Publications by authors named "Zhili Zheng"

74 Publications

Widespread signatures of natural selection across human complex traits and functional genomic categories.

Nat Commun 2021 02 19;12(1):1164. Epub 2021 Feb 19.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

Understanding how natural selection has shaped genetic architecture of complex traits is of importance in medical and evolutionary genetics. Bayesian methods have been developed using individual-level GWAS data to estimate multiple genetic architecture parameters including selection signature. Here, we present a method (SBayesS) that only requires GWAS summary statistics. We analyse data for 155 complex traits (n = 27k-547k) and project the estimates onto those obtained from evolutionary simulations. We estimate that, on average across traits, about 1% of human genome sequence are mutational targets with a mean selection coefficient of ~0.001. Common diseases, on average, show a smaller number of mutational targets and have been under stronger selection, compared to other traits. SBayesS analyses incorporating functional annotations reveal that selection signatures vary across genomic regions, among which coding regions have the strongest selection signature and are enriched for both the number of associated variants and the magnitude of effect sizes.
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http://dx.doi.org/10.1038/s41467-021-21446-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896067PMC
February 2021

Phenotypic covariance across the entire spectrum of relatedness for 86 billion pairs of individuals.

Nat Commun 2021 02 16;12(1):1050. Epub 2021 Feb 16.

Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.

Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship ([Formula: see text]) among 417,060 individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and [Formula: see text] that agree with the SNP-based heritability ([Formula: see text]) in unrelated pairs ([Formula: see text]), and with pedigree-estimated heritability in close relatives ([Formula: see text]). The covariance increases faster than [Formula: see text] in distant relatives ([Formula: see text]), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct [Formula: see text]. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.
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http://dx.doi.org/10.1038/s41467-021-21283-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886899PMC
February 2021

Tumor Mutational Burden Is Polygenic and Genetically Associated with Complex Traits and Diseases.

Cancer Res 2021 03 8;81(5):1230-1239. Epub 2021 Jan 8.

Institute for Advanced Research, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.

Tumor mutational burden (TMB) is an emerging biomarker of response to immunotherapy in solid tumors. However, the extent to which variation in TMB between patients is attributable to germline genetic variation remains elusive. Here, using 7,004 unrelated patients of European descent across 33 cancer types from The Cancer Genome Atlas, we show that pan-cancer TMB is polygenic with approximately 13% of its variation explained by approximately 1.1 million common variants altogether. We identify germline variants that affect TMB in stomach adenocarcinoma through altering the expression levels of and . Further analyses provide evidence that TMB is genetically associated with complex traits and diseases, such as smoking, rheumatoid arthritis, height, and cancers, and some of the associations are likely causal. Overall, these results provide new insights into the genetic basis of somatic mutations in tumors and may inform future efforts to use genetic variants to stratify patients for immunotherapy. SIGNIFICANCE: This study provides evidence for a polygenic architecture of tumor mutational burden and opens an avenue for the use of whole-genome germline genetic variations to stratify patients with cancer for immunotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3459DOI Listing
March 2021

A unified framework for association and prediction from vertex-wise grey-matter structure.

Hum Brain Mapp 2020 Oct 20;41(14):4062-4076. Epub 2020 Jul 20.

Institute for Molecular Bioscience, the University of Queensland, St Lucia, Queensland, Australia.

The recent availability of large-scale neuroimaging cohorts facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. Here, we investigate the association (previously coined morphometricity) of a phenotype with all 652,283 vertex-wise measures of cortical and subcortical morphology in a large data set from the UK Biobank (UKB; N = 9,497 for discovery, N = 4,323 for replication) and the Human Connectome Project (N = 1,110). We used a linear mixed model with the brain measures of individuals fitted as random effects with covariance relationships estimated from the imaging data. We tested 167 behavioural, cognitive, psychiatric or lifestyle phenotypes and found significant morphometricity for 58 phenotypes (spanning substance use, blood assay results, education or income level, diet, depression, and cognition domains), 23 of which replicated in the UKB replication set or the HCP. We then extended the model for a bivariate analysis to estimate grey-matter correlation between phenotypes, which revealed that body size (i.e., height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the morphometricity (confirmed using a conditional analysis), providing possible insight into previous MRI case-control results for psychiatric disorders where case status is associated with body mass index. Our LMM framework also allowed to predict some of the associated phenotypes from the vertex-wise measures, in two independent samples. Finally, we demonstrated additional new applications of our approach (a) region of interest (ROI) analysis that retain the vertex-wise complexity; (b) comparison of the information retained by different MRI processings.
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http://dx.doi.org/10.1002/hbm.25109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469763PMC
October 2020

Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data.

Nat Commun 2020 04 28;11(1):2061. Epub 2020 Apr 28.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

Promoter-anchored chromatin interactions (PAIs) play a pivotal role in transcriptional regulation. Current high-throughput technologies for detecting PAIs, such as promoter capture Hi-C, are not scalable to large cohorts. Here, we present an analytical approach that uses summary-level data from cohort-based DNA methylation (DNAm) quantitative trait locus (mQTL) studies to predict PAIs. Using mQTL data from human peripheral blood ([Formula: see text]), we predict 34,797 PAIs which show strong overlap with the chromatin contacts identified by previous experimental assays. The promoter-interacting DNAm sites are enriched in enhancers or near expression QTLs. Genes whose promoters are involved in PAIs are more actively expressed, and gene pairs with promoter-promoter interactions are enriched for co-expression. Integration of the predicted PAIs with GWAS data highlight interactions among 601 DNAm sites associated with 15 complex traits. This study demonstrates the use of mQTL data to predict PAIs and provides insights into the role of PAIs in complex trait variation.
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http://dx.doi.org/10.1038/s41467-020-15587-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188843PMC
April 2020

Algorithm based on the optimal block zonal strategy for fast wavefront reconstruction.

Appl Opt 2020 Feb;59(5):1383-1396

Fast wavefront reconstruction is crucial for improving the temporal frequency of adaptive optics systems, in which a mass of subapertures is used. In this paper, we present a novel block zonal reconstruction algorithm based on Southwell geometry to speed up the wavefront reconstruction from Shack-Hartmann wavefront sensor measurements. Therein, we use the theory of computational complexity to install a novel optimal block zonal strategy to get the best size of the subwavefront and give the verification through simulations. Compared with the classical Southwell entire wavefront reconstruction algorithm, the algorithm based on the optimal block zonal strategy needs only a few milliseconds to finish the reconstruction process from 100×100 subapertures. Moreover, we analyze the superiority to use our algorithm to realize the phase reconstruction of the unconnected subwavefront, which cannot be reconstructed via traditional methods. Further, the simulation and experiments show that the precision of the algorithm based on the proposed optimal block zonal strategy is comparable with the commercial wavefront sensor HASO, the time consumption is much less than that of the traditional zonal reconstruction, and it is applicable to the square wavefront, circular wavefront, and local unconnected wavefront. Our proposed algorithm can be widely utilized in astronomical observation, laser transmission, and remote sensing.
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http://dx.doi.org/10.1364/AO.380999DOI Listing
February 2020

Efficient Estimation and Applications of Cross-Validated Genetic Predictions to Polygenic Risk Scores and Linear Mixed Models.

J Comput Biol 2020 04 20;27(4):599-612. Epub 2020 Feb 20.

Neurology, UCLA, Los Angeles, California.

Large-scale cohorts with combined genetic and phenotypic data, coupled with methodological advances, have produced increasingly accurate genetic predictors of complex human phenotypes called polygenic risk scores (PRSs). In addition to the potential translational impacts of identifying at-risk individuals, PRS are being utilized for a growing list of scientific applications, including causal inference, identifying pleiotropy and genetic correlation, and powerful gene-based and mixed-model association tests. Existing PRS approaches rely on external large-scale genetic cohorts that have also measured the phenotype of interest. They further require matching on ancestry and genotyping platform or imputation quality. In this work, we present a novel reference-free method to produce a PRS that does not rely on an external cohort. We show that naive implementations of reference-free PRS either result in substantial overfitting or prohibitive increases in computational time. We show that our algorithm avoids both of these issues and can produce informative in-sample PRSs over a single cohort without overfitting. We then demonstrate several novel applications of reference-free PRSs, including detection of pleiotropy across 246 metabolic traits and efficient mixed-model association testing.
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http://dx.doi.org/10.1089/cmb.2019.0325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185352PMC
April 2020

A resource-efficient tool for mixed model association analysis of large-scale data.

Nat Genet 2019 12 25;51(12):1749-1755. Epub 2019 Nov 25.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.

The genome-wide association study (GWAS) has been widely used as an experimental design to detect associations between genetic variants and a phenotype. Two major confounding factors, population stratification and relatedness, could potentially lead to inflated GWAS test statistics and hence to spurious associations. Mixed linear model (MLM)-based approaches can be used to account for sample structure. However, genome-wide association (GWA) analyses in biobank samples such as the UK Biobank (UKB) often exceed the capability of most existing MLM-based tools especially if the number of traits is large. Here, we develop an MLM-based tool (fastGWA) that controls for population stratification by principal components and for relatedness by a sparse genetic relationship matrix for GWA analyses of biobank-scale data. We demonstrate by extensive simulations that fastGWA is reliable, robust and highly resource-efficient. We then apply fastGWA to 2,173 traits on array-genotyped and imputed samples from 456,422 individuals and to 2,048 traits on whole-exome-sequenced samples from 46,191 individuals in the UKB.
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http://dx.doi.org/10.1038/s41588-019-0530-8DOI Listing
December 2019

Improved polygenic prediction by Bayesian multiple regression on summary statistics.

Nat Commun 2019 11 8;10(1):5086. Epub 2019 Nov 8.

Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, 4072, QLD, Australia.

Accurate prediction of an individual's phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. We extend a powerful individual-level data Bayesian multiple regression model (BayesR) to one that utilises summary statistics from genome-wide association studies (GWAS), SBayesR. In simulation and cross-validation using 12 real traits and 1.1 million variants on 350,000 individuals from the UK Biobank, SBayesR improves prediction accuracy relative to commonly used state-of-the-art summary statistics methods at a fraction of the computational resources. Furthermore, using summary statistics for variants from the largest GWAS meta-analysis (n ≈ 700, 000) on height and BMI, we show that on average across traits and two independent data sets that SBayesR improves prediction R by 5.2% relative to LDpred and by 26.5% relative to clumping and p value thresholding.
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http://dx.doi.org/10.1038/s41467-019-12653-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841727PMC
November 2019

Single-Cell Transcriptome Analysis Reveals Gene Signatures Associated with T-cell Persistence Following Adoptive Cell Therapy.

Cancer Immunol Res 2019 Nov 4;7(11):1824-1836. Epub 2019 Sep 4.

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can mediate responses in some patients with metastatic epithelial cancer. Identifying gene signatures associated with successful ACT might enable the development of improved therapeutic approaches. The persistence of transferred T cells in the peripheral blood is one indication of clinical effectiveness, but many T-cell and host factors may influence T-cell persistence. To limit these variables, we previously studied a patient with metastatic colorectal cancer treated with polyclonal TILs targeting the (G12D) hotspot mutation, who experienced a partial response for 9 months. Three dominant clonotypes specifically recognizing KRAS(G12D) epitopes were identified, but we found that only two clonotypes persisted 40 days after ACT. Because of these findings, in this study, we performed the single-cell transcriptome analysis of the infused TILs. The analysis revealed a total of 472 genes that were differentially expressed between clonotypes 9.1-NP and 9.2-P single cells, and 528 genes between 9.1-NP and 10-P. Following these clonotypes in the peripheral blood after ACT, the gene expression patterns changed, but , and remained expressed in the persistent 9.2-P and 10-P cells, compared with the nonpersistent 9.1-NP cells. In addition, four autologous TILs, which were used for treatment but persisted poorly 1 month after ACT, did not express the gene profiles associated with persistence. These results suggest that certain TIL populations possess a unique gene expression profile that can lead to the persistence of T cells. Thus, this single-patient study provides insight into how to improve ACT for solid cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825592PMC
November 2019

The Effects of Spatial Frequency on the Accommodative Responses of Myopic and Emmetropic Chinese Children.

Transl Vis Sci Technol 2019 May 28;8(3):65. Epub 2019 Jun 28.

Wenzhou Medical University (WMU), Wenzhou, China.

Purpose: The spatial frequency (SF) characteristics of accommodation in children are not well understood. In this study, we measured accommodative responses to grating targets to investigate the SF dependence of accommodation in children.

Methods: The effects of SF and contrast on the accommodative system were evaluated in two groups of children, including 22 with emmetropia and 20 with myopia. The contrast detection thresholds at five SFs were measured using a near-contrast sensitivity function test. The accommodative responses to grating targets with low (1.5 cycles per degree [cpd]), medium (6 cpd), and high (18 cpd) SFs were measured with a Grand Seiko WAM-5500 in dynamic mode for 30 seconds under standard and detection threshold contrast conditions. The accommodative lag and accommodative microfluctuations (AMFs) were compared between the two groups.

Results: Under standard contrast conditions, no significant difference was found in the accommodative lag across SFs ( = 2.03, = 0.14) or between the two groups ( = 3.57, 0.07). The AMFs were lowest at 6 cpd in emmetropia group ( = 6.51, = 0.003) and in total ( = 10.82, < 0.001). Children in emmetropia group showed greater AMFs at high SFs under detection threshold contrast conditions than under standard contrast conditions ( < 0.05).

Conclusions: This study demonstrated that the instability of accommodation was SF dependent in children. The AMFs in children were smallest at the medium SF for standard contrast grating targets. Myopic children are less sensitive to the low-contrast-induced blur for high SFs than emmetropic children.

Translational Relevance: This study provides a possibility to stabilize accommodative response of children by transforming SF components of fixation targets.
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http://dx.doi.org/10.1167/tvst.8.3.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602141PMC
May 2019

Identification of Neoantigen-Reactive Tumor-Infiltrating Lymphocytes in Primary Bladder Cancer.

J Immunol 2019 06 29;202(12):3458-3467. Epub 2019 Apr 29.

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

Immune checkpoint inhibitors are effective in treating a variety of malignancies, including metastatic bladder cancer. A generally accepted hypothesis suggests that immune checkpoint inhibitors induce tumor regressions by reactivating a population of endogenous tumor-infiltrating lymphocytes (TILs) that recognize cancer neoantigens. Although previous studies have identified neoantigen-reactive TILs from several types of cancer, no study to date has shown whether neoantigen-reactive TILs can be found in bladder tumors. To address this, we generated TIL cultures from patients with primary bladder cancer and tested their ability to recognize tumor-specific mutations. We found that CD4 TILs from one patient recognized mutated C-terminal binding protein 1 in an MHC class II-restricted manner. This finding suggests that neoantigen-reactive TILs reside in bladder cancer, which may help explain the effectiveness of immune checkpoint blockade in this disease and also provides a rationale for the future use of adoptive T cell therapy targeting neoantigens in bladder cancer.
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http://dx.doi.org/10.4049/jimmunol.1801022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548619PMC
June 2019

Genome-wide association study of medication-use and associated disease in the UK Biobank.

Nat Commun 2019 04 23;10(1):1891. Epub 2019 Apr 23.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

Genome-wide association studies (GWASs) of medication use may contribute to understanding of disease etiology, could generate new leads relevant for drug discovery and can be used to quantify future risk of medication taking. Here, we conduct GWASs of self-reported medication use from 23 medication categories in approximately 320,000 individuals from the UK Biobank. A total of 505 independent genetic loci that meet stringent criteria (P < 10/23) for statistical significance are identified. We investigate the implications of these GWAS findings in relation to biological mechanism, potential drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes are 16 known therapeutic-effect target genes for medications from 9 categories. Two of the medication classes studied are for disorders that have not previously been subject to large GWAS (hypothyroidism and gastro-oesophageal reflux disease).
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http://dx.doi.org/10.1038/s41467-019-09572-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478889PMC
April 2019

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor-transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma.

J Immunother 2019 05;42(4):126-135

Surgery Branch.

A deletion variant of epidermal growth factor receptor (EGFRvIII) is a known driver mutation in a subset of primary and secondary glioblastoma multiforme. Adoptive transfer of genetically modified chimeric antigen receptor (CAR) lymphocytes has demonstrated efficacy in hematologic malignancies but is still early in development for solid cancers. The surface expression of the truncated extracellular ligand domain created by EGFRvIII makes it an attractive target for a CAR-based cancer treatment. Patients with recurrent glioblastoma expressing EGFRvIII were enrolled in a dose escalation phase I trial, using a third-generation CAR construct derived from a human antibody. Transduced cells were administered after lymphodepleting chemotherapy and supported posttransfer with intravenous interleukin-2. The dose escalation proceeded at half-log increments from 10 to >10 cells. Primary endpoints were safety and progression-free survival. Eighteen patients were treated with final infusion products ranging from 6.3×10 to 2.6×10 anti-EGFRvIII CAR T cells. Median progression-free survival was 1.3 months (interquartile range: 1.1-1.9), with a single outlier of 12.5 months. Two patients experienced severe hypoxia, including one treatment-related mortality after cell administration at the highest dose level. All patients developed expected transient hematologic toxicities from preparative chemotherapy. Median overall survival was 6.9 months (interquartile range: 2.8-10). Two patients survived over 1 year, and a third patient was alive at 59 months. Persistence of CAR cells correlated with cell dose, but there were no objective responses. Administration of anti-EGFRvIII CAR-transduced T cells did not demonstrate clinically meaningful effect in patients with glioblastoma multiforme in this phase I pilot trial.
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http://dx.doi.org/10.1097/CJI.0000000000000260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691897PMC
May 2019

Identification of potential biomarkers in cholestasis and the therapeutic effect of melatonin by metabolomics, multivariate data and pathway analyses.

Int J Mol Med 2018 Nov 5;42(5):2515-2526. Epub 2018 Sep 5.

Synopsis of Golden Chamber, Chinese Medicine College, Beijing University of Chinese Medicine, Chaoyang, Beijing 100029, P.R. China.

The present study investigated the anti‑cholestatic effect of melatonin (MT) against α‑naphthyl isothiocyanate (ANIT)‑induced liver injury in rats and screened for potential biomarkers of cholestasis. Rats were administered ANIT by intraperitoneal injection and then sacrificed 36 h later. Serum biochemical parameters were measured and liver tissue samples were subjected to histological analysis. Active components in the serum were identified by gas chromatography‑mass spectrometry, while biomarkers and biochemical pathways were identified by multivariate data analysis. The results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, γ‑glutamyl transpeptidase, and alkaline phosphatase were reduced in rats with ANIT‑induced cholestasis that were treated with MT. The histological observations indicated that MT had a protective effect against ANIT‑induced hepatic tissue damage. Metabolomics analysis revealed that this effect was likely to be associated with the regulation of compounds related to MT synthesis and catabolism, and amino acid metabolism, including 5‑aminopentanoate, 5‑methoxytryptamine, L‑tryptophan, threonine, glutathione, L‑methionine, and indolelactate. In addition, principal component analysis demonstrated that the levels of these metabolites differed significantly between the MT and control groups, providing further evidence that they may be responsible for the effects induced by MT. These results provide an insight into the mechanisms underlying cholestasis development and highlight potential biomarkers for disease diagnosis.
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http://dx.doi.org/10.3892/ijmm.2018.3859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192756PMC
November 2018

Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry.

Hum Mol Genet 2018 10;27(20):3641-3649

Institute for Molecular Bioscience, The University of Queensland, Australia.

Recent genome-wide association studies (GWAS) of height and body mass index (BMI) in ∼250000 European participants have led to the discovery of ∼700 and ∼100 nearly independent single nucleotide polymorphisms (SNPs) associated with these traits, respectively. Here we combine summary statistics from those two studies with GWAS of height and BMI performed in ∼450000 UK Biobank participants of European ancestry. Overall, our combined GWAS meta-analysis reaches N ∼700000 individuals and substantially increases the number of GWAS signals associated with these traits. We identified 3290 and 941 near-independent SNPs associated with height and BMI, respectively (at a revised genome-wide significance threshold of P < 1 × 10-8), including 1185 height-associated SNPs and 751 BMI-associated SNPs located within loci not previously identified by these two GWAS. The near-independent genome-wide significant SNPs explain ∼24.6% of the variance of height and ∼6.0% of the variance of BMI in an independent sample from the Health and Retirement Study (HRS). Correlations between polygenic scores based upon these SNPs with actual height and BMI in HRS participants were ∼0.44 and ∼0.22, respectively. From analyses of integrating GWAS and expression quantitative trait loci (eQTL) data by summary-data-based Mendelian randomization, we identified an enrichment of eQTLs among lead height and BMI signals, prioritizing 610 and 138 genes, respectively. Our study demonstrates that, as previously predicted, increasing GWAS sample sizes continues to deliver, by the discovery of new loci, increasing prediction accuracy and providing additional data to achieve deeper insight into complex trait biology. All summary statistics are made available for follow-up studies.
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http://dx.doi.org/10.1093/hmg/ddy271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488973PMC
October 2018

Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.

Nat Commun 2018 07 27;9(1):2941. Epub 2018 Jul 27.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.
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http://dx.doi.org/10.1038/s41467-018-04951-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063971PMC
July 2018

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Nat Genet 2018 07 23;50(8):1112-1121. Epub 2018 Jul 23.

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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http://dx.doi.org/10.1038/s41588-018-0147-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393768PMC
July 2018

Association Between Population Density and Genetic Risk for Schizophrenia.

JAMA Psychiatry 2018 09;75(9):901-910

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Importance: Urban life has been proposed as an environmental risk factor accounting for the increased prevalence of schizophrenia in urban areas. An alternative hypothesis is that individuals with increased genetic risk tend to live in urban/dense areas.

Objective: To assess whether adults with higher genetic risk for schizophrenia have an increased probability to live in more populated areas than those with lower risk.

Design, Setting, And Participants: Four large, cross-sectional samples of genotyped individuals of European ancestry older than 18 years with known addresses in Australia, the United Kingdom, and the Netherlands were included in the analysis. Data were based on the postcode of residence at the time of last contact with the participants. Community-based samples who took part in studies conducted by the Queensland Institute for Medical Research Berghofer Medical Research Institute (QIMR), UK Biobank (UKB), Netherlands Twin Register (NTR), or QSkin Sun and Health Study (QSKIN) were included. Genome-wide association analysis and mendelian randomization (MR) were included. The study was conducted between 2016 and 2018.

Exposures: Polygenic risk scores for schizophrenia derived from genetic data (genetic risk is independently measured from the occurrence of the disease). Socioeconomic status of the area was included as a moderator in some of the models.

Main Outcomes And Measures: Population density of the place of residence of the participants determined from census data. Remoteness and socioeconomic status of the area were also tested.

Results: The QIMR participants (15 544; 10 197 [65.6%] women; mean [SD] age, 54.4 [13.2] years) living in more densely populated areas (people per square kilometer) had a higher genetic loading for schizophrenia (r2 = 0.12%; P = 5.69 × 10-5), a result that was replicated across all 3 other cohorts (UKB: 345 246; 187 469 [54.3%] women; age, 65.7 [8.0] years; NTR: 11 212; 6727 [60.0%] women; age, 48.6 [17.5] years; and QSKIN: 15 726; 8602 [54.7%] women; age, 57.0 [7.9] years). This genetic association could account for 1.7% (95% CI, 0.8%-3.2%) of the schizophrenia risk. Estimates from MR analyses performed in the UKB sample were significant (b = 0.049; P = 3.7 × 10-7 using GSMR), suggesting that the genetic liability to schizophrenia may have a causal association with the tendency to live in urbanized locations.

Conclusions And Relevance: The results of this study appear to support the hypothesis that individuals with increased genetic risk tend to live in urban/dense areas and suggest the need to refine the social stress model for schizophrenia by including genetics as well as possible gene-environment interactions.
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http://dx.doi.org/10.1001/jamapsychiatry.2018.1581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142911PMC
September 2018

Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood.

Nat Commun 2018 06 11;9(1):2282. Epub 2018 Jun 11.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples ([Formula: see text] for cis-eQTLs and [Formula: see text] for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.
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http://dx.doi.org/10.1038/s41467-018-04558-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995828PMC
June 2018

Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer.

Nat Med 2018 06 4;24(6):724-730. Epub 2018 Jun 4.

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations-such as melanoma, smoking-induced lung cancers and bladder cancer-with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins-SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.
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http://dx.doi.org/10.1038/s41591-018-0040-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348479PMC
June 2018

Global genetic differentiation of complex traits shaped by natural selection in humans.

Nat Commun 2018 05 14;9(1):1865. Epub 2018 May 14.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

There are mean differences in complex traits among global human populations. We hypothesize that part of the phenotypic differentiation is due to natural selection. To address this hypothesis, we assess the differentiation in allele frequencies of trait-associated SNPs among African, Eastern Asian, and European populations for ten complex traits using data of large sample size (up to ~405,000). We show that SNPs associated with height ([Formula: see text]), waist-to-hip ratio ([Formula: see text]), and schizophrenia ([Formula: see text]) are significantly more differentiated among populations than matched "control" SNPs, suggesting that these trait-associated SNPs have undergone natural selection. We further find that SNPs associated with height ([Formula: see text]) and schizophrenia ([Formula: see text]) show significantly higher variance in linkage disequilibrium (LD) scores across populations than control SNPs. Our results support the hypothesis that natural selection has shaped the genetic differentiation of complex traits, such as height and schizophrenia, among worldwide populations.
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http://dx.doi.org/10.1038/s41467-018-04191-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951811PMC
May 2018

Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits.

Nat Commun 2018 03 2;9(1):918. Epub 2018 Mar 2.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i.e., pleiotropy). We identify pleiotropic associations between 7858 DNAm sites and 2733 genes. These DNAm sites are enriched in enhancers and promoters, and >40% of them are mapped to distal genes. Further pleiotropic association analyses, which link both the methylome and transcriptome to 12 complex traits, identify 149 DNAm sites and 66 genes, indicating a plausible mechanism whereby the effect of a genetic variant on phenotype is mediated by genetic regulation of transcription through DNAm.
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http://dx.doi.org/10.1038/s41467-018-03371-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834629PMC
March 2018

Causal associations between risk factors and common diseases inferred from GWAS summary data.

Nat Commun 2018 01 15;9(1):224. Epub 2018 Jan 15.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

Health risk factors such as body mass index (BMI) and serum cholesterol are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. We develop and apply a method (called GSMR) that performs a multi-SNP Mendelian randomization analysis using summary-level data from genome-wide association studies to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height, and years of schooling (EduYears) with common diseases (sample sizes of up to 405,072). We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer's disease, and bidirectional associations with opposite effects (e.g., higher BMI increases the risk of T2D but the effect of T2D on BMI is negative).
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http://dx.doi.org/10.1038/s41467-017-02317-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768719PMC
January 2018

An Efficient Single-Cell RNA-Seq Approach to Identify Neoantigen-Specific T Cell Receptors.

Mol Ther 2018 02 28;26(2):379-389. Epub 2017 Oct 28.

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

The adoptive transfer of neoantigen-reactive tumor-infiltrating lymphocytes (TILs) can result in tumor regression in patients with metastatic cancer. To improve the efficacy of adoptive T cell therapy targeting these tumor-specific mutations, we have proposed a new therapeutic strategy, which involves the genetic modification of autologous T cells with neoantigen-specific T cell receptors (TCRs) and the transfer of these modified T cells back to cancer patients. However, the current techniques to isolate neoantigen-specific TCRs are labor intensive, time consuming, and technically challenging, not suitable for clinical applications. To facilitate this process, a new approach was developed, which included the co-culture of TILs with tandem minigene (TMG)-transfected or peptide-pulsed autologous antigen-presenting cells (APCs) and the single-cell RNA sequencing (RNA-seq) analysis of T cells to identify paired TCR sequences associated with cells expressing high levels of interferon-γ (IFN-γ) and interleukin-2 (IL-2). Following this new approach, multiple TCRs were identified, synthesized, cloned into a retroviral vector, and then transduced into donor T cells. These transduced T cells were shown to specifically recognize the neoantigens presented by autologous APCs. In conclusion, this approach provides an efficient procedure to isolate neoantigen-specific TCRs for clinical applications, as well as for basic and translational research.
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http://dx.doi.org/10.1016/j.ymthe.2017.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835023PMC
February 2018

Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II-Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3.

J Clin Oncol 2017 Oct 15;35(29):3322-3329. Epub 2017 Aug 15.

Yong-Chen Lu, Linda L. Parker, Tangying Lu, Zhili Zheng, Mary Ann Toomey, Donald E. White, Xin Yao, Yong F. Li, Paul F. Robbins, Steven A. Feldman, Christopher A. Klebanoff, Stephanie L. Goff, Richard M. Sherry, Udai S. Kammula, James C. Yang, and Steven A. Rosenberg, National Cancer Institute, Bethesda, MD; Pierre van der Bruggen, Ludwig Institute for Cancer Research; De Duve Institute, Université Catholique de Louvain, Brussels; and Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wallonia, Belgium; Christopher A. Klebanoff, Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy, New York, NY.

Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class I-restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8 T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4 T-cell therapy using an MHC class II-restricted, HLA-DPB1*0401-restricted TCR that recognized the cancer germline antigen, MAGE-A3 (melanoma-associated antigen-A3). Patients and Methods Patients received a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4 T cells, retrovirally transduced with MAGE-A3 TCR plus systemic high-dose IL-2. A cell dose escalation was conducted, starting at 10 total cells and escalating at half-log increments to approximately 10 cells. Nine patients were treated at the highest dose level (0.78 to 1.23 × 10 cells). Results Seventeen patients were treated. During the cell dose-escalation phase, an objective complete response was observed in a patient with metastatic cervical cancer who received 2.7 × 10 cells (ongoing at ≥ 29 months). Among nine patients who were treated at the highest dose level, objective partial responses were observed in a patient with esophageal cancer (duration, 4 months), a patient with urothelial cancer (ongoing at ≥ 19 months), and a patient with osteosarcoma (duration, 4 months). Most patients experienced transient fevers and the expected hematologic toxicities from lymphodepletion pretreatment. Two patients experienced transient grade 3 and 4 transaminase elevations. There were no treatment-related deaths. Conclusion These results demonstrate the safety and efficacy of administering autologous CD4 T cells that are genetically engineered to express an MHC class II-restricted antitumor TCR that targets MAGE-A3. This clinical trial extends the reach of TCR gene therapy for patients with metastatic cancer.
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http://dx.doi.org/10.1200/JCO.2017.74.5463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652397PMC
October 2017

Quantifying the mapping precision of genome-wide association studies using whole-genome sequencing data.

Genome Biol 2017 05 16;18(1):86. Epub 2017 May 16.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

Background: Understanding the mapping precision of genome-wide association studies (GWAS), that is the physical distances between the top associated single-nucleotide polymorphisms (SNPs) and the causal variants, is essential to design fine-mapping experiments for complex traits and diseases.

Results: Using simulations based on whole-genome sequencing (WGS) data from 3642 unrelated individuals of European descent, we show that the association signals at rare causal variants (minor allele frequency ≤ 0.01) are very unlikely to be mapped to common variants in GWAS using either WGS data or imputed data and vice versa. We predict that at least 80% of the common variants identified from published GWAS using imputed data are within 33.5 Kbp of the causal variants, a resolution that is comparable with that using WGS data. Mapping precision at these loci will improve with increasing sample sizes of GWAS in the future. For rare variants, the mapping precision of GWAS using WGS data is extremely high, suggesting WGS is an efficient strategy to detect and fine-map rare variants simultaneously. We further assess the mapping precision by linkage disequilibrium between GWAS hits and causal variants and develop an online tool (gwasMP) to query our results with different thresholds of physical distance and/or linkage disequilibrium ( http://cnsgenomics.com/shiny/gwasMP ).

Conclusions: Our findings provide a benchmark to inform future design and development of fine-mapping experiments and technologies to pinpoint the causal variants at GWAS loci.
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http://dx.doi.org/10.1186/s13059-017-1216-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432979PMC
May 2017

Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple-Negative Breast Cancer.

Clin Cancer Res 2017 Aug 4;23(15):4347-4353. Epub 2017 Apr 4.

Surgery Branch, NCI, Bethesda, Maryland.

The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer. A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized. We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4 and HLA-DRB1*1501-restricted TILs isolated from this tumor recognized a single mutation in (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples. Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348475PMC
August 2017

Genetic signatures of high-altitude adaptation in Tibetans.

Proc Natl Acad Sci U S A 2017 04 3;114(16):4189-4194. Epub 2017 Apr 3.

The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, China National Engineering Research Center of Ophthalmology and Optometry, State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou 325027, China

Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase () and ] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.
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http://dx.doi.org/10.1073/pnas.1617042114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402460PMC
April 2017

T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer.

N Engl J Med 2016 Dec;375(23):2255-2262

From the Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.

We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×10 HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.
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http://dx.doi.org/10.1056/NEJMoa1609279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5178827PMC
December 2016