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Type 1 diabetes (T1D) patients with low genetic risk scores (GRS) may be non-autoimmune or autoimmune mediated by other genetic loci. The T1D-GRS2 provides us an opportunity to look into the genetic architecture of these patients. A total of 18,949 European individuals were included in this study, including 6599 T1D cases and 12,323 controls. 957 (14.5%) T1D patients were identified with low GRS (GRS < 8.43). The genome-wide association study on these patients identified 41 unreported loci. Two loci with common variants and 39 loci with rare variants were identified in this study. This study identified common SNPs associated with both low GRS T1D and expression levels of the interferon-α-induced MNDA gene, indicating the role of viral infection in T1D. Interestingly, 16 of the 41 unreported loci have been linked to autism spectrum disorder (ASD) by previous studies, suggesting that genes residing at these loci may underlie both T1D and autism.
Hui-Qi Qu; Jingchun Qu; Jonathan Bradfield; Luc Marchand; Joseph Glessner; Xiao Chang; Michael March; Jin Li; John J. Connolly; Jeffrey D. Roizen; Patrick Sleiman; Constantin Polychronakos; Hakon Hakonarson. Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci. Communications Biology 2021, 4, 1 -10.
AMA StyleHui-Qi Qu, Jingchun Qu, Jonathan Bradfield, Luc Marchand, Joseph Glessner, Xiao Chang, Michael March, Jin Li, John J. Connolly, Jeffrey D. Roizen, Patrick Sleiman, Constantin Polychronakos, Hakon Hakonarson. Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci. Communications Biology. 2021; 4 (1):1-10.
Chicago/Turabian StyleHui-Qi Qu; Jingchun Qu; Jonathan Bradfield; Luc Marchand; Joseph Glessner; Xiao Chang; Michael March; Jin Li; John J. Connolly; Jeffrey D. Roizen; Patrick Sleiman; Constantin Polychronakos; Hakon Hakonarson. 2021. "Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci." Communications Biology 4, no. 1: 1-10.
Current understanding of the underlying molecular network and mechanism for attention-deficit hyperactivity disorder (ADHD) is lacking and incomplete. Previous studies suggest that genomic structural variations play an important role in the pathogenesis of ADHD. For effective modeling, deep learning approaches have become a method of choice, with ability to predict the impact of genetic variations involving complicated mechanisms. In this study, we examined copy number variation in whole genome sequencing from 116 African Americans ADHD children and 408 African American controls. We divided the human genome into 150 regions, and the variation intensity in each region was applied as feature vectors for deep learning modeling to classify ADHD patients. The accuracy of deep learning for predicting ADHD diagnosis is consistently around 78% in a two-fold shuffle test, compared with ∼50% by traditional k-mean clustering methods. Additional whole genome sequencing data from 351 European Americans children, including 89 ADHD cases and 262 controls, were applied as independent validation using feature vectors obtained from the African American ethnicity analysis. The accuracy of ADHD labeling was lower in this setting (∼70–75%) but still above the results from traditional methods. The regions with highest weight overlapped with the previously reported ADHD-associated copy number variation regions, including genes such as GRM1 and GRM8, key drivers of metabotropic glutamate receptor signaling. A notable discovery is that structural variations in non-coding genomic (intronic/intergenic) regions show prediction weights that can be as high as prediction weight from variations in coding regions, results that were unexpected.
Yichuan Liu; Hui-Qi Qu; Xiao Chang; Kenny Nguyen; Jingchun Qu; Lifeng Tian; Joseph Glessner; Patrick Ma Sleiman; Hakon Hakonarson. Deep learning prediction of attention-deficit hyperactivity disorder in African Americans by copy number variation. Experimental Biology and Medicine 2021, 1 .
AMA StyleYichuan Liu, Hui-Qi Qu, Xiao Chang, Kenny Nguyen, Jingchun Qu, Lifeng Tian, Joseph Glessner, Patrick Ma Sleiman, Hakon Hakonarson. Deep learning prediction of attention-deficit hyperactivity disorder in African Americans by copy number variation. Experimental Biology and Medicine. 2021; ():1.
Chicago/Turabian StyleYichuan Liu; Hui-Qi Qu; Xiao Chang; Kenny Nguyen; Jingchun Qu; Lifeng Tian; Joseph Glessner; Patrick Ma Sleiman; Hakon Hakonarson. 2021. "Deep learning prediction of attention-deficit hyperactivity disorder in African Americans by copy number variation." Experimental Biology and Medicine , no. : 1.
Background: Thanks to the availability of new biomarkers, Prostate cancer (PCa) can now be diagnosed earlier and, as a result, PCa patients have a high 5-year survival rate. Nonetheless, the situation changes completely for patients who develop metastasis, for whom 5-year survival rate decreases to 29%. Recent candidate-gene approaches have identified new candidates, but there are still no drugs to prevent or cure metastatic PCa. Hence, there is an urgent need to find effective therapeutic targets. Methodology: In this study we have conducted a high-throughput CRISPR/Cas9 screening in highly metastatic PCa cell lines PC3 and DU145, using the CRISPR/Cas9 knock-out (GeCKO) library, that targets 18,080 genes with 64,751 unique gRNAs. To assess whether each gene loss-of-function may be critical for metastasis development, invasion assays in Matrigel-coated Boyden Chamber membranes were used. Next-generation sequencing and bioinformatic MaGECK analysis were then carried out to identify novel key genes in the development of PCa metastasis. siRNA approach was used to further validate the best candidates. Results: We found 29 candidates and several signaling pathways capable of significatively impair the invasion of, both, PC3 and DU145 cell lines when knocked-out, being PRMT7 the strongest regulator. PRMT7 gene encodes a type II methyltransferase involved in several cellular processes such as mRNA splicing or DNA repair. There are evidences that indicate it regulates EMT through methylation of E-cadherin promoter and other targets. Moreover, its overexpression correlates with higher levels of expression of MMP9 and MMP2 that lead to metastasis appearance in other types of tumors. Our results inhibiting PRMT7 expression with siRNA validated our high-throughput CRISPR/Cas9 screening results and confirmed the implication of PRMT7 in PCa invasion. Conclusions: We have conducted a novel high-throughput CRISPR-Cas9 screening, finding promising gene candidates, such as PRMT7, which, in the future could be used as therapeutical targets to prevent metastasis development in PCa patients. Furthermore, in this study we have also found genes that had been previously associated to PCa metastasis in other candidate-gene studies, giving a proof-of-concept for the use of high performance of CRISPR-Cas9 screenings for the search of candidate genes involved in PCa metastasis. Citation Format: Maria Rodrigo Faus, Sara Manzano Figueroa, Jingchun Qu, Huiqi Qu, Renata Pellegrino, Hakon Hakonarson, Paloma Bragado, Almudena Porras, Alvaro Gutierrez-Uzquiza. Identification of novel essential genes for prostate cancer metastasis by genome scale CRISPR approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2310.
Maria Rodrigo Faus; Sara Manzano Figueroa; Jingchun Qu; Huiqi Qu; Renata Pellegrino; Hakon Hakonarson; Paloma Bragado; Almudena Porras; Alvaro Gutierrez-Uzquiza. Abstract 2310: Identification of novel essential genes for prostate cancer metastasis by genome scale CRISPR approaches. Molecular and Cellular Biology/Genetics 2021, 81, 2310 -2310.
AMA StyleMaria Rodrigo Faus, Sara Manzano Figueroa, Jingchun Qu, Huiqi Qu, Renata Pellegrino, Hakon Hakonarson, Paloma Bragado, Almudena Porras, Alvaro Gutierrez-Uzquiza. Abstract 2310: Identification of novel essential genes for prostate cancer metastasis by genome scale CRISPR approaches. Molecular and Cellular Biology/Genetics. 2021; 81 (13 Supplem):2310-2310.
Chicago/Turabian StyleMaria Rodrigo Faus; Sara Manzano Figueroa; Jingchun Qu; Huiqi Qu; Renata Pellegrino; Hakon Hakonarson; Paloma Bragado; Almudena Porras; Alvaro Gutierrez-Uzquiza. 2021. "Abstract 2310: Identification of novel essential genes for prostate cancer metastasis by genome scale CRISPR approaches." Molecular and Cellular Biology/Genetics 81, no. 13 Supplem: 2310-2310.
Objective The cytokines, LIGHT (TNFSF14) and Interleukin-18 (IL-18), are two important therapeutic targets due to their central roles in the function of activated T cells and inflammatory injury. LIGHT was recently shown to play a major role in COVID19 induced acute respiratory distress syndrome (ARDS), reducing mortality and hospital stay. This study aims to investigate the associations of LIGHT and IL-18 with non-COVID19 related ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), secondary to viral or bacterial sepsis. Research Design and Methods A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this study and compared to healthy controls. Serum LIGHT, IL-18, and 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured and associated with symptom severity. Results ARDS was observed in 36% of the patients, with 29% of the total patient cohort developing multi-organ failure (failure of two or more organs). We observed significantly increased LIGHT level (>2SD above mean of healthy subjects) in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures, suggesting LIGHT may be an inflammatory driver. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis. Conclusions For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. LIGHT levels are significantly elevated in non-COVID19 sepsis patients with ARDS and/or multi-organ failures suggesting that anti-LIGHT therapy may be effective therapy in a subset of patients with sepsis. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway raises opportunities that require a precision application.
Hui-Qi Qu; Jingchun Qu; Thomas Dunn; James Snyder; Todd A. Miano; John Connolly; Joseph Glessner; Brian J. Anderson; John P. Reilly; Tiffanie K. Jones; Heather M. Giannini; Roseline S. Agyekum; Ariel R. Weisman; Caroline A.G. Ittner; Laura G. Rodrigues; Charlly Kao; Michael G.S. Shashaty; Patrick Sleiman; Nuala J. Meyer; Hakon Hakonarson. Elevation of Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries. medRxiv 2021, 1 .
AMA StyleHui-Qi Qu, Jingchun Qu, Thomas Dunn, James Snyder, Todd A. Miano, John Connolly, Joseph Glessner, Brian J. Anderson, John P. Reilly, Tiffanie K. Jones, Heather M. Giannini, Roseline S. Agyekum, Ariel R. Weisman, Caroline A.G. Ittner, Laura G. Rodrigues, Charlly Kao, Michael G.S. Shashaty, Patrick Sleiman, Nuala J. Meyer, Hakon Hakonarson. Elevation of Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries. medRxiv. 2021; ():1.
Chicago/Turabian StyleHui-Qi Qu; Jingchun Qu; Thomas Dunn; James Snyder; Todd A. Miano; John Connolly; Joseph Glessner; Brian J. Anderson; John P. Reilly; Tiffanie K. Jones; Heather M. Giannini; Roseline S. Agyekum; Ariel R. Weisman; Caroline A.G. Ittner; Laura G. Rodrigues; Charlly Kao; Michael G.S. Shashaty; Patrick Sleiman; Nuala J. Meyer; Hakon Hakonarson. 2021. "Elevation of Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries." medRxiv , no. : 1.
We previously observed enhanced immunoglobulin A (IgA) responses in severe COVID‐19, which might confer damaging effects. Given the important role of IgA in immune and inflammatory responses, the aim of this study was to investigate the dynamic response of the IgA isotype switch factor TGF‐β1 in COVID‐19 patients. We observed, in a total of 153 COVID‐19 patients, that the serum levels of TGF‐β1 were increased significantly at the early and middle stages of COVID‐19, and correlated with the levels of SARS‐CoV‐2‐specific IgA, as well as with the APACHE‐II score in patients with severe disease. In view of the genetic association of the TGF‐β1 activator THBS3 with severe COVID‐19 identified by the COVID‐19 Host Genetics Initiative, this study suggests TGF‐β1 may play a key role in COVID‐19.
Er‐Yi Wang; Hao Chen; Bao‐Qing Sun; Hui Wang; Hui‐Qi Qu; Yichuan Liu; Xi‐Zhuo Sun; Jingchun Qu; Zhang‐Fu Fang; Lifeng Tian; Yi‐Feng Zeng; Shau‐Ku Huang; Hakon Hakonarson; Zhi‐Gang Liu. Serum levels of the IgA isotype switch factor TGF‐β1 are elevated in patients with COVID‐19. FEBS Letters 2021, 1 .
AMA StyleEr‐Yi Wang, Hao Chen, Bao‐Qing Sun, Hui Wang, Hui‐Qi Qu, Yichuan Liu, Xi‐Zhuo Sun, Jingchun Qu, Zhang‐Fu Fang, Lifeng Tian, Yi‐Feng Zeng, Shau‐Ku Huang, Hakon Hakonarson, Zhi‐Gang Liu. Serum levels of the IgA isotype switch factor TGF‐β1 are elevated in patients with COVID‐19. FEBS Letters. 2021; ():1.
Chicago/Turabian StyleEr‐Yi Wang; Hao Chen; Bao‐Qing Sun; Hui Wang; Hui‐Qi Qu; Yichuan Liu; Xi‐Zhuo Sun; Jingchun Qu; Zhang‐Fu Fang; Lifeng Tian; Yi‐Feng Zeng; Shau‐Ku Huang; Hakon Hakonarson; Zhi‐Gang Liu. 2021. "Serum levels of the IgA isotype switch factor TGF‐β1 are elevated in patients with COVID‐19." FEBS Letters , no. : 1.
While there is no cure for chronic obstructive pulmonary disease (COPD), its progressive nature and the formidable challenge to manage its symptoms warrant a more extensive study of the pathogenesis and related mechanisms. A new emphasis on COPD study is the change of energy metabolism. For the first time, this study investigated the anaerobic and aerobic energy metabolic pathways in COPD using the metabolomic approach. Metabolomic analysis was used to investigate energy metabolites in 140 COPD patients. The significance of energy metabolism in COPD was comprehensively explored by the Global Initiative for Chronic Obstructive Lung Disease–GOLD grading, acute exacerbation vs. stable phase (either clinical stability or four-week stable phase), age group, smoking index, lung function, and COPD Assessment Test (CAT) score. Through comprehensive evaluation, we found that COPD patients have a significant imbalance in the aerobic and anaerobic energy metabolisms in resting state, and a high tendency of anaerobic energy supply mechanism that correlates positively with disease progression. This study highlighted the significance of anaerobic and low-efficiency energy supply pathways in lung injury and linked it to the energy-inflammation-lung ventilatory function and the motion limitation mechanism in COPD patients, which implies a novel therapeutic direction for this devastating disease.
Mingshan Xue; Yifeng Zeng; Runpei Lin; Hui-Qi Qu; Teng Zhang; Xiaohua Douglas Zhang; Yueting Liang; Yingjie Zhen; Hao Chen; Zhifeng Huang; Haisheng Hu; Peiyan Zheng; Hakon Hakonarson; Luqian Zhou; Baoqing Sun. Metabolomic profiling of anaerobic and aerobic energy metabolic pathways in chronic obstructive pulmonary disease. Experimental Biology and Medicine 2021, 246, 1586 -1596.
AMA StyleMingshan Xue, Yifeng Zeng, Runpei Lin, Hui-Qi Qu, Teng Zhang, Xiaohua Douglas Zhang, Yueting Liang, Yingjie Zhen, Hao Chen, Zhifeng Huang, Haisheng Hu, Peiyan Zheng, Hakon Hakonarson, Luqian Zhou, Baoqing Sun. Metabolomic profiling of anaerobic and aerobic energy metabolic pathways in chronic obstructive pulmonary disease. Experimental Biology and Medicine. 2021; 246 (14):1586-1596.
Chicago/Turabian StyleMingshan Xue; Yifeng Zeng; Runpei Lin; Hui-Qi Qu; Teng Zhang; Xiaohua Douglas Zhang; Yueting Liang; Yingjie Zhen; Hao Chen; Zhifeng Huang; Haisheng Hu; Peiyan Zheng; Hakon Hakonarson; Luqian Zhou; Baoqing Sun. 2021. "Metabolomic profiling of anaerobic and aerobic energy metabolic pathways in chronic obstructive pulmonary disease." Experimental Biology and Medicine 246, no. 14: 1586-1596.
Hui‐Qi Qu; Jingchun Qu; Jonathan Bradfield; Joseph Glessner; Xiao Chang; Michael March; Frank D Mentch; Jeffrey D Roizen; John J Connolly; Patrick Sleiman; Hakon Hakonarson. Combined Application of Genetic and Polygenic Risk Score for Type 1 Diabetes Risk Prediction. Diabetes, Obesity and Metabolism 2021, 1 .
AMA StyleHui‐Qi Qu, Jingchun Qu, Jonathan Bradfield, Joseph Glessner, Xiao Chang, Michael March, Frank D Mentch, Jeffrey D Roizen, John J Connolly, Patrick Sleiman, Hakon Hakonarson. Combined Application of Genetic and Polygenic Risk Score for Type 1 Diabetes Risk Prediction. Diabetes, Obesity and Metabolism. 2021; ():1.
Chicago/Turabian StyleHui‐Qi Qu; Jingchun Qu; Jonathan Bradfield; Joseph Glessner; Xiao Chang; Michael March; Frank D Mentch; Jeffrey D Roizen; John J Connolly; Patrick Sleiman; Hakon Hakonarson. 2021. "Combined Application of Genetic and Polygenic Risk Score for Type 1 Diabetes Risk Prediction." Diabetes, Obesity and Metabolism , no. : 1.
The traditional view is that the occurrence and development of hallux valgus (HV) are mainly due to environmental factors. Recent studies have suggested the large contribution of genetic heritability to HV, but it remains elusive about the genetic variants underlying the development of HV. To gain knowledge about the molecular mechanisms of HV pathogenesis by genetic approach, whole exome sequencing studies were performed in 10 individuals (7 affected by HV and 3 unaffected) from three independent families. Specific mutations were found to be related to the pathogenesis of HV and conform to the laws of inheritance. A total of 36 genes with functional candidate single nucleotide variants were identified. Genetic predisposition plays an important role in the development of HV. Interestingly, some of these genes are related to chronic arthritis, such as the complement encoding gene C7, or are related to long toe or long fingers, such as TTN, COL6A3, LARS, FIG4, and CBS. This study identified rare potentially pathogenic mutations represented by genes related to digital anomalies and chronic arthritis underlying the familial types of HV, which acquired new insights into the genetic and physiological foundations of HV, thereby might improve accurate prevention and drug development for HV.
Jun Jia; Junyi Li; Huiqi Qu; Mengyu Li; Sipeng Zhang; Jun Hao; Xinyi Gao; Xinyi Meng; Yan Sun; Hakon Hakonarson; Xiantie Zeng; Qianghua Xia; Jin Li. New insights into hallux valgus by whole exome sequencing study. Experimental Biology and Medicine 2021, 246, 1607 -1616.
AMA StyleJun Jia, Junyi Li, Huiqi Qu, Mengyu Li, Sipeng Zhang, Jun Hao, Xinyi Gao, Xinyi Meng, Yan Sun, Hakon Hakonarson, Xiantie Zeng, Qianghua Xia, Jin Li. New insights into hallux valgus by whole exome sequencing study. Experimental Biology and Medicine. 2021; 246 (14):1607-1616.
Chicago/Turabian StyleJun Jia; Junyi Li; Huiqi Qu; Mengyu Li; Sipeng Zhang; Jun Hao; Xinyi Gao; Xinyi Meng; Yan Sun; Hakon Hakonarson; Xiantie Zeng; Qianghua Xia; Jin Li. 2021. "New insights into hallux valgus by whole exome sequencing study." Experimental Biology and Medicine 246, no. 14: 1607-1616.
Xiao Chang; Yun Li; Kenny Nguyen; Huiqi Qu; Yichuan Liu; Joseph Glessner; Patrick M.A. Sleiman; Hakon Hakonarson. Genetic correlations between COVID-19 and a variety of traits and diseases. The Innovation 2021, 2, 100112 .
AMA StyleXiao Chang, Yun Li, Kenny Nguyen, Huiqi Qu, Yichuan Liu, Joseph Glessner, Patrick M.A. Sleiman, Hakon Hakonarson. Genetic correlations between COVID-19 and a variety of traits and diseases. The Innovation. 2021; 2 (2):100112.
Chicago/Turabian StyleXiao Chang; Yun Li; Kenny Nguyen; Huiqi Qu; Yichuan Liu; Joseph Glessner; Patrick M.A. Sleiman; Hakon Hakonarson. 2021. "Genetic correlations between COVID-19 and a variety of traits and diseases." The Innovation 2, no. 2: 100112.
RNA-seq has been a powerful method to detect the differentially expressed genes/long non-coding RNAs (lncRNAs) in schizophrenia (SCZ) patients; however, due to overfitting problems differentially expressed targets (DETs) cannot be used properly as biomarkers. This study used machine learning to reduce gene/non-coding RNA features. Dorsolateral prefrontal cortex (dlpfc) RNA-seq data from 254 individuals was obtained from the CommonMind consortium. The average predictive accuracy for SCZ patients was 67% based on coding genes, and 96% based on long non-coding RNAs (lncRNAs). Machine learning is a powerful algorithm to reduce functional biomarkers in SCZ patients. The lncRNAs capture the characteristics of SCZ tissue more accurately than mRNA as the former regulate every level of gene expression, not limited to mRNA levels.
Yichuan Liu; Hui-Qi Qu; Xiao Chang; Lifeng Tian; Jingchun Qu; Joseph Glessner; Patrick Sleiman; Hakon Hakonarson. Machine Learning Reduced Gene/Non-Coding RNA Features That Classify Schizophrenia Patients Accurately and Highlight Insightful Gene Clusters. International Journal of Molecular Sciences 2021, 22, 3364 .
AMA StyleYichuan Liu, Hui-Qi Qu, Xiao Chang, Lifeng Tian, Jingchun Qu, Joseph Glessner, Patrick Sleiman, Hakon Hakonarson. Machine Learning Reduced Gene/Non-Coding RNA Features That Classify Schizophrenia Patients Accurately and Highlight Insightful Gene Clusters. International Journal of Molecular Sciences. 2021; 22 (7):3364.
Chicago/Turabian StyleYichuan Liu; Hui-Qi Qu; Xiao Chang; Lifeng Tian; Jingchun Qu; Joseph Glessner; Patrick Sleiman; Hakon Hakonarson. 2021. "Machine Learning Reduced Gene/Non-Coding RNA Features That Classify Schizophrenia Patients Accurately and Highlight Insightful Gene Clusters." International Journal of Molecular Sciences 22, no. 7: 3364.
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA. Multiple novel rare recurrent variants were identified in exonic regions, functionally classified as stop-gains and frameshifts for known ADHD genes. Deletion in introns of the protocadherins families and the ncRNA HGB8P were identified in two independent EA ADHD patients. A meta-analysis of the two ethnicities for differential ADHD recurrent variants compared to controls shows a small number of overlaps. These results suggest that rare recurrent variants in noncoding regions may be involved in the pathogenesis of ADHD in children of both AA and EA ancestry; thus, WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.
Yichuan Liu; Xiao Chang; Hui-Qi Qu; Lifeng Tian; Joseph Glessner; Jingchun Qu; Dong Li; Haijun Qiu; Patrick Sleiman; Hakon Hakonarson. Rare Recurrent Variants in Noncoding Regions Impact Attention-Deficit Hyperactivity Disorder (ADHD) Gene Networks in Children of both African American and European American Ancestry. Genes 2021, 12, 310 .
AMA StyleYichuan Liu, Xiao Chang, Hui-Qi Qu, Lifeng Tian, Joseph Glessner, Jingchun Qu, Dong Li, Haijun Qiu, Patrick Sleiman, Hakon Hakonarson. Rare Recurrent Variants in Noncoding Regions Impact Attention-Deficit Hyperactivity Disorder (ADHD) Gene Networks in Children of both African American and European American Ancestry. Genes. 2021; 12 (2):310.
Chicago/Turabian StyleYichuan Liu; Xiao Chang; Hui-Qi Qu; Lifeng Tian; Joseph Glessner; Jingchun Qu; Dong Li; Haijun Qiu; Patrick Sleiman; Hakon Hakonarson. 2021. "Rare Recurrent Variants in Noncoding Regions Impact Attention-Deficit Hyperactivity Disorder (ADHD) Gene Networks in Children of both African American and European American Ancestry." Genes 12, no. 2: 310.
Mutations in the sarcomeric protein filamin C (FLNC) gene have been linked to hypertrophic cardiomyopathy (HCM), as they have been determined to increase the risk of ventricular arrhythmia and sudden death. Thus, in this study, we identified a novel missense mutation of FLNC in a Chinese family with HCM, and, interestingly, a second novel truncating mutation of MYLK2 was discobered in one family member with different phenotype. We performed whole-exome sequencing in a Chinese family with HCM of unknown cause. To determine and confirm the function of a novel mutation of FLNC, we introduced the mutant and wild-type gene into AC16 cells (human cardiomyocytes): we then used western blotting to analyze the expression of FLNC in subcellular fractions, and confocal microscope to observe the subcellular distribution of the protein. As per our findings, we were able to identify a novel missense single nucleotide variant (FLNC c.G5935A [p.A1979T]) in the family, which segregates with the disease. FLNC expression levels were observed to be equivalent in both wild-type and p.A1979T cardiomyocytes. However, the expression of the mutant protein has resulted in cytoplasmic protein aggregations, in contrast to wild-type FLNC, which was distributed in the cytoplasm and did not form aggregates. Unexpectedly, a second truncating mutation, NM_033118:exon8:c.G1138T:p.E380X of the MYLK2 gene, was identified in the mother of the proband with dilated cardiomyopathy, which was not found in other subjects. We then identified the FLNC A1979T mutation as a novel pathogenic variant associated with HCM in a Chinese family as well as a second causal mutation in a family member with a distinct phenotype. The possibility that there is more than one causal mutation in cardiomyopathy warrants clinical attention, especially for patients with atypical clinical features.
Xianyu Qin; Ping Li; Hui-Qi Qu; Yichuan Liu; Yu Xia; Shaoxian Chen; Yongchao Yang; Shufang Huang; Pengju Wen; Xianwu Zhou; Xiaofeng Li; Yonghua Wang; Lifeng Tian; Hakon Hakonarson; Yueheng Wu; Jian Zhuang. FLNC and MYLK2 Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy. International Heart Journal 2021, 62, 127 -134.
AMA StyleXianyu Qin, Ping Li, Hui-Qi Qu, Yichuan Liu, Yu Xia, Shaoxian Chen, Yongchao Yang, Shufang Huang, Pengju Wen, Xianwu Zhou, Xiaofeng Li, Yonghua Wang, Lifeng Tian, Hakon Hakonarson, Yueheng Wu, Jian Zhuang. FLNC and MYLK2 Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy. International Heart Journal. 2021; 62 (1):127-134.
Chicago/Turabian StyleXianyu Qin; Ping Li; Hui-Qi Qu; Yichuan Liu; Yu Xia; Shaoxian Chen; Yongchao Yang; Shufang Huang; Pengju Wen; Xianwu Zhou; Xiaofeng Li; Yonghua Wang; Lifeng Tian; Hakon Hakonarson; Yueheng Wu; Jian Zhuang. 2021. "FLNC and MYLK2 Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy." International Heart Journal 62, no. 1: 127-134.
Objective Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children, but a few studies have investigated the contribution of rare variants to JIA. In this study, we aimed to identify rare coding variants associated with JIA for the genome-wide landscape. Methods We established a rare variant calling and filtering pipeline and performed rare coding variant and gene-based association analyses on three RNA-seq datasets composed of 228 JIA patients in the Gene Expression Omnibus against different sets of controls, and further conducted replication in our whole-exome sequencing (WES) data of 56 JIA patients. Then we conducted differential gene expression analysis and assessed the impact of recurrent functional coding variants on gene expression and signalling pathway. Results By the RNA-seq data, we identified variants in two genes reported in literature as JIA causal variants, as well as additional 63 recurrent rare coding variants seen only in JIA patients. Among the 44 recurrent rare variants found in polyarticular patients, 10 were replicated by our WES of patients with the same JIA subtype. Several genes with recurrent functional rare coding variants have also common variants associated with autoimmune diseases. We observed immune pathways enriched for the genes with rare coding variants and differentially expressed genes. Conclusion This study elucidated a novel landscape of recurrent rare coding variants in JIA patients and uncovered significant associations with JIA at the gene pathway level. The convergence of common variants and rare variants for autoimmune diseases is also highlighted in this study.
Xinyi Meng; Xiaoyuan Hou; Ping Wang; Joseph T Glessner; Hui-Qi Qu; Michael E March; Sipeng Zhang; Xiaohui Qi; Chonggui Zhu; Kenny Nguyen; Xinyi Gao; Xiaoge Li; Yichuan Liu; Wentao Zhou; Shuyue Zhang; Junyi Li; Yan Sun; Jie Yang; Patrick M A Sleiman; Qianghua Xia; Hakon Hakonarson; Jin Li. Association of novel rare coding variants with juvenile idiopathic arthritis. Annals of the Rheumatic Diseases 2021, 80, 626 -631.
AMA StyleXinyi Meng, Xiaoyuan Hou, Ping Wang, Joseph T Glessner, Hui-Qi Qu, Michael E March, Sipeng Zhang, Xiaohui Qi, Chonggui Zhu, Kenny Nguyen, Xinyi Gao, Xiaoge Li, Yichuan Liu, Wentao Zhou, Shuyue Zhang, Junyi Li, Yan Sun, Jie Yang, Patrick M A Sleiman, Qianghua Xia, Hakon Hakonarson, Jin Li. Association of novel rare coding variants with juvenile idiopathic arthritis. Annals of the Rheumatic Diseases. 2021; 80 (5):626-631.
Chicago/Turabian StyleXinyi Meng; Xiaoyuan Hou; Ping Wang; Joseph T Glessner; Hui-Qi Qu; Michael E March; Sipeng Zhang; Xiaohui Qi; Chonggui Zhu; Kenny Nguyen; Xinyi Gao; Xiaoge Li; Yichuan Liu; Wentao Zhou; Shuyue Zhang; Junyi Li; Yan Sun; Jie Yang; Patrick M A Sleiman; Qianghua Xia; Hakon Hakonarson; Jin Li. 2021. "Association of novel rare coding variants with juvenile idiopathic arthritis." Annals of the Rheumatic Diseases 80, no. 5: 626-631.
We analyzed GWAS results released by COVID-19 Host Genetics Initiative, UK biobank and GWAS Catalog to explore the genetic overlap between COVID-19 and a broad spectrum of traits and diseases. We validate previously reported medical conditions and risk factors based on epidemiological studies, including but not limited to hypertension, type 2 diabetes and obesity. We also report novel traits associated with COVID-19, which have not been previously reported from epidemiological data, such as opioid use and educational attainment. Taken together, this study extends our understanding of the genetic basis of COVID-19, and provides target traits for further epidemiological studies.
Xiao Chang; Yun Li; Kenny Nguyen; Huiqi Qu; Yichuan Liu; Joseph Glessner; Patrick Sleiman; Hakon Hakonarson. Genetic correlations between COVID-19 and a variety of diseases and other medically relevant traits. 2020, 1 .
AMA StyleXiao Chang, Yun Li, Kenny Nguyen, Huiqi Qu, Yichuan Liu, Joseph Glessner, Patrick Sleiman, Hakon Hakonarson. Genetic correlations between COVID-19 and a variety of diseases and other medically relevant traits. . 2020; ():1.
Chicago/Turabian StyleXiao Chang; Yun Li; Kenny Nguyen; Huiqi Qu; Yichuan Liu; Joseph Glessner; Patrick Sleiman; Hakon Hakonarson. 2020. "Genetic correlations between COVID-19 and a variety of diseases and other medically relevant traits." , no. : 1.
Background Maturity-onset diabetes of the young (MODY) is a group of dominantly inherited monogenic diabetes, with HNF4A-MODY, GCK-MODY, and HNF1A-MODY as the three most common forms based on the causal genes. Molecular diagnosis of MODY is important for precise treatment. Although a DNA variant causing MODY can be assessed based on the criteria of the American College of Medical Genetics and Genomics (ACMG) guidelines, gene-specific assessment of disease-causing mutations is important to differentiate among MODY subtypes. As the ACMG criteria were not originally designed for machine-learning algorithms, they are not true independent variables. Objective The aim of this study was to develop machine-learning models for interpretation of DNA variants and MODY diagnosis using the ACMG criteria. Methods We applied machine-learning models for interpretation of DNA variants in MODY genes defined by the ACMG criteria based on the Human Gene Mutation Database (HGMD) and ClinVar database. Results With a machine-learning procedure, we found that the weight matrix of the ACMG criteria was significantly different between the three MODY genes HNF1A, HNF4A, and GCK. The models showed high predictive abilities with accuracy over 95%. Conclusions Our results highlight the need for applying different weights of the ACMG criteria in relation to different MODY genes for accurate functional classification. As proof of principle, we applied the ACMG criteria as feature vectors in a machine-learning model and obtained a precision-based result.
Yichuan Liu; Hui-Qi Qu; Adam S Wenocur; Jingchun Qu; Xiao Chang; Joseph Glessner; Patrick Sleiman; Lifeng Tian; Hakon Hakonarson. Interpretation of Maturity-Onset Diabetes of the Young Genetic Variants Based on American College of Medical Genetics and Genomics Criteria: Machine-Learning Model Development. JMIR Biomedical Engineering 2020, 5, e20506 .
AMA StyleYichuan Liu, Hui-Qi Qu, Adam S Wenocur, Jingchun Qu, Xiao Chang, Joseph Glessner, Patrick Sleiman, Lifeng Tian, Hakon Hakonarson. Interpretation of Maturity-Onset Diabetes of the Young Genetic Variants Based on American College of Medical Genetics and Genomics Criteria: Machine-Learning Model Development. JMIR Biomedical Engineering. 2020; 5 (1):e20506.
Chicago/Turabian StyleYichuan Liu; Hui-Qi Qu; Adam S Wenocur; Jingchun Qu; Xiao Chang; Joseph Glessner; Patrick Sleiman; Lifeng Tian; Hakon Hakonarson. 2020. "Interpretation of Maturity-Onset Diabetes of the Young Genetic Variants Based on American College of Medical Genetics and Genomics Criteria: Machine-Learning Model Development." JMIR Biomedical Engineering 5, no. 1: e20506.
Background Critically ill coronavirus disease 2019 (COVID-19) patients may suffer persistent systemic inflammation and multiple organ failure, leading to a poor prognosis. Research question To examine the relevance of the novel inflammatory factor heparin-binding protein (HBP) in critically ill COVID-19 patients, and evaluate the correlation of the biomarker with disease progression. Study design and methods 18 critically ill COVID-19 patients who suffered from respiratory failure and sepsis, including 12 cases who experienced a rapidly deteriorating clinical condition and six cases without deterioration, were investigated. They were compared with 15 age- and sex- matched COVID-19-negative patients with respiratory failure. Clinical data were collected and HBP levels were investigated. Results HBP was significantly increased in critically ill COVID-19 patients following disease aggravation and tracked with disease progression. HBP elevation preceded the clinical manifestations for up to 5 days and was closely correlated with patients’ pulmonary ventilation and perfusion status. Interpretation HBP levels are associated with COVID-19 disease progression in critically ill patients. As a potential mediator of disease aggravation and multiple organ injuries that are triggered by continuing inflammation and oxygen deficits, HBP warrants further study as a disease biomarker and potential therapeutic target.
Mingshan Xue; Yifeng Zeng; Hui-Qi Qu; Teng Zhang; Ning Li; Huimin Huang; Peiyan Zheng; Haisheng Hu; Luqian Zhou; Zhifeng Duan; Yong Zhang; Wei Bao; Li-Feng Tian; Hakon Hakonarson; Nanshan Zhong; Xiaohua Douglas Zhang; Baoqing Sun. Heparin-binding protein levels correlate with aggravation and multiorgan damage in severe COVID-19. ERJ Open Research 2020, 7, 1 .
AMA StyleMingshan Xue, Yifeng Zeng, Hui-Qi Qu, Teng Zhang, Ning Li, Huimin Huang, Peiyan Zheng, Haisheng Hu, Luqian Zhou, Zhifeng Duan, Yong Zhang, Wei Bao, Li-Feng Tian, Hakon Hakonarson, Nanshan Zhong, Xiaohua Douglas Zhang, Baoqing Sun. Heparin-binding protein levels correlate with aggravation and multiorgan damage in severe COVID-19. ERJ Open Research. 2020; 7 (1):1.
Chicago/Turabian StyleMingshan Xue; Yifeng Zeng; Hui-Qi Qu; Teng Zhang; Ning Li; Huimin Huang; Peiyan Zheng; Haisheng Hu; Luqian Zhou; Zhifeng Duan; Yong Zhang; Wei Bao; Li-Feng Tian; Hakon Hakonarson; Nanshan Zhong; Xiaohua Douglas Zhang; Baoqing Sun. 2020. "Heparin-binding protein levels correlate with aggravation and multiorgan damage in severe COVID-19." ERJ Open Research 7, no. 1: 1.
Type 1 diabetes (T1D) is a heterogeneous disease. This study identified T1D cases with low polygenic risk score (PRS) to better represent T1D cases with less prominent autoimmune response (T1bD), and performed a gene-based association study to identify novel susceptibility loci in two independent cohorts, characterized by low PRS. The Notch ligand Delta-like 1 gene (DLL1) was identified with genome-wide significance in both cohorts, highlighting the roles of DLL1 genetic variants in T1D patients with low PRS, supported by functional evidence from a recent study by Rubey et al.
Jingchun Qu; Hui-Qi Qu; Jonathan P. Bradfield; Joseph T. Glessner; Xiao Chang; Lifeng Tian; Michael E. March; Jeffrey D. Roizen; Patrick M. Sleiman; Hakon Hakonarson. Association of DLL1 with type 1 diabetes in patients characterized by low polygenic risk score. Metabolism 2020, 114, 154418 .
AMA StyleJingchun Qu, Hui-Qi Qu, Jonathan P. Bradfield, Joseph T. Glessner, Xiao Chang, Lifeng Tian, Michael E. March, Jeffrey D. Roizen, Patrick M. Sleiman, Hakon Hakonarson. Association of DLL1 with type 1 diabetes in patients characterized by low polygenic risk score. Metabolism. 2020; 114 ():154418.
Chicago/Turabian StyleJingchun Qu; Hui-Qi Qu; Jonathan P. Bradfield; Joseph T. Glessner; Xiao Chang; Lifeng Tian; Michael E. March; Jeffrey D. Roizen; Patrick M. Sleiman; Hakon Hakonarson. 2020. "Association of DLL1 with type 1 diabetes in patients characterized by low polygenic risk score." Metabolism 114, no. : 154418.
Although mitochondrial dysfunction has been implicated in the pathophysiology of attention deficit and hyperactivity disorder ADHD, the role of mitochondrial DNA (mtDNA) has not been extensively investigated. To determine whether mtDNA haplogroups influence risk of ADHD, we performed a case-control study comprising 2076 ADHD cases and 5078 healthy controls, all of whom were European decedents recruited from The Children’s Hospital of Philadelphia (CHOP). Associations between eight major European mtDNA Haplogroups and ADHD risk were assessed in three independent European cohorts. Meta-analysis of the three studies indicated that mtDNA haplogroups K (odds ratio = 0.69, P = 2.24 × 10−4, Pcorrected = 1.79 × 10−3) and U (odds ratio = 0.77, P = 8.88 × 10−4, Pcorrected = 7.11 × 10−3) were significantly associated with reduced risk of ADHD. In contrast, haplogroup HHV* (odds ratio = 1.18, P = 2.32 × 10−3, Pcorrected = 0.019) was significantly associated with increased risk of ADHD. Our results provide novel insight into the genetic basis of ADHD, implicating mitochondrial mechanisms in the pathophysiology of this relatively common psychiatric disorder.
Xiao Chang; Yichuan Liu; Frank Mentch; Joseph Glessner; Huiqi Qu; Kenny Nguyen; Patrick M. A. Sleiman; Hakon Hakonarson. Mitochondrial DNA haplogroups and risk of attention deficit and hyperactivity disorder in European Americans. Translational Psychiatry 2020, 10, 1 -6.
AMA StyleXiao Chang, Yichuan Liu, Frank Mentch, Joseph Glessner, Huiqi Qu, Kenny Nguyen, Patrick M. A. Sleiman, Hakon Hakonarson. Mitochondrial DNA haplogroups and risk of attention deficit and hyperactivity disorder in European Americans. Translational Psychiatry. 2020; 10 (1):1-6.
Chicago/Turabian StyleXiao Chang; Yichuan Liu; Frank Mentch; Joseph Glessner; Huiqi Qu; Kenny Nguyen; Patrick M. A. Sleiman; Hakon Hakonarson. 2020. "Mitochondrial DNA haplogroups and risk of attention deficit and hyperactivity disorder in European Americans." Translational Psychiatry 10, no. 1: 1-6.
There is a current pandemic of a new type of coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The number of confirmed infected cases has been rapidly increasing. This paper analyzes the characteristics of SARS-CoV-2 in comparison with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and influenza. COVID-19 is similar to the diseases caused by SARS-CoV and MERS-CoV virologically and etiologically, but closer to influenza in epidemiology and virulence. The comparison provides a new perspective for the future of the disease control, and offers some ideas in the prevention and control management strategy. The large number of infectious people from the origin, and the highly infectious and occult nature have been two major problems, making the virus difficult to eradicate. We thus need to contemplate the possibility of long-term co-existence with COVID-19.
Zhangkai J. Cheng; Hui-Qi Qu; Lifeng Tian; Zhifeng Duan; Hakon Hakonarson. COVID-19: Look to the Future, Learn from the Past. Viruses 2020, 12, 1226 .
AMA StyleZhangkai J. Cheng, Hui-Qi Qu, Lifeng Tian, Zhifeng Duan, Hakon Hakonarson. COVID-19: Look to the Future, Learn from the Past. Viruses. 2020; 12 (11):1226.
Chicago/Turabian StyleZhangkai J. Cheng; Hui-Qi Qu; Lifeng Tian; Zhifeng Duan; Hakon Hakonarson. 2020. "COVID-19: Look to the Future, Learn from the Past." Viruses 12, no. 11: 1226.
To address the expression pattern of the SARS-CoV-2 receptor ACE2 and the viral priming protease TMPRSS2 in the respiratory tract, this study investigated RNA sequencing transcriptome profiling of samples of airway and oral mucosa. As shown, ACE2 has medium levels of expression in both small airway epithelium and masticatory mucosa, and high levels of expression in nasal epithelium. The expression of ACE2 is low in mucosal-associated invariant T (MAIT) cells and cannot be detected in alveolar macrophages. TMPRSS2 is highly expressed in small airway epithelium and nasal epithelium and has lower expression in masticatory mucosa. Our results provide the molecular basis that the nasal mucosa is the most susceptible locus in the respiratory tract for SARS-CoV-2 infection and consequently for subsequent droplet transmission and should be the focus for protection against SARS-CoV-2 infection.
Yichuan Liu; Hui-Qi Qu; Jingchun Qu; Lifeng Tian; Hakon Hakonarson. Expression Pattern of the SARS-CoV-2 Entry Genes ACE2 and TMPRSS2 in the Respiratory Tract. Viruses 2020, 12, 1174 .
AMA StyleYichuan Liu, Hui-Qi Qu, Jingchun Qu, Lifeng Tian, Hakon Hakonarson. Expression Pattern of the SARS-CoV-2 Entry Genes ACE2 and TMPRSS2 in the Respiratory Tract. Viruses. 2020; 12 (10):1174.
Chicago/Turabian StyleYichuan Liu; Hui-Qi Qu; Jingchun Qu; Lifeng Tian; Hakon Hakonarson. 2020. "Expression Pattern of the SARS-CoV-2 Entry Genes ACE2 and TMPRSS2 in the Respiratory Tract." Viruses 12, no. 10: 1174.