Genome‐wide search for genes affecting the age at diagnosis of type 1 diabetes

Abstract

Background. Type 1 diabetes (T1D) is an autoimmune disease affecting individuals in the early years of life. Although previous studies have identified genetic loci influencing T1D diagnosis age, these studies did not investigate the genome with high resolution.Objective and methods. We performed a genome-wide meta-analysis for age at diagnosis with cohorts from Finland (Finnish Diabetic Nephropathy Study), the United Kingdom (UK Genetic Resource Investigating Diabetes) and Sardinia. Through SNP associations, transcriptome-wide association analysis linked T1D diagnosis age and gene expression.Results. We identified two chromosomal regions associated with T1D diagnosis age: multiple independent variants in the HLA region on chromosome 6 and a locus on chromosome 17q12. We performed gene-level association tests with transcriptome prediction models from two whole blood datasets, lymphocyte cell line, spleen, pancreas and small intestine tissues. Of the non-HLA genes, lower PNMT expression in whole blood, and higher IKZF3 and ZPBP2, and lower ORMDL3 and GSDMB transcription levels in multiple tissues were associated with lower T1D diagnosis age (FDR = 0.05). These genes lie on chr17q12 which is associated with T1D, other autoimmune diseases, and childhood asthma. Additionally, higher expression of PHF20L1, a gene not previously implicated in T1D, was associated with lower diagnosis age in lymphocytes, pancreas, and spleen. Altogether, the non-HLA associations were enriched in open chromatin in various blood cells, blood vessel tissues and foetal thymus tissue. Conclusion.Multiple genes on chr17q12 and PHF20L1 on chr8 were associated with T1D diagnosis age and only further studies may elucidate the role of these genes for immunity and T1D onset.

Is anxiety a pathway to Alcohol Use Disorders? A phenome-wide association study of theGABRA2coding variant rs279858

“…GABRA2 has been associated with a number of other traits in GWAS, including epilepsy [17,58], post bronchodilator FEV1/FVC ratio [59], Alzheimer disease and age of onset [18], Mononucleosis [60], general cognitive ability [61], general risk tolerance (MTAG) [19], adventurousness [19], protein quantitative trait loci (liver)[62], and Type 1 diabetes (age at diagnosis)[63]. It is notable that the association findings for general cognitive ability, general risk tolerance, and adventurousness were found in UKBB data.…”

Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants

“…Recent genetic analyses have reported a novel susceptibility locus associated with early diagnosis of T1D between the PTPRK and THEMIS genes 13 , 32 . As the thymus is likely to play a major role in early-onset autoimmune diseases, and the THEMIS gene contributes to the thymocyte selection in the thymus, we hypothesised that the underlying causal genetic variant would affect a regulatory motif active in thymocytes.…”

Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants

“…Recent genetic analyses have reported a novel susceptibility locus associated with early diagnosis of type 1 diabetes between the PTPRK and THEMIS genes (13,30). As the thymus is likely to play a major role in early onset autoimmune diseases, and the THEMIS gene contributes to positive and negative T cell selection in thymus, we hypothesised that the underlying causal genetic variant would affect a regulatory motif active in thymocytes.…”