Improved genetic risk scoring algorithm for type 1 diabetes prediction

Qu, Hui‐Qi; Qu, Jingchun; Glessner, Joseph; Liu, Yichuan; Mentch, Frank; Chang, Xiao; March, Michael; Jin, Li; Roizen, Jeffrey D.; Connolly, John J.; Sleiman, Patrick; Hákonarson, Hákon

doi:10.1111/pedi.13310

Cited by 13 publications

(17 citation statements)

References 16 publications

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“…The HLA region is highly polymorphic, with highly diverse frequencies across different populations, as well as extended and strong LD due to significant evolutionary selection pressure in human populations 21 22 . Including the HLA region will cause significant difference of PRS across different ethnicities, as we have observed in the trans-ethnic scoring of an autoimmune disease, type 1 diabetes (T1D), with HLA as a major risk factor 23 . In addition, there has been no GWAS study to date suggesting the role of the HLA region in BMI or obesity.…”

Section: Discussionmentioning

confidence: 89%

Trans-ethnic Polygenic Risk Scores for Body Mass Index: An International Hundred K+ Cohorts Consortium Study

Connolly

Kraft

et al. 2023

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Background While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort. Methods The PRS model was developed trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis. Results We show that in the absence of a well powered trans-ethnic GWAS from which to derive SNPs and effect estimates, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred to adjust the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort. Conclusions Widespread use of PRS in the clinic is hampered by a lack of genotyping data in individuals of non-European ancestry for the vast majority of traits. Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.

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Section: Discussionmentioning

confidence: 89%

Trans-ethnic Polygenic Risk Scores for Body Mass Index: An International Hundred K+ Cohorts Consortium Study

Connolly

Kraft

et al. 2023

Preprint

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“…In addition, such vaccines would need to elicit adequate levels of neutralizing but not enhancing antibodies. Candidate children for vaccination could be selected using a GRS for T1DM 4 , 5 .…”

Section: Prevention and Treatment Of T1dmmentioning

confidence: 99%

“…Genetic risk score (GRS) models derived from the combination of HLA and non-HLA T1DM-associated loci were designed to predict the progression of islet autoimmunity and clinical T1DM 4 . The performance of T1DM GRS models still needs to be improved based on racial and ethnic genetic differences 5 . However, genetic susceptibility is insufficient to explain the increasing annual incidence rate of T1DM, which in many locations has been 3–4% in children and adolescents over the past few decades 6 .…”

Section: Introductionmentioning

confidence: 99%

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

2022

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Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.

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“…The PRS aggregated the effects of GWAS loci other than the APOE locus into a single score, an approach that has been shown as an effective approach to identify patients with high risk of many complex diseases [17][18][19] . In particular, a PRS with selected loci has been demonstrated for precise prediction of type 1 diabetes (T1D) 20 . Compared to AD with APOE as a major genetic locus plus a number of minor loci, T1D has also the human leukocyte antigen (HLA) region as a major genetic locus plus a number of minor loci 20 .…”

Section: Introductionmentioning

confidence: 99%

“…In particular, a PRS with selected loci has been demonstrated for precise prediction of type 1 diabetes (T1D) 20 . Compared to AD with APOE as a major genetic locus plus a number of minor loci, T1D has also the human leukocyte antigen (HLA) region as a major genetic locus plus a number of minor loci 20 . Enabled by risk prediction using GIRA, and with more attention given to the high risk patients, this will consequently enable early diagnosis and early intervention for the disease.…”

Section: Introductionmentioning

confidence: 99%

Trans-ethnic Genomic Informed Risk Assessment for Alzheimer’s disease: An International Hundred K+ Cohorts Consortium Study

Sleiman

Connolly

et al. 2022

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Background Alzheimer's disease (AD) is a complex multifactorial progressive dementia affecting all human populations. As a collaboration model between the International Hundred K+ Cohorts Consortium (IHCC) and the Davos Alzheimer Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for AD. Methods The GIRA model was created to include a polygenic risk score (PRS) calculated from the AD GWAS loci, the APOE haplotypes, and non-genetic covariates including age, sex and first 3 principal components of population substructure. The model was first validated using a dataset from the eMERGE network, and subsequently validated in a South-Asian population in UK and 3 East-Asian populations. The distributions of the PRS scores were also explored in populations from 3 African regions. In two validation sites, the PRS was tested for associated with the levels of plasma proteomics markers. Results We created a trans-ethnic GIRA model for the risk prediction of AD and validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD, highlighting molecular mechanisms underlying the previously observed correlations between these clinical diseases. Conclusions As the initial effort by the IHCC to leverage existing large scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA on AD with the potential of identifying individuals at high risk of developing AD for future clinical applications. The PRS scores in this model also contribute new research discoveries for the molecular pathogenesis of AD as demonstrated by the proteomic data.

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Improved genetic risk scoring algorithm for type 1 diabetes prediction

Cited by 13 publications

References 16 publications

Trans-ethnic Polygenic Risk Scores for Body Mass Index: An International Hundred K+ Cohorts Consortium Study

Trans-ethnic Polygenic Risk Scores for Body Mass Index: An International Hundred K+ Cohorts Consortium Study

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Trans-ethnic Genomic Informed Risk Assessment for Alzheimer’s disease: An International Hundred K+ Cohorts Consortium Study

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