Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals

Ching-Ti Liu; Jordi Merino; Denis Rybin; Daniel DiCorpo; Kelly S Benke; Jennifer L Bragg-Gresham; Mickaël Canouil; Tanguy Corre; Harald Grallert; Aaron Isaacs; Zoltan Kutalik; Jari Lahti; Letizia Marullo; Carola Marzi; Laura J Rasmussen-Torvik; Ghislain Rocheleau; Rico Rueedi; Chiara Scapoli; Niek Verweij; Nicole Vogelzangs; Sara M Willems; Loïc Yengo; Stephan J L Bakker; John Beilby; Jennie Hui; Eero Kajantie; Martina Müller-Nurasyid; Wolfgang Rathmann; Beverley Balkau; Sven Bergmann; Johan G Eriksson; Jose C Florez; Philippe Froguel; Tamara Harris; Joseph Hung; Alan L James; Maryam Kavousi; Iva Miljkovic; Arthur W Musk; Lyle J Palmer; Annette Peters; Ronan Roussel; Pim van der Harst; Cornelia M van Duijn; Peter Vollenweider; Inês Barroso; Inga Prokopenko; Josée Dupuis; James B Meigs; Nabila Bouatia-Naji

doi:10.1038/s41598-019-45823-7

Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals

Ching-Ti Liu^*, Jordi Merino, Denis Rybin, Daniel DiCorpo, Kelly S Benke, Jennifer L Bragg-Gresham, Mickaël Canouil, Tanguy Corre, Harald Grallert, Aaron Isaacs, Zoltan Kutalik, Jari Lahti, Letizia Marullo, Carola Marzi, Laura J Rasmussen-Torvik, Ghislain Rocheleau, Rico Rueedi, Chiara Scapoli, Niek Verweij, Nicole VogelzangsSara M Willems, Loïc Yengo, Stephan J L Bakker, John Beilby, Jennie Hui, Eero Kajantie, Martina Müller-Nurasyid, Wolfgang Rathmann, Beverley Balkau, Sven Bergmann, Johan G Eriksson, Jose C Florez, Philippe Froguel, Tamara Harris, Joseph Hung, Alan L James, Maryam Kavousi, Iva Miljkovic, Arthur W Musk, Lyle J Palmer, Annette Peters, Ronan Roussel, Pim van der Harst, Cornelia M van Duijn, Peter Vollenweider, Inês Barroso, Inga Prokopenko, Josée Dupuis, James B Meigs, Nabila Bouatia-Naji^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

Original language	English
Article number	9439
Number of pages	8
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-45823-7
Publication status	Published - 1 Jul 2019

Keywords

GENETIC ARCHITECTURE
LIFE-STYLE INTERVENTION
LOCI
POPULATION
PREDICTION
PREVENTION
RISK
TYPE-2
VARIANTS
WEIGHT-LOSS

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Cite this

Liu, C.-T., Merino, J., Rybin, D., DiCorpo, D., Benke, K. S., Bragg-Gresham, J. L., Canouil, M., Corre, T., Grallert, H., Isaacs, A., Kutalik, Z., Lahti, J., Marullo, L., Marzi, C., Rasmussen-Torvik, L. J., Rocheleau, G., Rueedi, R., Scapoli, C., Verweij, N., ... Bouatia-Naji, N. (2019). Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals. Scientific Reports, 9(1), Article 9439. https://doi.org/10.1038/s41598-019-45823-7

@article{c5aea4f7f04f46c7a7510fb8c3d40d33,

title = "Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals",

abstract = "Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.",

keywords = "GENETIC ARCHITECTURE, LIFE-STYLE INTERVENTION, LOCI, POPULATION, PREDICTION, PREVENTION, RISK, TYPE-2, VARIANTS, WEIGHT-LOSS",

author = "Ching-Ti Liu and Jordi Merino and Denis Rybin and Daniel DiCorpo and Benke, {Kelly S} and Bragg-Gresham, {Jennifer L} and Micka{\"e}l Canouil and Tanguy Corre and Harald Grallert and Aaron Isaacs and Zoltan Kutalik and Jari Lahti and Letizia Marullo and Carola Marzi and Rasmussen-Torvik, {Laura J} and Ghislain Rocheleau and Rico Rueedi and Chiara Scapoli and Niek Verweij and Nicole Vogelzangs and Willems, {Sara M} and Lo{\"i}c Yengo and Bakker, {Stephan J L} and John Beilby and Jennie Hui and Eero Kajantie and Martina M{\"u}ller-Nurasyid and Wolfgang Rathmann and Beverley Balkau and Sven Bergmann and Eriksson, {Johan G} and Florez, {Jose C} and Philippe Froguel and Tamara Harris and Joseph Hung and James, {Alan L} and Maryam Kavousi and Iva Miljkovic and Musk, {Arthur W} and Palmer, {Lyle J} and Annette Peters and Ronan Roussel and {van der Harst}, Pim and {van Duijn}, {Cornelia M} and Peter Vollenweider and In{\^e}s Barroso and Inga Prokopenko and Jos{\'e}e Dupuis and Meigs, {James B} and Nabila Bouatia-Naji",

note = "Funding Information: BHS. The Busselton Health Study acknowledges the generous support for the 1994/5 follow-up study from Healthway, Western Australia and the numerous Busselton community volunteers who assisted with data collection and the study participants from the Shire of Busselton. The Busselton Health Study is supported by The Great Wine Estates of the Margaret River region of Western Australia. The BHS gratefully acknowledges the assistance of the Western Australian DNA Bank (NHMRC Enabling Facility) with DNA samples and the support provided by the Ark (NHMRC Enabling Facility) for this study. CoLaus. The CoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468 and 33CS30-148401). The authors also express their gratitude to the participants in the Lausanne CoLaus study and to the investigators who have contributed to the recruitment, in particular research nurses Yolande Barreau, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey and Sylvie Mermoud for data collection. We would also like to thank G{\'e}rard Waeber, Vincent Mooser and Dawn Waterworth, co-PIs of the study. Researchers must obtain approval from the Steering Committee of the CoLaus Study and from the Institutional Ethics Committee of the University in Lausanne, Switzerland. Researchers using the data are required to follow the terms of an Assistance Agreement containing a number of clauses designed to ensure protection of privacy and compliance with relevant laws. For further information go to www.colaus.ch or contact Peter Vollenweider (peter.vollenweider@chuv.ch). DESIR. The D.E.S.I.R. study has been funded by INSERM contracts with Caisse nationale de l{\textquoteright}assurancemaladie des travailleurs salari{\'e}s (CNAMTS), Lilly, Novartis Pharma, and sanofi-aventis; INSERM (R{\'e}seaux en Sant{\'e} Publique, Interactions entre les d{\'e}terminants de la sant{\'e}, Cohortes Sant{\'e} TGIR 2008); the Association Diab{\`e}te Risque Vasculaire; the F{\'e}d{\'e}ration Fran{\c c}aise de Cardiologie; La Fondation de France; Association de Langue Fran{\c c}aise pour l{\textquoteright}Etude du Diab{\`e}te et des Maladies M{\'e}taboliques (ALFEDIAM)/ Soci{\'e}t{\'e} Francophone de Diab{\'e}tologie (SFD); l{\textquoteright}Office national interprofessionnel des vins (ONIVINS); Ardix Medical; Bayer Diagnostics; Becton Dickinson; Cardionics; Merck Sant{\'e}; Novo Nordisk; Pierre Fabre; Roche; Topcon. ERGO. 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. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. Maryam Kavousi is supported by the VENI grant (91616079) from The Netherlands Organization for Health Research and Development (ZonMw). 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 (nr. 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 nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and 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, MSc, for the creation and analysis of imputed data. FHS. This work was in part supported by the grant R01 DK078616, U01 DK078616 and K24 DK080140. Jordi Merino was supported by a postdoctoral fellowship funded by the European Commission Horizon 2020 program and Marie Sk{\l}odowska-Curie actions (H2020-MSCA-IF-2015-703787). Also, supported using data and resources from the FHS of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP Health Association Resource (SHARe) project. This work was also partially supported by the National Heart, Lung and Blood Institute{\textquoteright}s Framingham Heart Study (Contract No. N01‐HC‐25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02‐HL‐6‐4278). HBCS. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkh{\"a}lsan Research Foundation, Novo Nordisk Foundation, Finska L{\"a}kares{\"a}llskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. HBCS Acknowledgements: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkh{\"a}lsan Research Foundation, Novo Nordisk Foundation, Finska L{\"a}kares{\"a}llskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. KORA. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum M{\"u}nchen – German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF), the Federal Ministry of Health (Berlin, Germany), the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (D{\"u}sseldorf, Germany), and the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. This research was supported by the European Union{\textquoteright}s Seventh Framework Programme (FP7-Health-F5-2012) under grant agreement no. 305280 (MIMOmics), by the Helmholtz-Russia Joint Research Group (HRJRG) 310, and by the German Center for Diabetes Research (DZD). We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PREVEND. PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant 2R01LM010098), The Netherlands organisation for health research and development (NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441), the Netherlands Heart Foundation (grant NHS2010B280) and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Verweij is supported by NWO VENI (016.186.125) and by a Marie Sklodowska-Curie GF (call: H2020-MSCA-IF-2014, Project ID: 661395). We would like to thank the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine high performance computing cluster. SARDINIA. None. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = jul,

day = "1",

doi = "10.1038/s41598-019-45823-7",

language = "English",

volume = "9",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Liu, C-T, Merino, J, Rybin, D, DiCorpo, D, Benke, KS, Bragg-Gresham, JL, Canouil, M, Corre, T, Grallert, H, Isaacs, A, Kutalik, Z, Lahti, J, Marullo, L, Marzi, C, Rasmussen-Torvik, LJ, Rocheleau, G, Rueedi, R, Scapoli, C, Verweij, N, Vogelzangs, N, Willems, SM, Yengo, L, Bakker, SJL, Beilby, J, Hui, J, Kajantie, E, Müller-Nurasyid, M, Rathmann, W, Balkau, B, Bergmann, S, Eriksson, JG, Florez, JC, Froguel, P, Harris, T, Hung, J, James, AL, Kavousi, M, Miljkovic, I, Musk, AW, Palmer, LJ, Peters, A, Roussel, R, van der Harst, P, van Duijn, CM, Vollenweider, P, Barroso, I, Prokopenko, I, Dupuis, J, Meigs, JB & Bouatia-Naji, N 2019, 'Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals', Scientific Reports, vol. 9, no. 1, 9439. https://doi.org/10.1038/s41598-019-45823-7

TY - JOUR

T1 - Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals

AU - Liu, Ching-Ti

AU - Merino, Jordi

AU - Rybin, Denis

AU - DiCorpo, Daniel

AU - Benke, Kelly S

AU - Bragg-Gresham, Jennifer L

AU - Canouil, Mickaël

AU - Corre, Tanguy

AU - Grallert, Harald

AU - Isaacs, Aaron

AU - Kutalik, Zoltan

AU - Lahti, Jari

AU - Marullo, Letizia

AU - Marzi, Carola

AU - Rasmussen-Torvik, Laura J

AU - Rocheleau, Ghislain

AU - Rueedi, Rico

AU - Scapoli, Chiara

AU - Verweij, Niek

AU - Vogelzangs, Nicole

AU - Willems, Sara M

AU - Yengo, Loïc

AU - Bakker, Stephan J L

AU - Beilby, John

AU - Hui, Jennie

AU - Kajantie, Eero

AU - Müller-Nurasyid, Martina

AU - Rathmann, Wolfgang

AU - Balkau, Beverley

AU - Bergmann, Sven

AU - Eriksson, Johan G

AU - Florez, Jose C

AU - Froguel, Philippe

AU - Harris, Tamara

AU - Hung, Joseph

AU - James, Alan L

AU - Kavousi, Maryam

AU - Miljkovic, Iva

AU - Musk, Arthur W

AU - Palmer, Lyle J

AU - Peters, Annette

AU - Roussel, Ronan

AU - van der Harst, Pim

AU - van Duijn, Cornelia M

AU - Vollenweider, Peter

AU - Barroso, Inês

AU - Prokopenko, Inga

AU - Dupuis, Josée

AU - Meigs, James B

AU - Bouatia-Naji, Nabila

N1 - Funding Information: BHS. The Busselton Health Study acknowledges the generous support for the 1994/5 follow-up study from Healthway, Western Australia and the numerous Busselton community volunteers who assisted with data collection and the study participants from the Shire of Busselton. The Busselton Health Study is supported by The Great Wine Estates of the Margaret River region of Western Australia. The BHS gratefully acknowledges the assistance of the Western Australian DNA Bank (NHMRC Enabling Facility) with DNA samples and the support provided by the Ark (NHMRC Enabling Facility) for this study. CoLaus. The CoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468 and 33CS30-148401). The authors also express their gratitude to the participants in the Lausanne CoLaus study and to the investigators who have contributed to the recruitment, in particular research nurses Yolande Barreau, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey and Sylvie Mermoud for data collection. We would also like to thank Gérard Waeber, Vincent Mooser and Dawn Waterworth, co-PIs of the study. Researchers must obtain approval from the Steering Committee of the CoLaus Study and from the Institutional Ethics Committee of the University in Lausanne, Switzerland. Researchers using the data are required to follow the terms of an Assistance Agreement containing a number of clauses designed to ensure protection of privacy and compliance with relevant laws. For further information go to www.colaus.ch or contact Peter Vollenweider (peter.vollenweider@chuv.ch). DESIR. The D.E.S.I.R. study has been funded by INSERM contracts with Caisse nationale de l’assurancemaladie des travailleurs salariés (CNAMTS), Lilly, Novartis Pharma, and sanofi-aventis; INSERM (Réseaux en Santé Publique, Interactions entre les déterminants de la santé, Cohortes Santé TGIR 2008); the Association Diabète Risque Vasculaire; the Fédération Française de Cardiologie; La Fondation de France; Association de Langue Française pour l’Etude du Diabète et des Maladies Métaboliques (ALFEDIAM)/ Société Francophone de Diabétologie (SFD); l’Office national interprofessionnel des vins (ONIVINS); Ardix Medical; Bayer Diagnostics; Becton Dickinson; Cardionics; Merck Santé; Novo Nordisk; Pierre Fabre; Roche; Topcon. ERGO. 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. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. Maryam Kavousi is supported by the VENI grant (91616079) from The Netherlands Organization for Health Research and Development (ZonMw). 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 (nr. 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 nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and 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, MSc, for the creation and analysis of imputed data. FHS. This work was in part supported by the grant R01 DK078616, U01 DK078616 and K24 DK080140. Jordi Merino was supported by a postdoctoral fellowship funded by the European Commission Horizon 2020 program and Marie Skłodowska-Curie actions (H2020-MSCA-IF-2015-703787). Also, supported using data and resources from the FHS of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP Health Association Resource (SHARe) project. This work was also partially supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01‐HC‐25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02‐HL‐6‐4278). HBCS. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. HBCS Acknowledgements: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. KORA. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF), the Federal Ministry of Health (Berlin, Germany), the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Düsseldorf, Germany), and the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. This research was supported by the European Union’s Seventh Framework Programme (FP7-Health-F5-2012) under grant agreement no. 305280 (MIMOmics), by the Helmholtz-Russia Joint Research Group (HRJRG) 310, and by the German Center for Diabetes Research (DZD). We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PREVEND. PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant 2R01LM010098), The Netherlands organisation for health research and development (NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441), the Netherlands Heart Foundation (grant NHS2010B280) and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Verweij is supported by NWO VENI (016.186.125) and by a Marie Sklodowska-Curie GF (call: H2020-MSCA-IF-2014, Project ID: 661395). We would like to thank the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine high performance computing cluster. SARDINIA. None. Publisher Copyright: © 2019, The Author(s).

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

AB - Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

KW - GENETIC ARCHITECTURE

KW - LIFE-STYLE INTERVENTION

KW - LOCI

KW - POPULATION

KW - PREDICTION

KW - PREVENTION

KW - RISK

KW - TYPE-2

KW - VARIANTS

KW - WEIGHT-LOSS

U2 - 10.1038/s41598-019-45823-7

DO - 10.1038/s41598-019-45823-7

M3 - Article

C2 - 31263163

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 9439

ER -