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Multi-Trait Genomic Risk Stratification for Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is continuously rising with more disease cases every year. T2DM is a chronic disease with many severe comorbidities and therefore remains a burden for the patient and the society. Disease prevention, early diagnosis, and stratified treatment are important elements in...

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Autores principales: Rohde, Palle Duun, Nyegaard, Mette, Kjolby, Mads, Sørensen, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455930/
https://www.ncbi.nlm.nih.gov/pubmed/34568370
http://dx.doi.org/10.3389/fmed.2021.711208
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author Rohde, Palle Duun
Nyegaard, Mette
Kjolby, Mads
Sørensen, Peter
author_facet Rohde, Palle Duun
Nyegaard, Mette
Kjolby, Mads
Sørensen, Peter
author_sort Rohde, Palle Duun
collection PubMed
description Type 2 diabetes mellitus (T2DM) is continuously rising with more disease cases every year. T2DM is a chronic disease with many severe comorbidities and therefore remains a burden for the patient and the society. Disease prevention, early diagnosis, and stratified treatment are important elements in slowing down the increase in diabetes prevalence. T2DM has a substantial genetic component with an estimated heritability of 40–70%, and more than 500 genetic loci have been associated with T2DM. Because of the intrinsic genetic basis of T2DM, one tool for risk assessment is genome-wide genetic risk scores (GRS). Current GRS only account for a small proportion of the T2DM risk; thus, better methods are warranted for more accurate risk assessment. T2DM is correlated with several other diseases and complex traits, and incorporating this information by adjusting effect size of the included markers could improve risk prediction. The aim of this study was to develop multi-trait (MT)-GRS leveraging correlated information. We used phenotype and genotype information from the UK Biobank, and summary statistics from two independent T2DM studies. Marker effects for T2DM and seven correlated traits, namely, height, body mass index, pulse rate, diastolic and systolic blood pressure, smoking status, and information on current medication use, were estimated (i.e., by logistic and linear regression) within the UK Biobank. These summary statistics, together with the two independent training summary statistics, were incorporated into the MT-GRS prediction in different combinations. The prediction accuracy of the MT-GRS was improved by 12.5% compared to the single-trait GRS. Testing the MT-GRS strategy in two independent T2DM studies resulted in an elevated accuracy by 50–94%. Finally, combining the seven information traits with the two independent T2DM studies further increased the prediction accuracy by 34%. Across comparisons, body mass index and current medication use were the two traits that displayed the largest weights in construction of the MT-GRS. These results explicitly demonstrate the added benefit of leveraging correlated information when constructing genetic scores. In conclusion, constructing GRS not only based on the disease itself but incorporating genomic information from other correlated traits as well is strongly advisable for obtaining improved individual risk stratification.
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spelling pubmed-84559302021-09-23 Multi-Trait Genomic Risk Stratification for Type 2 Diabetes Rohde, Palle Duun Nyegaard, Mette Kjolby, Mads Sørensen, Peter Front Med (Lausanne) Medicine Type 2 diabetes mellitus (T2DM) is continuously rising with more disease cases every year. T2DM is a chronic disease with many severe comorbidities and therefore remains a burden for the patient and the society. Disease prevention, early diagnosis, and stratified treatment are important elements in slowing down the increase in diabetes prevalence. T2DM has a substantial genetic component with an estimated heritability of 40–70%, and more than 500 genetic loci have been associated with T2DM. Because of the intrinsic genetic basis of T2DM, one tool for risk assessment is genome-wide genetic risk scores (GRS). Current GRS only account for a small proportion of the T2DM risk; thus, better methods are warranted for more accurate risk assessment. T2DM is correlated with several other diseases and complex traits, and incorporating this information by adjusting effect size of the included markers could improve risk prediction. The aim of this study was to develop multi-trait (MT)-GRS leveraging correlated information. We used phenotype and genotype information from the UK Biobank, and summary statistics from two independent T2DM studies. Marker effects for T2DM and seven correlated traits, namely, height, body mass index, pulse rate, diastolic and systolic blood pressure, smoking status, and information on current medication use, were estimated (i.e., by logistic and linear regression) within the UK Biobank. These summary statistics, together with the two independent training summary statistics, were incorporated into the MT-GRS prediction in different combinations. The prediction accuracy of the MT-GRS was improved by 12.5% compared to the single-trait GRS. Testing the MT-GRS strategy in two independent T2DM studies resulted in an elevated accuracy by 50–94%. Finally, combining the seven information traits with the two independent T2DM studies further increased the prediction accuracy by 34%. Across comparisons, body mass index and current medication use were the two traits that displayed the largest weights in construction of the MT-GRS. These results explicitly demonstrate the added benefit of leveraging correlated information when constructing genetic scores. In conclusion, constructing GRS not only based on the disease itself but incorporating genomic information from other correlated traits as well is strongly advisable for obtaining improved individual risk stratification. Frontiers Media S.A. 2021-09-08 /pmc/articles/PMC8455930/ /pubmed/34568370 http://dx.doi.org/10.3389/fmed.2021.711208 Text en Copyright © 2021 Rohde, Nyegaard, Kjolby and Sørensen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Rohde, Palle Duun
Nyegaard, Mette
Kjolby, Mads
Sørensen, Peter
Multi-Trait Genomic Risk Stratification for Type 2 Diabetes
title Multi-Trait Genomic Risk Stratification for Type 2 Diabetes
title_full Multi-Trait Genomic Risk Stratification for Type 2 Diabetes
title_fullStr Multi-Trait Genomic Risk Stratification for Type 2 Diabetes
title_full_unstemmed Multi-Trait Genomic Risk Stratification for Type 2 Diabetes
title_short Multi-Trait Genomic Risk Stratification for Type 2 Diabetes
title_sort multi-trait genomic risk stratification for type 2 diabetes
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455930/
https://www.ncbi.nlm.nih.gov/pubmed/34568370
http://dx.doi.org/10.3389/fmed.2021.711208
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