Dataset Information

A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes.

ABSTRACT: AIMS/HYPOTHESIS:Identifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies. METHODS:We studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS. RESULTS:Of the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p?

SUBMITTER: Johnson MB

PROVIDER: S-EPMC6448971 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes.

Johnson Matthew B MB Patel Kashyap A KA De Franco Elisa E Houghton Jayne A L JAL McDonald Timothy J TJ Ellard Sian S Flanagan Sarah E SE Hattersley Andrew T AT

Diabetologia 20180207 4

<h4>Aims/hypothesis</h4>Identifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise ...[more]

PMID: 29417186

Similar Datasets

Project description:BackgroundThe relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.MethodsWe performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.ResultsThe mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).ConclusionsBoth familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.Clinical trial registrationURL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.

Project description:BackgroundEvidence is lacking on the impact of alcohol consumption on colorectal cancer (CRC) risk (overall and by age at diagnosis) by polygenic risk score (PRS) levels, and it is unclear how the magnitude of CRC risk associated with alcohol consumption compares to the magnitude of genetically determined risk.MethodsMultiple logistic regression was used to assess the association between alcohol consumption and colorectal cancer (CRC) across PRS levels based on 140 CRC-related loci among 5104 CRC cases and 4131 controls from a large population-based case-control study. We compared the effects for alcohol consumption and PRS on CRC risk using the "Genetic Risk Equivalent (GRE)" for effective risk communication. Specific analyses were conducted for early-onset CRC (EOCRC, <55 years) and late-onset CRC (LOCRC, ≥55 years).FindingsHigh alcohol consumption, and to a lower extent, also alcohol abstinence were associated with increased CRC risk. Compared to low alcohol consumption (0·1-<25 g/d), lifetime average alcohol consumption ≥25 g/d was more strongly associated with EOCRC [odds ratio (OR) 1·8, 95% confidence interval (CI) 1·2-2·8] than with LOCRC risk (OR 1·3, 95% CI 1·1-1·4) (P-value for interaction with age =0·011). Interactions between alcohol consumption and PRS did not reach statistical significance for either EOCRC or LOCRC risk. The estimated impact of high lifetime alcohol consumption on EOCRC was equivalent to the effect of having 47 percentiles higher PRS (GRE 47, 95% CI 12-82), stronger than the impact on LOCRC (GRE 18, 95% CI 8-29).InterpretationExcessive alcohol use was strongly associated with EOCRC risk, independent of PRS levels. Abstaining from heavy drinking could reduce risk for CRC, in particular for EOCRC to an extent that would be equivalent to having a much lower genetically determined risk.FundingThe first author (X.C.) was supported by the Guangzhou Elite Project (GEP). The DACHS study was supported by grants from the German Research Council (BR 1704/6-1, BR1704/6-3, BR 1704/6-4, BR 1704/6-6, CH 117/1-1, BR 1704/17-1, HO 5117/2-1) and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01GL1712).

Project description:IntroductionMonogenic diabetes is attributed to genetic variations in a single gene. Maturity-onset diabetes of the young (MODY) is the most common phenotype associated with monogenic diabetes, but is frequently misdiagnosed as either type 1 or type 2 diabetes. Increasing our basic understanding of genetic variations in MODY may help to improve the accuracy of providing the correct diagnosis and personalize subsequent treatment regimens in different racial populations. For this reason, this study was designed to identify nucleotide variants in early onset diabetes patients with clinically suspected MODY in a Korean population.Research design and methodsAmong 2908 Korean patients diagnosed with diabetes, we selected 40 patients who were diagnosed before 30 years old and were clinically suspected of MODY. Genetic testing was performed using a targeted gene sequencing panel that included 30 known monogenic diabetes genes. The pathogenicity of the identified variants was assessed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG-AMP) guidelines.ResultsA total of six rare missense variants (p.Ala544Thr in HNF1A, p.Val601Ile and p.His103Tyr in ABCC8, p.Pro33Ala in PDX1, p.Gly18Glu in INS, and p.Arg164Gln in PAX4) in five distinct MODY genes were identified in five patients. In addition, a variant was identified in mitochondrial DNA at 3243A>G in one patient. The identified variants were either absent or detected at a rare frequency in the 1000 Genomes Project. These variants were classified as uncertain significance using the ACMG-AMP guidelines.ConclusionUsing a targeted gene sequencing panel, we identified seven variants in either MODY genes or mitochondrial DNA using a Korean patient population with early onset diabetes who were clinically suspected of MODY. This genetic approach provides the ability to compare distinct populations of racial and ethnic groups to determine whether specific gene is involved in their diagnosis of MODY.

Project description:OBJECTIVE:In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). METHODS:Treatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003 to 2008. Mayo Clinic Bipolar Biobank samples were collected from 2009 to 2013. Genotyping and analyses for the present study took place from 2013 to 2014. The diagnosis of BD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with BD, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly "odz, odd Oz/10-m homolog 4 {Drosophila}, ODZ4"]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n = 69); adult patients with BD (n = 732), including a subset with early-onset illness (n = 192); and healthy controls (n = 776). GRS analyses were performed to compare early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored. RESULTS:GRS analysis revealed associations of the risk score with early-onset BD (P = .01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset BD with a CACNA1C haplotype (global test, P = .01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset BD (P = .017), which did not remain significant after correction for multiple comparisons. CONCLUSIONS:These preliminary analyses suggest that previously identified BD risk loci, especially CACNA1C, have a role in early-onset BD, possibly with stronger effects than for late-onset BD.

Dataset Information

A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes.

Publications

A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets