Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility

Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are no...

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Main Authors: Boehm, Bernhard Otto, Morahan, Grant, Ram, Ramesh, Mehta, Munish, Nguyen, Quang T., Larma, Irma, Pociot, Flemming, Concannon, Patrick
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2018
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Online Access:https://hdl.handle.net/10356/87809
http://hdl.handle.net/10220/46817
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-878092022-02-16T16:29:31Z Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility Boehm, Bernhard Otto Morahan, Grant Ram, Ramesh Mehta, Munish Nguyen, Quang T. Larma, Irma Pociot, Flemming Concannon, Patrick Lee Kong Chian School of Medicine (LKCMedicine) Diabetes Genes and Genetic Variants DRNTU::Science::Medicine Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r2 > 0.8) with the reported single nucleotide polymorphisms for each locus were tested for commonly occurring nonsynonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4+ and CD8+ T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting that most of the T1D risk alleles mediate their effect by influencing expression of multiple nearby genes. 2018-12-05T04:15:29Z 2019-12-06T16:49:54Z 2018-12-05T04:15:29Z 2019-12-06T16:49:54Z 2016 Journal Article Ram, R., Mehta, M., Nguyen, Q. T., Larma, I., Boehm, B. O., Pociot, F., . . . Morahan, G. (2016). Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility. The Journal of Immunology, 196(7), 3043-3053. doi:10.4049/jimmunol.1502056 0022-1767 https://hdl.handle.net/10356/87809 http://hdl.handle.net/10220/46817 10.4049/jimmunol.1502056 26912320 en The Journal of Immunology © 2016 American Association of Immunologists (AAI).
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Diabetes
Genes and Genetic Variants
DRNTU::Science::Medicine
spellingShingle Diabetes
Genes and Genetic Variants
DRNTU::Science::Medicine
Boehm, Bernhard Otto
Morahan, Grant
Ram, Ramesh
Mehta, Munish
Nguyen, Quang T.
Larma, Irma
Pociot, Flemming
Concannon, Patrick
Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility
description Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r2 > 0.8) with the reported single nucleotide polymorphisms for each locus were tested for commonly occurring nonsynonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4+ and CD8+ T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting that most of the T1D risk alleles mediate their effect by influencing expression of multiple nearby genes.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Boehm, Bernhard Otto
Morahan, Grant
Ram, Ramesh
Mehta, Munish
Nguyen, Quang T.
Larma, Irma
Pociot, Flemming
Concannon, Patrick
format Article
author Boehm, Bernhard Otto
Morahan, Grant
Ram, Ramesh
Mehta, Munish
Nguyen, Quang T.
Larma, Irma
Pociot, Flemming
Concannon, Patrick
author_sort Boehm, Bernhard Otto
title Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility
title_short Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility
title_full Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility
title_fullStr Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility
title_full_unstemmed Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility
title_sort systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility
publishDate 2018
url https://hdl.handle.net/10356/87809
http://hdl.handle.net/10220/46817
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