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

Ramesh Ram, Munish Mehta, Quang Nguyen, Irma Larma, B.O. Boehm, F. Pociot, P. Concannon, Grant Morahan

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Copyright © 2016 by The American Association of Immunologists, Inc. 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.
Original languageEnglish
Pages (from-to)3043-3053
Number of pages11
JournalJournal of Immunology
Volume196
Issue number7
Early online date24 Feb 2016
DOIs
Publication statusPublished - 1 Apr 2016

Fingerprint Dive into the research topics of 'Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility'. Together they form a unique fingerprint.

Cite this