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Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To d...

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Autores principales: Pang, Haipeng, Xia, Ying, Luo, Shuoming, Huang, Gan, Li, Xia, Xie, Zhiguo, Zhou, Zhiguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086251/
https://www.ncbi.nlm.nih.gov/pubmed/33753534
http://dx.doi.org/10.1136/jmedgenet-2020-107350
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author Pang, Haipeng
Xia, Ying
Luo, Shuoming
Huang, Gan
Li, Xia
Xie, Zhiguo
Zhou, Zhiguang
author_facet Pang, Haipeng
Xia, Ying
Luo, Shuoming
Huang, Gan
Li, Xia
Xie, Zhiguo
Zhou, Zhiguang
author_sort Pang, Haipeng
collection PubMed
description Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%–85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM.
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spelling pubmed-80862512021-05-14 Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus Pang, Haipeng Xia, Ying Luo, Shuoming Huang, Gan Li, Xia Xie, Zhiguo Zhou, Zhiguang J Med Genet Review Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%–85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM. BMJ Publishing Group 2021-05 2021-03-22 /pmc/articles/PMC8086251/ /pubmed/33753534 http://dx.doi.org/10.1136/jmedgenet-2020-107350 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Review
Pang, Haipeng
Xia, Ying
Luo, Shuoming
Huang, Gan
Li, Xia
Xie, Zhiguo
Zhou, Zhiguang
Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus
title Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus
title_full Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus
title_fullStr Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus
title_full_unstemmed Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus
title_short Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus
title_sort emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086251/
https://www.ncbi.nlm.nih.gov/pubmed/33753534
http://dx.doi.org/10.1136/jmedgenet-2020-107350
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