. 2017 Nov 10;12(11):e0186669.

doi: 10.1371/journal.pone.0186669. eCollection 2017.

Evaluating the glucose raising effect of established loci via a genetic risk score

Eirini Marouli¹, Stavroula Kanoni¹, Vasiliki Mamakou², Sophie Hackinger³, Lorraine Southam^{3

4}, Bram Prins³, Angela Rentari⁵, Maria Dimitriou⁵, Eleni Zengini^{2

6}, Fragiskos Gonidakis⁷, Genovefa Kolovou⁸, Vassilis Kontaxakis⁹, Loukianos Rallidis¹⁰, Nikolaos Tentolouris¹¹, Anastasia Thanopoulou¹², Klea Lamnissou¹³, George Dedoussis⁵, Eleftheria Zeggini³, Panagiotis Deloukas^{1

14}

Affiliations

¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
² Dromokaiteio Psychiatric Hospital, Athens, Greece.
³ Wellcome Trust Sanger Institute, Hinxton, Cambridge.
⁴ Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
⁵ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
⁶ Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
⁷ 1st Psychiatric Department, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece.
⁸ Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece.
⁹ Early Psychosis Unit, 1st Department of Psychiatry, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece.
¹⁰ Second Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Attikon Hospital, Athens, Greece.
¹¹ First Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Medical School, Laiko General Hospital, Athens, Greece.
¹² Diabetes Centre, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Hippokration General Hospital, Athens, Greece.
¹³ Division of Genetics & Biotechnology, Department of Biology, National & Kapodistrian University of Athens, Greece.
¹⁴ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

PMID: 29125842
PMCID: PMC5681259
DOI: 10.1371/journal.pone.0186669

Evaluating the glucose raising effect of established loci via a genetic risk score

Eirini Marouli et al. PLoS One. 2017.

. 2017 Nov 10;12(11):e0186669.

doi: 10.1371/journal.pone.0186669. eCollection 2017.

Authors

Affiliations

¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
² Dromokaiteio Psychiatric Hospital, Athens, Greece.
³ Wellcome Trust Sanger Institute, Hinxton, Cambridge.
⁴ Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
⁵ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
⁶ Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
⁷ 1st Psychiatric Department, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece.
⁸ Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece.
⁹ Early Psychosis Unit, 1st Department of Psychiatry, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece.
¹⁰ Second Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Attikon Hospital, Athens, Greece.
¹¹ First Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Medical School, Laiko General Hospital, Athens, Greece.
¹² Diabetes Centre, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Hippokration General Hospital, Athens, Greece.
¹³ Division of Genetics & Biotechnology, Department of Biology, National & Kapodistrian University of Athens, Greece.
¹⁴ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

PMID: 29125842
PMCID: PMC5681259
DOI: 10.1371/journal.pone.0186669

Abstract

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with glucose levels. We tested the hypothesis here whether the cumulative effect of glucose raising SNPs, assessed via a score, is associated with glucose levels. A total of 1,434 participants of Greek descent from the THISEAS study and 1,160 participants form the GOMAP study were included in this analysis. We developed a genetic risk score (GRS), based on the known glucose-raising loci, in order to investigate the cumulative effect of known glucose loci on glucose levels. In the THISEAS study, the GRS score was significantly associated with increased glucose levels (mmol/L) (β ± SE: 0.024 ± 0.004, P = 8.27e-07). The effect of the genetic risk score was also significant in the GOMAP study (β ± SE: 0.011 ± 0.005, P = 0.031). In the meta-analysis of the two studies both scores were significantly associated with higher glucose levels GRS: β ± SE: 0.019 ± 0.003, P = 1.41e-09. Also, variants at the SLC30A8, PROX1, MTNR1B, ADRA2A, G6PC2, LPIN3 loci indicated nominal evidence for association with glucose levels (p < 0.05). We replicate associations of the established glucose raising variants in the Greek population and confirm directional consistency of effects (binomial sign test p = 6.96e-05). We also demonstrate that the cumulative effect of the established glucose loci yielded a significant association with increasing glucose levels.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

**Fig 1. Forest plots of the Meta-Analysis results.**
Forest plots showing the beta estimates and confidence intervals of the A. GRS and B. wGRS association in the different populations studied in the discovery cohorts and the meta-analysis fixed model results. An inverse variance weighted meta-analysis was performed.

**Fig 2. Distribution of individuals in every genotype score group and cumulative effects of the risk alleles from the 36 SNPs for glucose levels.**
The bar plots show the average and standard error of glucose in mmol/L for each genotype score group distribution of the genetic risk score.

See this image and copyright information in PMC

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Evaluating the glucose raising effect of established loci via a genetic risk score

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Evaluating the glucose raising effect of established loci via a genetic risk score

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