Tobias A. Knoch, Anis Abuseiris, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP, and we thank BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015G) for access to their grid computing resources. Rush Memory and Aging Project (MAP): The Memory and Aging Project was supported by National Institute on Aging grants R01AG17917, R01AG15819, and R01AG24480, the Illinois Department of Public Health, the Rush Clinical Translational Science Consortium, and a gift from Ms Marsha Dowd. TwinsUK (TUK): The study was funded by the Wellcome Trust, Arthritis Research UK, and the Chronic Disease Research Foundation. The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff and volunteers of the TwinsUK study. The study was also supported by Israel Science Foundation, grant number 994/10. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Berlin Aging Study II (BASE-II) was supported by the German Federal Ministry of Education and Research (BMBF (grants #16SV5536K, #16SV5537, #16SV5538, and #16SV5837; previously #01UW0808)). Additional contributions (e.g., financial, equipment, logistics, personnel) are made from each of the other participating sites, i.e., the Max Planck Institute for Human Development (MPIB), Max Planck Institute for Molecular Genetics (MPIMG), Charite University Medicine, German Institute for Economic Research (DIW), all located in Berlin, Germany, and University of Lübeck in Lübeck, Germany. B-vitamins in the prevention of osteoporotic fractures (B-PROOF): B-PROOF is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam. All organizations are based in the Netherlands. We thank Dr Tobias A. Knoch, Anis Abuseiris, Karol Estrada, and Rob de Graaf as well as their institutions the Erasmus Grid Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology (grants #01 AK 803 A-H and #01 IG 07015G) for access to their gird resources. Further, we gratefully thank all participants. Calcium Intake Fracture Outcome Study (CAIFOS): This study was funded by Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grants (254627, 303169, and 572604). We are grateful to the participants of the CAIFOS Study. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship. Danish Osteoporosis Study (DOPS): The study was supported by Karen Elise Jensen foundation. Family Heart Study (FamHS): The study was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from NHLBI; and R01-DK-089256 and R01-DK-075681 from NIDDK. GenMets (Health 2000): S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. S.M. was supported by grants #136895 and #141005, V.S. by grants #139635 and 129494, and M.P. by grant #269517 from the Academy of Finland and a grant from the Finnish Foundation for Cardiovascular Research. M.P. was supported by the Yrjö Jahnsson Foundation. Helsinki Birth Cohort Study (HBCS): We thank all study participants as well as everybody involved in the HBCS. HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Samfundet Folkhälsann, Novo Nordisk Foundation, Liv och Hälsa, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). Johnston County Study: The Johnston County Osteoarthritis Project is supported in part by cooperative agreements S043, S1734, and S3486 from the Centers for Disease Control and Prevention/Association of Schools of Public Health; the NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant 5-P60-AR30701; and the NIAMS Multidisciplinary Clinical Research Center grant 5 P60 AR49465-03. Genotyping services were provided by Algynomics company. Korean Genome Epidemiology Study (KoGES): Korean Genome Epidemiology Study (KoGES): This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (found 2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00). Kora F3 and Kora F4: The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. LOLIP-REP-IA610: The study was supported by the Wellcome Trust. We thank the participants and research teams involved in LOLIPOP. LOLIP-REP-IA_I: The study was supported by the British Heart Foundation Grant SP/04/002. LOLIP-REP-IA_P: The study was supported by the British Heart Foundation Grant SP/04/002. METSIM: The study was supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and the EVO grant 5263 from the Kuopio University Hospital. MrOS Sweden: Financial support was received from the Swedish Research Council (2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Novo Nordisk foundation. Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. MrOS US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Orkney Complex Disease Study (ORCADES): ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK (17539) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PEAK 25: This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS): The study was supported by grants from the Swedish research council (projects 2008-2202 and 2005-8214) and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC): The RISC study is supported by European Union Grant QLG1-CT-2001-01252 and AstraZeneca. We thank Merck Research Labs for conducting DNA genotyping on RISC samples.Rotterdam III: Rotterdam Study (RS): See discovery. SHIP and SHIP TREND: This work was supported by SHIP, which is part of the Community Medicine Research Network of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens. A.G. and the Cache´ Campus program of the InterSystems GmbH. The SHIP authors are grateful to the contribution of Florian Ernst, Anja Wiechert, and Astrid Petersmann in generating the SNP data and to Mario Stanke for the opportunity to use his Server Cluster for SNP Imputation. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-1) and the Federal Ministry of Nutrition, Agriculture and Consumer’s Safety. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Uppsala Longitudinal Study of Adult Men (ULSAM): The study was funded by grants from the Swedish research council (projects 2008-2202 and 2005-8214), the Wallenberg foundation, and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, grant number WT098017. CROATIA-VIS (VIS): The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). We acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Women’s Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. FUSION: This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank all the subjects for participation and the study personnel for excellent technical assistance. The Pima Indian Study: This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA. Studies of a Targeted Risk Reduction Intervention with Defined Exercise (STRRIDE): This study was supported by the National Heart Lung and Blood Institute of the National Institutes of Health, HL57453 (WEK). Gene expression in old and young muscle biopsies: S.M. and T.G. were supported in part by NIH U24AG051129.

Published
2017

33. Genome-wide association study of electrocardiographic parameters identifies a new association for PR interval and confirms previously reported associations

Author

Bok-Ghee Han, Keiichi Fukuda, Yeonjung Kim, Motoaki Sano, Shigeo Kamitsuji, Naoyuki Kamatani, Yoshiyasu Aizawa, Jong Wook Kim, and Kyung-Won Hong

Subjects
Adult, Male, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, QT interval, Sodium-Calcium Exchanger, Electrocardiography, Mice, QRS complex, Asian People, Gene Frequency, Heart Conduction System, Genetics, Animals, Humans, SNP, PR interval, Molecular Biology, Alleles, Genetics (clinical), Aged, Genetic association, Mice, Knockout, General Medicine, Middle Aged, Minor allele frequency, Female, Gene Deletion, Genome-Wide Association Study
Abstract

Previous reports have described several associations of PR, QRS, QT and heart rate with genomic variations by genome-wide association studies (GWASs). In the present study, we examined the association of ∼2.5 million SNPs from 2994 Japanese healthy volunteers obtained from the JPDSC database with electrocardiographic parameters. We confirmed associations of PR interval, QRS duration and QT interval in individuals of Japanese ancestry with 11 of the 45 SNPs (6 of 20 for QT, 5 of 19 for PR and 0 of 6 for QRS) observed among individuals of European, African and Asian (Indian and Korean) ancestries. Those results indicate that many of the electrocardiographic associations with genes are shared by different ethnic groups including Japanese. Possible novel associations found in this study were validated by Korean data. As a result, we identified a novel association of SNP rs4952632[G] (maps near SLC8A1, sodium-calcium exchanger) (P = 7.595 × 10(-6)) with PR interval in Japanese individuals, and replication testing among Koreans confirmed the association of the same SNP with prolonged PR interval. Meta-analysis of the Japanese and Korean datasets demonstrated highly significant associations of SNP rs4952632[G] with a 2.325-ms (95% CI, 1.693-2.957 ms) longer PR interval per minor allele copy (P = 5.598 × 10(-13)). Cell-type-specific SLC8A1 knockout mice have demonstrated a regulatory role of sodium-calcium exchanger in automaticity and conduction in sinoatrial node, atrium and atrioventricular node. Our findings support a functional role of sodium-calcium exchanger in human atrial and atrioventricular nodal conduction as suggested by genetically modified mouse models.

Published
2014

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

Author

Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. 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Subjects
CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract

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

Published
2014

35. Multistage genome-wide association meta-analyses identified two new loci for bone mineral density

Author

Yong Jun Liu, Hyung Jin Choi, Richard Eastell, Han Yan, Matthew A. Brown, Ian R. Reid, Jian Li, Yan Fang Guo, Elizabeth A. Streeten, Qing Tian, Feng Zhang, Nam H. Cho, Xiao-Gang Liu, Eugene V. McCloskey, Li-Jun Tan, Yong Lin, Shu Ran, Shuyan Wu, Graeme Jones, Jong-Young Lee, Shuanglin Xiang, Li-Shu Zhang, Ji Gang Zhang, Philip N. Sambrook, Xue Zhen Zhu, Yin-Ping Zhang, Geoffrey C. Nicholson, Rong Hai, Laura M. Yerges-Armstrong, Christopher J. Papasian, Yingchun Zhao, Karol Estrada, Tian Hu, Yu-Fang Pei, Fei-Yan Deng, Patrick Danoy, Bok Ghee Han, Richard L. Prince, Yan Guo, H.-W. Deng, André G. Uitterlinden, Yao Zhong Liu, Yingying Han, Yuan Chen, Emma L. Duncan, Paul Leo, John A. Eisman, Chan Soo Shin, Elaine M. Dennison, Fernando Rivadeneira, Yu-Ping Wang, Hui Shen, Hong-Wen Deng, Tie-Lin Yang, Xiang-Ding Chen, Lei Zhang, Clinical Genetics, and Internal Medicine

Subjects
Male, Candidate gene, Bone density, Osteoporosis, Gene Expression, Osteoclasts, 030209 endocrinology & metabolism, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Bone and Bones, Bone remodeling, 03 medical and health sciences, 0302 clinical medicine, Bone Density, Osteogenesis, Genetics, medicine, Humans, Genetic Predisposition to Disease, Osteonectin, Molecular Biology, Genetics (clinical), Aged, 030304 developmental biology, Bone mineral, 0303 health sciences, Hip, Lumbar Vertebrae, Femur Neck, Association Studies Articles, General Medicine, Anatomy, Middle Aged, medicine.disease, Claudins, Female, Candidate Disease Gene, Genome-Wide Association Study
Abstract

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10−8) level: 14q24.2 (rs227425, P-value 3.98 × 10−13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10−9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

Published
2014

36. Network signatures of cellular immortalization in human lymphoblastoid cell lines

Author

Sung-Mi Shim, Jun-Woo Kim, Hye Ryun Kim, Hye-Young Nam, Mee-Hee Lee, Jae-Pil Jeon, So-Young Jung, and Bok-Ghee Han

Subjects
Cyclin-Dependent Kinase Inhibitor p21, In silico, Cell, Biophysics, Lymphocyte proliferation, Biology, Biochemistry, Transcriptome, Gene expression, microRNA, otorhinolaryngologic diseases, medicine, Humans, Gene Regulatory Networks, RNA, Messenger, Molecular Biology, Gene, Cell Line, Transformed, Genetics, Chromosomes, Human, X, Gene Expression Regulation, Leukemic, Cell growth, Cell Biology, Cell biology, MicroRNAs, stomatognathic diseases, medicine.anatomical_structure
Abstract

Highlights: •We identified network signatures of LCL immortalization from transcriptomic profiles. •More than 41% of DEGs are possibly regulated by miRNAs in LCLs. •MicroRNA target genes in LCLs are involved in apoptosis and immune-related functions. •This approach is useful to find functional miRNA targets in specific cell conditions. -- Abstract: Human lymphoblastoid cell line (LCL) has been used as an in vitro cell model in genetic and pharmacogenomic studies, as well as a good model for studying gene expression regulatory machinery using integrated genomic analyses. In this study, we aimed to identify biological networks of LCL immortalization from transcriptomic profiles of microRNAs and their target genes in LCLs. We first selected differentially expressed genes (DEGs) and microRNAs (DEmiRs) between early passage LCLs (eLCLs) and terminally differentiated late passage LCLs (tLCLs). The in silico and correlation analysis of these DEGs and DEmiRs revealed that 1098 DEG–DEmiR pairs were found to be positively (n = 591 pairs) or negatively (n = 507 pairs) correlated with each other. More than 41% of DEGs are possibly regulated by miRNAs in LCL immortalizations. The target DEGs of DEmiRs were enriched for cellular functions associated with apoptosis, immune response, cell death, JAK–STAT cascade and lymphocyte activationmore » while non-miRNA target DEGs were over-represented for basic cell metabolisms. The target DEGs correlated negatively with miR-548a-3p and miR-219-5p were significantly associated with protein kinase cascade, and the lymphocyte proliferation and apoptosis, respectively. In addition, the miR-106a and miR-424 clusters located in the X chromosome were enriched in DEmiR–mRNA pairs for LCL immortalization. In this study, the integrated transcriptomic analysis of LCLs could identify functional networks of biologically active microRNAs and their target genes involved in LCL immortalization.« less

Published
2013

37. Genome-Wide Association Study Meta-Analysis Reveals Transethnic Replication of Mean Arterial and Pulse Pressure Loci

Author

Satoshi Umemura, Mohammad Kamran Ikram, Linda S. Adair, Yong-Bing Xiang, Xin Gao, Jingwen Zhu, Tien Yin Wong, Ju Young Lee, Tanika N. Kelly, Dongfeng Gu, Jiang He, Min Jin Go, Ying Wu, Yoshikuni Kita, Peng Chen, Nanette R. Lee, Miki Tetsuro, Yik Ying Teo, Dabeeru C. Rao, Young-Jin Kim, Hao Peng, Yiqin Wang, Aili Wang, Eitaro Nakashima, Changwei Li, Qiuyin Cai, James E. Hixson, E. Shyong Tai, Ling Lu, Yonghong Zhang, Yu Tang Gao, Wei Zheng, Shihiu Zhang, Todd L. Edwards, Jong-Young Lee, Yasuharu Tabara, Toru Nabika, Chien Hsiun Chen, Fuu Jen Tsai, Bok Ghee Han, Jer-Yuarn Wu, Yoon Shin Cho, Norihiro Kato, Myeong Chan Cho, Nam Hee Kim, Xu Lin, Ching-Yu Cheng, Huaixing Li, Qi Zhao, Karen L. Mohlke, Xiao-Ou Shu, Hui Cai, Li Ching Chang, Chi Fan Yang, Fumihiko Takeuchi, Takayoshi Ohkubo, Tomohiro Katsuya, Virology, Obstetrics & Gynecology, Epidemiology, Ophthalmology, and Neurology

Subjects
Adult, Male, Mean arterial pressure, Population, Blood Pressure, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Asian People, Polymorphism (computer science), Statistical significance, Replication (statistics), Internal Medicine, Humans, Arterial Pressure, Genetic Predisposition to Disease, education, Genetics, education.field_of_study, Pulse pressure, Blood pressure, Genetic Loci, Hypertension, Female, Genome-Wide Association Study
Abstract

We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26 600 East Asian participants (stage 1) followed by replication study of up to 28 783 participants (stage 2). For novel loci, statistical significance was determined by a P –8 in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P –3 . No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 ( P =7.5×10 –15 ), rs2681492 at ATP2B1 ( P =3.4×10 –7 ), rs11191593 at NT5C2 (1.1×10 –6 ), rs3824755 at CYP17A1 ( P =1.2×10 –6 ), and rs13149993 at FGF5 ( P =2.4×10 –4 ). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P MAP4 ( P =0.014) and rs1173771 at NPR3 ( P =0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 ( P =1.2×10 –5 ) and rs11191593 at NT5C2 ( P =1.1×10 –3 ), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 ( P =6.1×10 –3 ) and rs2681492 at ATP2B1 ( P =9.0×10 –3 ). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.

Published
2013

38. Replication of Caucasian loci associated with bone mineral density in Koreans

Author

Bok Ghee Han, Jeoung-Gil Lee, Hyung Jin Choi, Chan Soo Shin, Ye An Kim, and Nam H. Cho

Subjects
Genetic Markers, Male, musculoskeletal diseases, Genotyping Techniques, Bone density, Endocrinology, Diabetes and Metabolism, Population, Osteoporosis, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, White People, Cohort Studies, Asian People, Bone Density, Polymorphism (computer science), medicine, Humans, Genetic Predisposition to Disease, education, Aged, Genetic association, Bone mineral, Genetics, Sex Characteristics, education.field_of_study, Lumbar Vertebrae, Femur Neck, business.industry, musculoskeletal, neural, and ocular physiology, Middle Aged, musculoskeletal system, medicine.disease, Genetic Loci, Female, Hip Joint, business, Genome-Wide Association Study
Abstract

Most bone mineral density (BMD) loci were reported in Caucasian genome-wide association studies (GWAS). This study investigated the association between 59 known BMD loci (+200 suggestive SNPs) and DXA-derived BMD in East Asian population with respect to sex and site specificity. We also identified four novel BMD candidate loci from the suggestive SNPs.Most GWAS have reported BMD-related variations in Caucasian populations. This study investigates whether the BMD loci discovered in Caucasian GWAS are also associated with BMD in East Asian ethnic samples.A total of 2,729 unrelated Korean individuals from a population-based cohort were analyzed. We selected 747 single-nucleotide polymorphisms (SNPs). These markers included 547 SNPs from 59 loci with genome-wide significance (GWS, p value less than 5 × 10(-8)) levels and 200 suggestive SNPs that showed weaker BMD association with p value less than 5 × 10(-5). After quality control, 535 GWS SNPs and 182 suggestive SNPs were included in the replication analysis.Of the 535 GWS SNPs, 276 from 25 loci were replicated (p 0.05) in the Korean population with 51.6 % replication rate. Of the 182 suggestive variants, 16 were replicated (p 0.05, 8.8 % of replication rate), and five reached a significant combined p value (less than 7.0 × 10(-5), 0.05/717 SNPs, corrected for multiple testing). Two markers (rs11711157, rs3732477) are for the same signal near the gene CPN2 (carboxypeptidase N, polypeptide 2). The other variants, rs6436440 and rs2291296, were located in the genes AP1S3 (adaptor-related protein complex 1, sigma 3 subunit) and RARB (retinoic acid receptor, beta).Our results illustrate ethnic differences in BMD susceptibility genes and underscore the need for further genetic studies in each ethnic group. We were also able to replicate some SNPs with suggestive associations. These SNPs may be BMD-related genetic markers and should be further investigated.

Published
2013

39. New susceptibility loci in MYL2, C12orf51 and OAS1 associated with 1-h plasma glucose as predisposing risk factors for type 2 diabetes in the Korean population

Author

Bok-Ghee Han, Myeong Chan Cho, Young-Jin Kim, Yoon Shin Cho, Joo-Yeon Hwang, Ju Young Lee, Jong-Young Lee, Bong-Jo Kim, Soo Heon Kwak, Yeonjung Kim, Ji Hee Oh, Min Jin Go, and Kyung Soo Park

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Myosin Light Chains, Genotype, Ubiquitin-Protein Ligases, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Asian People, Pregnancy, Risk Factors, Internal medicine, Republic of Korea, Genetic variation, 2',5'-Oligoadenylate Synthetase, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Risk factor, Genetics (clinical), Aged, Genetic association, Glycemic, Fasting, Glucose Tolerance Test, Middle Aged, medicine.disease, Gestational diabetes, Diabetes, Gestational, Endocrinology, Diabetes Mellitus, Type 2, Genetic Loci, Hyperglycemia, Linear Models, Female, Cardiac Myosins, Genome-Wide Association Study
Abstract

Most recently, 1-h hyperglycemia has been recognized as an additional risk factor for type 2 diabetes. To date, previous genome-wide association studies for glycemic traits have a limited impact on the fasting state and 2-h plasma glucose level in an oral glucose challenge. To identify genetic susceptibility in different stages of glucose tolerance, we performed a meta-analysis for glycemic traits including 1-h plasma glucose (1-hPG) from 14 232 non-diabetic individuals in the Korean population. Newly implicated variants (MYL2, C12orf51 and OAS1) were found to be significantly associated with 1-hPG. We also demonstrated associations with gestational diabetes mellitus. Our results could provide additional insight into the genetic variation in the clinical range of glycemia.

Published
2013

40. Identification of Clinical Biomarkers for Pre-Analytical Quality Control of Blood Samples

Author

Ji Young Yun, Jun-Woo Kim, Bok Ghee Han, Hyun Ju Kang, Mee-Hee Lee, Soon Young Jeon, Won Kyung Hong, Jae-Pil Jeon, Jae-Sun Park, and Han Na Kil

Subjects
Adult, Male, Quality Control, Serum, media_common.quotation_subject, Medicine (miscellaneous), Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, Freezing, Humans, Quality (business), media_common, Cryopreservation, Blood Specimen Collection, Reproducibility, Pre analytical, Original Articles, Cell Biology, General Medicine, Middle Aged, Identification (information), Key factors, Immunology, Regression Analysis, Biomarker (medicine), Female, human activities, Biomarkers
Abstract

Pre-analytical conditions are key factors in maintaining the high quality of biospecimens. They are necessary for accurate reproducibility of experiments in the field of biomarker discovery as well as achieving optimal specificity of laboratory tests for clinical diagnosis. In research at the National Biobank of Korea, we evaluated the impact of pre-analytical conditions on the stability of biobanked blood samples by measuring biochemical analytes commonly used in clinical laboratory tests.We measured 10 routine laboratory analytes in serum and plasma samples from healthy donors (n = 50) with a chemistry autoanalyzer (Hitachi 7600-110). The analyte measurements were made at different time courses based on delay of blood fractionation, freezing delay of fractionated serum and plasma samples, and at different cycles (0, 1, 3, 6, 9) of freeze-thawing. Statistically significant changes from the reference sample mean were determined using the repeated-measures ANOVA and the significant change limit (SCL).The serum levels of GGT and LDH were changed significantly depending on both the time interval between blood collection and fractionation and the time interval between fractionation and freezing of serum and plasma samples. The glucose level was most sensitive only to the elapsed time between blood collection and centrifugation for blood fractionation. Based on these findings, a simple formula (glucose decrease by 1.387 mg/dL per hour) was derived to estimate the length of time delay after blood collection. In addition, AST, BUN, GGT, and LDH showed sensitive responses to repeated freeze-thaw cycles of serum and plasma samples.These results suggest that GGT and LDH measurements can be used as quality control markers for certain pre-analytical conditions (eg, delayed processing or repeated freeze-thawing) of blood samples which are either directly used in the laboratory tests or stored for future research in the biobank.

Published
2013

41. Effect of glucose ingestion in plasma markers of inflammation and oxidative stress: Analysis of 16 plasma markers from oral glucose tolerance test samples of normal and diabetic patients

Author

Bok Ghee Han, Jae Pil Jeon, Seung Eun Jung, Hyun Ju Kang, Jun Woo Kim, Soon Young Jeon, Won Kyung Hong, and Hyung Jin Choi

Subjects
Blood Glucose, Leptin, Male, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Inflammation, medicine.disease_cause, Endocrinology, Diabetes mellitus, Internal medicine, Diabetes Mellitus, Internal Medicine, medicine, Humans, Interleukin 6, Chemokine CCL2, Aged, Chemokine CCL22, Retinol binding protein 4, biology, Interleukin-6, business.industry, C-reactive protein, nutritional and metabolic diseases, Ribonuclease, Pancreatic, General Medicine, Glucose Tolerance Test, Middle Aged, medicine.disease, carbohydrates (lipids), Oxidative Stress, C-Reactive Protein, Glucose, Cytokine, biology.protein, Female, Osteopontin, medicine.symptom, business, Retinol-Binding Proteins, Plasma, Biomarkers, hormones, hormone substitutes, and hormone antagonists, Oxidative stress
Abstract

Sixteen plasma markers of inflammation and oxidative stress were measured during OGTT in 54 subjects. Leptin, RBP4, CRP, OPN, ANG, MDC, and MCSF concentrations significantly decreased during OGTT (P0.05). IL6, IL8, and MCP3 concentrations significantly increased during OGTT (P0.05). These results provide evidence that glucose ingestion affects systemic inflammation and oxidative stress.

Published
2013

42. A genome-wide association study of a coronary artery disease risk variant

Author

Ji-Young Lee, Bok-Soo Lee, Dong-Jik Shin, Kyung Woo Park, Young-Ah Shin, Kwang Joong Kim, Lyong Heo, Ji Young Lee, Yun Kyoung Kim, Young Jin Kim, Chang Bum Hong, Sang-Hak Lee, Dankyu Yoon, Hyo Jung Ku, Il-Young Oh, Bong-Jo Kim, Juyoung Lee, Seon-Joo Park, Jimin Kim, Hye-kyung Kawk, Jong-Eun Lee, Hye-kyung Park, Jae-Eun Lee, Hye-young Nam, Hyun-young Park, Chol Shin, Mitsuhiro Yokota, Hiroyuki Asano, Masahiro Nakatochi, Tatsuaki Matsubara, Hidetoshi Kitajima, Ken Yamamoto, Hyung-Lae Kim, Bok-Ghee Han, Myeong-Chan Cho, Yangsoo Jang, Hyo-Soo Kim, Jeong Euy Park, and Jong-Young Lee

Subjects
Adult, Male, Genotyping Techniques, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, Polymorphism, Single Nucleotide, Asian People, Risk Factors, Genetics, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Genetics (clinical), Aged, Genetic association, Genome, Human, Middle Aged, Tag SNP, Genetic Loci, Case-Control Studies, Female, Imputation (genetics), Genome-Wide Association Study, SNP array
Abstract

Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. To maximize the coverage of the genome, imputation was performed based on 1000 Genome JPT+CHB and 5.1 million SNPs were retained. CAD association was replicated for three GWAS-identified loci (1p13.3/SORT1 (rs599839), 9p21.3/CDKN2A/2B (rs4977574), and 11q22.3/ PDGFD (rs974819)) in Koreans. From GWAS and a replication, SNP rs3782889 showed a strong association (combined P=3.95 × 10(-14)), although the association of SNP rs3782889 doesn't remain statistically significant after adjusting for SNP rs11066015 (proxy SNP with BRAP (r(2)=1)). But new possible CAD-associated variant was observed for rs9508025 (FLT1), even though its statistical significance did marginally reach at the genome-wide a significance level (combined P=6.07 × 10(-7)). This study shows that three CAD susceptibility loci, which were previously identified in European can be directly replicated in Koreans and also provides additional evidences implicating suggestive loci as risk variants for CAD in East Asian.

Published
2013

43. Meta-analysis identifies aMECOMgene as a novel predisposing factor of osteoporotic fracture

Author

Joo Yeon Hwang, Ji Young Yun, Lee Jong Young, Min Hye Lee, Myeong Chan Cho, Ho Young Son, Young Ah Kang, Heejo Koo, Hong-Wen Deng, Ghi Su Kim, Shin Yoon Kim, Yoon Shin Cho, Moo Il Kang, Seung Hun Lee, Shiro Ikegawa, Bok Ghee Han, Min Jin Go, Ki Won Oh, Beom-Jun Kim, Soumya Raychaudhuri, My Jung Cha, Sang-Wook Kim, Hye Sook Yoo, Ikuyo Kou, Jung Min Koh, Ji Hee Oh, Dong Joon Kim, Yan Guo, Young Jin Kim, Eun Hee Cho, Youngdoe Kim, and Sanghoon Moon

Subjects
medicine.medical_specialty, Genotype, MECOM, Quantitative Trait Loci, Population, Locus (genetics), Genome-wide association study, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Osteogenesis, Molecular genetics, Proto-Oncogenes, Genetics, medicine, Humans, Genetic Predisposition to Disease, education, Genetics (clinical), Aged, education.field_of_study, Case-control study, Middle Aged, MDS1 and EVI1 Complex Locus Protein, DNA-Binding Proteins, Gene Expression Regulation, Case-Control Studies, Gene Knockdown Techniques, Meta-analysis, Cohort, Osteoporosis, Osteoporotic Fractures, Genome-Wide Association Study, Transcription Factors
Abstract

Background Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population. Methods Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study. Results In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF ( rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10 −8 ; OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis. Conclusions Our findings provide new insights into the genetic architecture underlying OF in East Asians.

Published
2013

44. Human transcriptome analysis of acute responses to glucose ingestion reveals the role of leukocytes in hyperglycemia-induced inflammation

Author

Hyung Jin Choi, So Young Jung, Hyo Jeong Ban, Hye Sun Yun, Hye Young Nam, Yeonjung Kim, Bok Ghee Han, Jae Pil Jeon, Eun Jung Hong, Hyun Ju Kang, and Seung Eun Jung

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Physiology, medicine.medical_treatment, Inflammation, Biology, Real-Time Polymerase Chain Reaction, Transcriptome, Pathogenesis, Immunity, Diabetes mellitus, Internal medicine, Gene expression, Leukocytes, Genetics, medicine, Humans, Insulin, Cells, Cultured, Aged, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Models, Genetic, Gene Expression Profiling, Reproducibility of Results, Feeding Behavior, Middle Aged, medicine.disease, Glucose, Endocrinology, Gene Expression Regulation, Hyperglycemia, Immunology, Female, medicine.symptom
Abstract

Glucose ingestion-induced hyperglycemia has been known to induce inflammation, which is related to the pathogenesis of diabetic complications. To examine acute gene expression responses to physiological oral glucose ingestion in human circulating leukocytes, we conducted a microarray study of human circulating leukocytes sampled before, 1 h after, and 2 h after glucose ingestion in community-based participants without previous histories of diabetes ( n = 60). Ingestion of 75 g glucose successfully induced acute hyperglycemia (glucose concentration 91.6 ± 5.3 mg/dl for fasting and 180.7 ± 48.5 mg/dl for 1 h after glucose ingestion). Oral glucose ingestion significantly increased the expressions of 23 genes and decreased the expressions of 13 genes [false discovery rate (FDR) P value

Published
2012

45. Identification of putative biomarkers for type 2 diabetes using metabolomics in the Korea Association REsource (KARE) cohort

Author

Tao Xu, Yeon Jung Kim, Young Ho Lee, Karsten Suhre, Bong Jo Kim, Jerzy Adamski, Jeongmin Kim, Annette Peters, Moonsuk Nam, Wolfgang Rathmann, Rui Wang-Sattler, Nam Hee Kim, Bok Ghee Han, Kwang Youl Kim, Sang Yun Cho, and Heun Sik Lee

Subjects
0301 basic medicine, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Metabolite, Clinical Biochemistry, 030209 endocrinology & metabolism, Genome-wide association study, Type 2 diabetes, Biology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, symbols.namesake, 0302 clinical medicine, Metabolomics, medicine, Genetics, nutritional and metabolic diseases, medicine.disease, 030104 developmental biology, Bonferroni correction, chemistry, Multiple comparisons problem, Cohort, symbols, Cohort study
Abstract

Type 2 diabetes (T2D) is a multifactorial disease resulting from a complex interaction between environmental and genetic risk factors. Metabolomics provide a logical framework that reflects the functional endpoints of biological processes being triggered by genetic information and various external influences. Identification of metabolite biomarkers can shed insight into etiological pathways and improve the prediction of disease risk. Here, we aimed to identify serum metabolites as putative biomarkers for T2D and their association with genetic variants in the Korean population. A targeted metabolomics approach was employed to quantify serum metabolites for 2240 participants in the Korea Association REsource (KARE) cohort. T2D-related metabolites were identified by statistical methods including multivariable linear and logistic regression, and were independently replicated in the Cooperative Health Research in the Region of Augsburg (KORA) cohort. Additionally, by combining a genome wide association study (GWAS) with metabolomics, genetic variants associated with the identified T2D-related metabolites were uncovered. 123 metabolites were quantified from fasting serum samples and four metabolites, hexadecanoylcarnitine (C16), glycine, lysophosphatidylcholine acyl C18:2 (lysoPC a C18:2), and phosphatidylcholine acyl-alkyl C36:0 (PC ae C36:0), were significantly altered in T2D compared to non-T2D subjects (after the Bonferroni correction for multiple testing with P

Published
2016

46. Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference

Author

Dabeeru C. Rao, Mitsuhiro Yokota, Yoon Shin Cho, Chien-Hsiun Chen, Tangchun Wu, Joo Yeon Hwang, Juyoung Lee, Dmitry Shungin, Bo Youl Choi, Xingwang Ye, Masahiro Nakatochi, Karen L. Mohlke, Matthew A. Allison, Tetsuro Miki, Jiajun Shi, Wei Zheng, Yong-Bing Xiang, Zengnan Mo, Xu Lin, Yoshikuni Kita, Jer-Yuarn Wu, Jun Liang, Tao Huang, Dongxin Lin, Sanghoon Moon, Meian He, Sun Ha Jee, Shengxu Li, Linda S. Adair, Lu Qi, Qiuyin Cai, James E. Hixson, Jae Woong Sull, Jiang He, Min Jin Go, Yanling Hu, Xingyi Guo, Masato Isono, Keum Ji Jung, Jianjun Liu, E. Shyong Tai, Yan Zheng, Nanette R. Lee, Aihua Tan, Jeannette Lee, Xiaomin Zhang, Fuu Jen Tsai, Ken Yamamoto, Norihiro Kato, Soriul Kim, Koichi Akiyama, Rajkumar Dorajoo, Young Jin Kim, Ying Wu, Daehee Kang, Jie Yao, Hirotsugu Ueshima, Jerome I. Rotter, Xiaobo Yang, Li Ching Chang, Keizo Ohnaka, Huaixing Li, Bok Ghee Han, Yuan-Tsong Chen, Jirong Long, Xiuqing Guo, Dongfeng Gu, Yasuharu Tabara, Bong Jo Kim, Yiqin Wang, Chen Wu, Yasuyuki Nakamura, Xiao-Ou Shu, Wanqing Wen, Yu Tang Gao, and Fumihiko Takeuchi

Subjects
Male, 0301 basic medicine, Genome-wide association study, 030105 genetics & heredity, Cardiovascular, Waist–hip ratio, 2.1 Biological and endogenous factors, Aetiology, 10. No inequality, Abdominal obesity, 2. Zero hunger, Genetics, Multidisciplinary, Public Health, Global Health, Social Medicine and Epidemiology, Single Nucleotide, Other Physical Sciences, Female, Waist Circumference, medicine.symptom, Asian Continental Ancestry Group, Asia, Waist, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, abdominal obesity, Quantitative Trait, 03 medical and health sciences, Quantitative Trait, Heritable, Sex Factors, Asian People, Clinical Research, medicine, Humans, Genetic Predisposition to Disease, Obesity, Polymorphism, Heritable, Waist-Hip Ratio, nutritional and metabolic diseases, genetic loci, medicine.disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 030104 developmental biology, Biochemistry and Cell Biology, Body mass index, Genome-Wide Association Study
Abstract

Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2 and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI and three loci near the CEP120, TSC22D2 and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.

Published
2016

47. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. Scott, Mika Kähönen, Peter Schwarz, Psychiatry, EMGO - Mental health, Pattaro, Cristian, Teumer, Alexander, Gorski, Mathia, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Li, Yong, Taliun, Daniel, Olden, Matthia, Foster, Meredith, Yang, Qiong, Chen, Ming Huei, Pers, Tune H., Johnson, Andrew D., Ko, Yi An, Fuchsberger, Christian, Tayo, Bamidele, Nalls, Michael, Feitosa, Mary F., Isaacs, Aaron, Dehghan, Abba, D'Adamo, ADAMO PIO, Adeyemo, Adebowale, Dieffenbach, Aida Karina, Zonderman, Alan B., Nolte, Ilja M., Van Der Most, Peter J., Wright, Alan F., Shuldiner, Alan R., Morrison, Alanna C., Hofman, Albert, Smith, Albert V., Dreisbach, Albert W., Franke, Andre, Uitterlinden, Andre G., Metspalu, Andre, Tonjes, Anke, Lupo, Antonio, Robino, Antonietta, Johansson, Åsa, Demirkan, Ayse, Kollerits, Barbara, Freedman, Barry I., Ponte, Belen, Oostra, Ben A., Paulweber, Bernhard, Krämer, Bernhard K., Mitchell, Braxton D., Buckley, Brendan M., Peralta, Carmen A., Hayward, Caroline, Helmer, Catherine, Rotimi, Charles N., Shaffer, Christian M., Müller, Christian, Sala, Cinzia, Van Duijn, Cornelia M., Saint Pierre, Aude, Ackermann, Daniel, Shriner, Daniel, Ruggiero, Daniela, Toniolo, Daniela, Lu, Yingchang, Cusi, Daniele, Czamara, Darina, Ellinghaus, David, Siscovick, David S., Ruderfer, Dougla, Gieger, Christian, Grallert, Harald, Rochtchina, Elena, Atkinson, Elizabeth J., Holliday, Elizabeth G., Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Murgia, Federico, Rivadeneira, Fernando, Ernst, Florian, Kronenberg, Florian, Hu, Frank B., Navis, Gerjan J., Curhan, Gary C., Ehret, George B., Homuth, Georg, Coassin, Stefan, Thun, Gian Andri, Pistis, Giorgio, Gambaro, Giovanni, Malerba, Giovanni, Montgomery, Grant W., Eiriksdottir, Gudny, Jacobs, Gunnar, Li, Guo, Wichmann, H. Erich, Campbell, Harry, Schmidt, Helena, Wallaschofski, Henri, Völzke, Henry, Brenner, Hermann, Kroemer, Heyo K., Kramer, Holly, Lin, Honghuang, Leach, I. Mateo, Ford, Ian, Guessous, Idri, Rudan, Igor, Prokopenko, Inga, Borecki, Ingrid, Heid, Iris M., Kolcic, Ivana, Persico, Ivana, Jukema, J. Wouter, Wilson, James F., Felix, Janine F., Divers, Jasmin, Lambert, Jean Charle, Stafford, Jeanette M., Gaspoz, Jean Michel, Smith, Jennifer A., Faul, Jessica D., Wang, Jie Jin, Ding, Jingzhong, Hirschhorn, Joel N., Attia, John, Whitfield, John B., Chalmers, John, Viikari, Jorma, Coresh, Josef, Denny, Joshua C., Karjalainen, Juha, Fernandes, Jyotika K., Endlich, Karlhan, Butterbach, Katja, Keene, Keith L., Lohman, Kurt, Portas, Laura, Launer, Lenore J., Lyytikäinen, Leo Pekka, Yengo, Loic, Franke, Lude, Ferrucci, Luigi, Rose, Lynda M., Kedenko, Lyudmyla, Rao, Madhumathi, Struchalin, Maksim, Kleber, Marcus E., Cavalieri, Margherita, Haun, Margot, Cornelis, Marilyn C., Ciullo, Marina, Pirastu, Mario, De Andrade, Mariza, Mcevoy, Mark A., Woodward, Mark, Adam, Martin, Cocca, Massimiliano, Nauck, Matthia, Imboden, Medea, Waldenberger, Melanie, Pruijm, Menno, Metzger, Marie, Stumvoll, Michael, Evans, Michele K., Sale, Michele M., Kähönen, Mika, Boban, Mladen, Bochud, Murielle, Rheinberger, Myriam, Verweij, Niek, Bouatia Naji, Nabila, Martin, Nicholas G., Hastie, Nick, Probst Hensch, Nicole, Soranzo, Nicole, Devuyst, Olivier, Raitakari, Olli, Gottesman, Omri, Franco, Oscar H., Polasek, Ozren, Gasparini, Paolo, Munroe, Patricia B., Ridker, Paul M., Mitchell, Paul, Muntner, Paul, Meisinger, Christa, Smit, Johannes H., Abecasis, Goncalo R., Adair, Linda S., Alexander, Myriam, Altshuler, David, Amin, Najaf, Arking, Dan E., Arora, Pankaj, Aulchenko, Yurii, Bakker, Stephan J. 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Gerald R., Fox, Ervin R., Frayling, Timothy M., Galan, Pilar, Ganesh, Santhi K., Garcia, Melissa, Gaunt, Tom R., Glazer, Nicole L., Go, Min Jin, Goel, Anuj, Grässler, Jürgen, Grobbee, Diederick E., Groop, Leif, Guarrera, Simonetta, Guo, Xiuqing, Hadley, David, Hamsten, Ander, Han, Bok Ghee, Hardy, Rebecca, Hartikainen, Anna Liisa, Heath, Simon, Heckbert, Susan R., Hedblad, Bo, Hercberg, Serge, Hernandez, Dena, Hicks, Andrew A., Hilton, Gina, Hingorani, Aroon D., Hoffman Bolton, Judith A., Hopewell, Jemma C., Howard, Philip, Humphries, Steve E., Hunt, Steven C., Hveem, Kristian, Ikram, M. Arfan, Islam, Muhammad, Iwai, Naoharu, Jarvelin, Marjo Riitta, Jackson, Anne U., Jafar, Tazeen H., Janipalli, Charles S., Johnson, Toby, Kathiresan, Sekar, Khaw, Kay Tee, Kim, Hyung Lae, Kinra, Sanjay, Kita, Yoshikuni, Kivimaki, Mika, Kooner, Jaspal S., Kumar, M. J. Kranthi, Kuh, Diana, Kulkarni, Smita R., Kumari, Meena, Kuusisto, Johanna, Kuznetsova, Tatiana, Laakso, Markku, Laan, Mari, Laitinen, Jaana, Lakatta, Edward G., Langefeld, Carl D., Larson, Martin G., Lathrop, Mark, Lawlor, Debbie A., Lawrence, Robert W., Lee, Jong Young, Lee, Nanette R., Levy, Daniel, Li, Yali, Longstreth, Will T., Luan, Jian'An, Lucas, Gavin, Ludwig, Barbara, Mangino, Massimo, Mani, K. Radha, Marmot, Michael G., Mattace Raso, Francesco U. S., Matullo, Giuseppe, Mcardle, Wendy L., Mckenzie, Colin A., Meitinger, Thoma, Melander, Olle, Meneton, Pierre, Meschia, James F., Miki, Tetsuro, Milaneschi, Yuri, Mohlke, Karen L., Mooser, Vincent, Morken, Mario A., Morris, Richard W., Mosley, Thomas H., Najjar, Samer, Narisu, Narisu, Newton Cheh, Christopher, Nguyen, Khanh Dung Hoang, Nilsson, Peter, Nyberg, Fredrik, O'Donnell, Christopher J., Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ong, Rick Twee Hee, Ongen, Halit, Onland Moret, N. Charlotte, O'Reilly, Paul F., Org, Elin, Orru, Marco, Palmas, Walter, Palmen, Jutta, Palmer, Lyle J., Palmer, Nicholette D., Parker, Alex N., Peden, John F., Peltonen, Leena, Perola, Marku, Pihur, Vasyl, Platou, Carl G. P., Plump, Andrew, Prabhakaran, Dorairajan, Psaty, Bruce M., Raffel, Leslie J., Rao, Dabeeru C., Rasheed, Asif, Ricceri, Fulvio, Rice, Kenneth M., Rosengren, Annika, Rotter, Jerome I., Rudock, Megan E., Sõber, Siim, Salako, Tunde, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schwartz, Steven M., Schwarz, Peter E. H., Scott, Laura J., Scott, Jame, Scuteri, Angelo, Sehmi, Joban S., Seielstad, Mark, Seshadri, Sudha, Sharma, Pankaj, Shaw Hawkins, Sue, Shi, Gang, Shrine, Nick R. G., Sijbrands, Eric J. G., Sim, Xueling, Singleton, Andrew, Sjögren, Marketa, Smith, Nicholas L., Artigas, Maria Soler, Spector, Tim D., Staessen, Jan A., Stancakova, Alena, Steinle, Nanette I., Strachan, David P., Stringham, Heather M., Sun, Yan V., Swift, Amy J., Tabara, Yasuharu, Tai, E. Shyong, Talmud, Philippa J., Taylor, Andrew, Terzic, Jano, Thelle, Dag S., Tobin, Martin D., Tomaszewski, Maciej, Tripathy, Vikal, Tuomilehto, Jaakko, Tzoulaki, Ioanna, Uda, Manuela, Ueshima, Hirotsugu, Uiterwaal, Cuno S. P. M., Umemura, Satoshi, Van Der Harst, Pim, Van Der Schouw, Yvonne T., Van Gilst, Wiek H., Vartiainen, Erkki, Vasan, Ramachandran S., Veldre, Gudrun, Verwoert, Germaine C., Viigimaa, Margu, Vinay, D. G., Vineis, Paolo, Voight, Benjamin F., Vollenweider, Peter, Wagenknecht, Lynne E., Wain, Louise V., Wang, Xiaoling, Wang, Thomas J., Wareham, Nicholas J., Watkins, Hugh, Weder, Alan B., Whincup, Peter H., Wiggins, Kerri L., Witteman, Jacqueline C. M., Wong, Andrew, Wu, Ying, Yajnik, Chittaranjan S., Yao, Jie, Young, J. H., Zelenika, Diana, Zhai, Guangju, Zhang, Weihua, Zhang, Feng, Zhao, Jing Hua, Zhu, Haidong, Zhu, Xiaofeng, Zitting, Paavo, Zukowska Szczechowska, Ewa, Okada, Yukinori, Wu, Jer Yuarn, Gu, Dongfeng, Takeuchi, Fumihiko, Takahashi, Atsushi, Maeda, Shiro, Tsunoda, Tatsuhiko, Chen, Peng, Lim, Su Chi, Wong, Tien Yin, Liu, Jianjun, Young, Terri L., Aung, Tin, Teo, Yik Ying, Kim, Young Jin, Kang, Daehee, Chen, Chien Hsiun, Tsai, Fuu Jen, Chang, Li Ching, Fann, S. J. Cathy, Mei, Hao, Hixson, James E., Chen, Shufeng, Katsuya, Tomohiro, Isono, Masato, Albrecht, Eva, Yamamoto, Kazuhiko, Kubo, Michiaki, Nakamura, Yusuke, Kamatani, Naoyuki, Kato, Norihiro, He, Jiang, Chen, Yuan Tsong, Tanaka, Toshihiro, Reilly, Muredach P., Schunkert, Heribert, Assimes, Themistocles L., Hall, Alistair, Hengstenberg, Christian, König, Inke R., Laaksonen, Reijo, Mcpherson, Ruth, Thompson, John R., Thorsteinsdottir, Unnur, Ziegler, Andrea, Absher, Devin, Chen, Li, Cupples, L. Adrienne, Halperin, Eran, Li, Mingyao, Musunuru, Kiran, Preuss, Michael, Schillert, Arne, Thorleifsson, Gudmar, Wells, George A., Holm, Hilma, Roberts, Robert, Stewart, Alexandre F. R., Fortmann, Stephen, Go, Alan, Hlatky, Mark, Iribarren, Carlo, Knowles, Joshua, Myers, Richard, Quertermous, Thoma, Sidney, Steven, Risch, Neil, Tang, Hua, Blankenberg, Stefan, Schnabel, Renate, Sinning, Christoph, Lackner, Karl J., Tiret, Laurence, Nicaud, Viviane, Cambien, Francoi, Bickel, Christoph, Rupprecht, Hans J., Perret, Claire, Proust, Carole, Münzel, Thomas F., Barbalic, Maja, Chen, Ida Yii Der, Demissie Banjaw, Serkalem, Folsom, Aaron, Lumley, Thoma, Marciante, Kristin, Taylor, Kent D., Volcik, Kelly, Gretarsdottir, Solveig, Gulcher, Jeffrey R., Kong, Augustine, Stefansson, Kari, Thorgeirsson, Gudmundur, Andersen, Karl, Fischer, Marcu, Grosshennig, Anika, Linsel Nitschke, Patrick, Stark, Klau, Schreiber, Stefan, Aherrahrou, Zouhair, Bruse, Petra, Doering, Angela, Klopp, Norman, Diemert, Patrick, Loley, Christina, Medack, Anja, Nahrstedt, Janja, Peters, Annette, Wagner, Arnika K., Willenborg, Christina, Böhm, Bernhard O., Dobnig, Harald, Grammer, Tanja B., Hoffmann, Michael M., Meinitzer, Andrea, Winkelmann, Bernhard R., Pilz, Stefan, Renner, Wilfried, Scharnagl, Hubert, Stojakovic, Tatjana, Tomaschitz, Andrea, Winkler, Karl, Guiducci, Candace, Burtt, Noel, Gabriel, Stacey B., Dandona, Sonny, Jarinova, Olga, Qu, Liming, Wilensky, Robert, Matthai, William, Hakonarson, Hakon H., Devaney, Joe, Burnett, Mary Susan, Pichard, Augusto D., Kent, Kenneth M., Satler, Lowell, Lindsay, Joseph M., Waksman, Ron, Knouff, Christopher W., Waterworth, Dawn M., Walker, Max C., Epstein, Stephen E., Rader, Daniel J., Nelson, Christopher P., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Loehr, Laura R., Rosamond, Wayne D., Benjamin, Emelia, Haritunians, Talin, Couper, David, Murabito, Joanne, Wang, Ying A., Stricker, Bruno H., Chang, Patricia P., Willerson, James T., Felix, Stephan B., Watzinger, Norbert, Aragam, Jayashri, Zweiker, Robert, Lind, Lar, Rodeheffer, Richard J., Greiser, Karin Halina, Deckers, Jaap W., Stritzke, Jan, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johanne, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Arnett, Donna K., Gottdiener, John S., Blettner, Maria, Friedrich, Nele, Kovacs, Peter, Wild, Philipp S., Froguel, Philippe, Rettig, Rainer, Mägi, Reedik, Biffar, Reiner, Schmidt, Reinhold, Middelberg, Rita P. S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.

Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016

48. MicroRNAs in Human Lymphoblastoid Cell Lines

Author

Bok-Ghee Han, Sung-Mi Shim, Jun Woo Kim, Jae-Eun Lee, Hye-Young Nam, and Jae-Pil Jeon

Subjects
Genetics, Regulation of gene expression, B-Lymphocytes, Herpesvirus 4, Human, education.field_of_study, Population, Genomics, Biology, Cell Transformation, Viral, Human genetics, Epigenesis, Genetic, Transcriptome, MicroRNAs, stomatognathic diseases, Gene Expression Regulation, Databases, Genetic, DNA methylation, microRNA, Humans, Epigenetics, education, Molecular Biology, Cell Line, Transformed
Abstract

Human lymphoblastoid cell lines (LCLs) are generated by EBV-mediated B-cell transformation to provide unlimited genomic resources for human genetics and immunological studies. The LCL is a good in vitro cell model for assessing population differences in the basal expression of genes and miRNAs as well as in cellular responses to various stimulators. Recently, the utility of LCLs was extended to pharmacogenomic studies to discover genetic factors underlying individual variations in response to chemicals and environmental stresses. Although LCLs represent generally lymphoid tissue-specific biological characteristics, genomic signatures of LCLs can distinguish patients with brain-related diseases and nonlymphoid tumors from normal controls. MicroRNA is known to be an epigenetic transcriptional regulator, and its expression is induced in abnormal conditions such as perturbagen-stimulated, virus-infected, or cancer cells. The epigenetic regulation of gene expression mediated by microRNA and DNA methylation is important for understanding the pathogenesis of cancers and complex diseases as well as discovering for therapeutic targets. For integrative genomic analyses, LCLs can be utilized to generate cellular phenotypes and various genomic data (e.g., SNP, CNV, transcriptome, methylome, etc.), which can be linked to clinical information of donors. Here, we discuss miRNA-mediated gene expression in LCLs and its application to disease genomics and global transcriptional regulatory machinery studies.

Published
2012

49. Large-scale association analysis identifies new risk loci for coronary artery disease

Author

Benjamin F. Voight, Andrew D. Morris, G. Kees Hovingh, Anthony J. Balmforth, Hanneke Basart, Alistair S. Hall, Dominique Gauguier, Bok Ghee Han, Martina Müller-Nurasyid, Sarah Parish, Jarmo Virtamo, Christa Meisinger, Peter Wagner, George Dedoussis, Philipp S. Wild, Kari Stefansson, Jean-Baptiste Cazier, Kathleen Stirrups, Jiyoung Lee, Adrienne Cupples, Stavroula Kanoni, Danish Saleheen, Christian Hengstenberg, Svati H. Shah, Panos Deloukas, Anuj Goel, Stefan Blankenberg, Sian Tsung Tan, Alison H. Goodall, Tõnu Esko, Eric Boerwinkle, Gudmundur Thorgeirsson, Peter S. Braund, Joshua W. Knowles, Olle Melander, C. Ellen van der Schoot, Silke Rosinger, Maria Dimitriou, Wolfgang Koenig, Michael Boehnke, François Cambien, Per Lundmark, Dmitry Shungin, Wolfgang Kratzer, Pierre Zalloua, Reijo Laaksonen, Jean Ferrières, Villi Gudnason, Thorsten Kessler, Daniel J. Rader, Niclas Eriksson, Dominique Arveiler, Natalie R. van Zuydam, Kari Kuulasmaa, N. William Rayner, Sarah E. Hunt, Gudmar Thorleifsson, Jeanette Erdmann, Samuli Ripatti, Tsun-Po Yang, George A. Wells, Terho Lehtimäki, Kjell Nikus, Pierre Fontanillas, Jorg Hager, Martin Farrall, Jemma C. Hopewell, Frank Kee, Juha Sinisalo, Christopher J. O'Donnell, Asif Rasheed, Mika Kähönen, Genovefa Kolovou, Seraya Maouche, Suzanne Rafelt, Cordelia Langford, Winfried März, Leo-Pekka Lyytikäinen, Christina Willenborg, Weihua Zhang, Kati Kristiansson, Hyo-Soo Kim, Weang K. Ho, Jeong E. Park, Mohan U. Sivananthan, Moritz P. Rumpf, Markku Laakso, Klaus Stark, Philippe Amouyel, Paul W. Franks, Andres Metspalu, Anders Franco-Cereceda, Manjinder S. Sandhu, Nour Eddine El Mokhtari, Nicholas J. Wareham, Robert Roberts, Veikko Salomaa, Thomas Illig, Tomi Pastinen, Robert Clarke, Christof Burgdorf, Leif Groop, Devin Absher, Yangsoo Jang, Mark I. McCarthy, Bernhard O. Boehm, Per Eriksson, Nilesh J. Samani, Inke R. König, Stefan Schreiber, Karin Leander, Simone Claudi-Boehm, Ci Song, Benjamin A. Goldstein, Stephen E. Epstein, Andreas Ziegler, Stanley L. Hazen, Arne Schäfer, Elin Grundberg, Sekar Kathiresan, John R. Thompson, Unnur Thorsteinsdottir, Muredach P. Reilly, Heribert Schunkert, Rory Collins, Thomas Quertermous, Jong-Young Lee, John Danesh, John C. Chambers, Marco M Ferrario, Carlos Iribarren, Claudia Langenberg, Hilma Holm, Rona J. Strawbridge, Alan S. Go, Cristen J. Willer, Ron Do, Emmi Tikkanen, Abbas Dehghan, Evelin Mihailov, Lindsay L. Waite, Patrick Diemert, Willem H. Ouwehand, Eric E. Schadt, Diana Rubin, David Altshuler, Marcus E. Kleber, Markus Perola, Alexandre F.R. Stewart, Jaspal S. Kooner, Themistocles L. Assimes, Inês Barroso, Bruna Gigante, Göran Hallmans, Marja-Liisa Lokki, Aki S. Havulinna, Anders Hamsten, Agneta Siegbahn, Lasse Folkersen, Erik Ingelsson, Martina E. Zimmermann, Colin N. A. Palmer, Paolo Brambilla, Ann-Christine Syvänen, Alun Evans, Åsa Johansson, John F. Peden, Alex S. F. Doney, Hugh Watkins, Johanna Kuusisto, Anders Lundmark, David G. Cox, Hyun Min Kang, Lars Lind, Krista Fischer, Markku S. Nieminen, Annette Peters, Norman Klopp, Stefan Gustafsson, Lars Wallentin, Nancy L. Pedersen, David-Alexandre Trégouët, Ulf de Faire, Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, B, Stirrups, K, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Willer, C, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, J, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Salomaa, V, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Franks, P, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Boehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Schunkert, H, Samani, N, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine

Subjects
Adult, Asian Continental Ancestry Group, Male, Candidate gene, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Population, European Continental Ancestry Group, Quantitative Trait Loci, CAD, Genome-wide association study, Single-nucleotide polymorphism, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Bioinformatics, Polymorphism, Single Nucleotide, Article, White People, coronary artery disease, risk loci, Cell Line, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Risk Factors, medicine, Humans, genetics, Gene Regulatory Networks, Genetic Predisposition to Disease, cardiovascular diseases, Polymorphism, education, 030304 developmental biology, Genetic association, Aged, Genetics, 0303 health sciences, education.field_of_study, Adult, Aged, Asian Continental Ancestry Group, Cell Line, Coronary Artery Disease, genetics, European Continental Ancestry Group, genetics, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Single Nucleotide, Middle Aged, medicine.disease, 3. Good health, Female, Genome-Wide Association Study
Abstract

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r 2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. © 2013 Nature America, Inc. All rights reserved.

Published
2012
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50. A Genome-Wide Association Study of Gestational Diabetes Mellitus in Korean Women

Author

Nam H. Cho, Young Min Cho, Sunghoon Kim, Hye Seung Jung, Seong Yeon Kim, Bok Ghee Han, Hyoung Doo Shin, Hak Chul Jang, Yoon Shin Cho, Min Jin Go, Sung Hee Choi, Soo Heon Kwak, Hyun Min Kang, Inkyu Lee, Kyong Soo Park, and Min Kyong Moon

Subjects
Adult, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, Type 2 diabetes, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Pregnancy, Risk Factors, Internal medicine, Internal Medicine, medicine, Humans, Genotyping, CDKAL1, 030304 developmental biology, Genetic association, Aged, 0303 health sciences, tRNA Methyltransferases, Korea, Obstetrics, business.industry, Receptor, Melatonin, MT1, nutritional and metabolic diseases, Genetics/Genomes/Proteomics/Metabolomics, Cyclin-Dependent Kinase 5, Odds ratio, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Gestational diabetes, Diabetes, Gestational, Endocrinology, Logistic Models, Diabetes Mellitus, Type 2, Female, Insulin Resistance, business, Genome-Wide Association Study
Abstract

Knowledge regarding the genetic risk loci for gestational diabetes mellitus (GDM) is still limited. In this study, we performed a two-stage genome-wide association analysis in Korean women. In the stage 1 genome scan, 468 women with GDM and 1,242 nondiabetic control women were compared using 2.19 million genotyped or imputed markers. We selected 11 loci for further genotyping in stage 2 samples of 931 case and 783 control subjects. The joint effect of stage 1 plus stage 2 studies was analyzed by meta-analysis. We also investigated the effect of known type 2 diabetes variants in GDM. Two loci known to be associated with type 2 diabetes had a genome-wide significant association with GDM in the joint analysis. rs7754840, a variant in CDKAL1, had the strongest association with GDM (odds ratio 1.518; P = 6.65 × 10−16). A variant near MTNR1B, rs10830962, was also significantly associated with the risk of GDM (1.454; P = 2.49 × 10−13). We found that there is an excess of association between known type 2 diabetes variants and GDM above what is expected under the null hypothesis. In conclusion, we have confirmed that genetic variants in CDKAL1 and near MTNR1B are strongly associated with GDM in Korean women. There seems to be a shared genetic basis between GDM and type 2 diabetes.

Published
2012

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