Publications by authors named "Jingyun Yang"

113 Publications

Lymph-Node-Targeted Cholesterolized TLR7 Agonist Liposomes Provoke a Safe and Durable Antitumor Response.

Nano Lett 2021 10 17;21(19):7960-7969. Epub 2021 Sep 17.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, PR China.

Toll-like receptor (TLR) agonists as the potent stimulants of an innate immune system hold promises for applications in anticancer immunotherapy. However, most of them are limited in the clinical translation due to the uncontrolled systemic inflammatory response. In the current study, 1V209, a small molecule TLR7 agonist, was conjugated with cholesterol (1V209-Cho) and prepared into liposomes (1V209-Cho-Lip). 1V209-Cho-Lip exerted minimal toxic effects and enhanced the transportation ability in lymph nodes (LNs) compared with 1V209. 1V209-Cho-Lip treatment inhibited tumor progression in CT26 colorectal cancer, 4T1 breast cancer, and Pan02 pancreatic ductal cancer models through inducing effective DC activation and eliciting CD8 T cell responses. Furthermore, 1V209-Cho-Lip induced tumor-specific memory immunity to inhibit cancer recurrence and metastasis. These results indicate that cholesterol conjugation with 1V209 is an effective approach to target lymph nodes and to reduce the adverse effects. This work provides a rational basis for the distribution optimization of TLR agonists for potential clinical use.
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http://dx.doi.org/10.1021/acs.nanolett.1c01968DOI Listing
October 2021

S19W, T27W, and N330Y mutations in ACE2 enhance SARS-CoV-2 S-RBD binding toward both wild-type and antibody-resistant viruses and its molecular basis.

Signal Transduct Target Ther 2021 09 16;6(1):343. Epub 2021 Sep 16.

West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

SARS-CoV-2 recognizes, via its spike receptor-binding domain (S-RBD), human angiotensin-converting enzyme 2 (ACE2) to initiate infection. Ecto-domain protein of ACE2 can therefore function as a decoy. Here we show that mutations of S19W, T27W, and N330Y in ACE2 could individually enhance SARS-CoV-2 S-RBD binding. Y330 could be synergistically combined with either W19 or W27, whereas W19 and W27 are mutually unbeneficial. The structures of SARS-CoV-2 S-RBD bound to the ACE2 mutants reveal that the enhanced binding is mainly contributed by the van der Waals interactions mediated by the aromatic side-chains from W19, W27, and Y330. While Y330 and W19/W27 are distantly located and devoid of any steric interference, W19 and W27 are shown to orient their side-chains toward each other and to cause steric conflicts, explaining their incompatibility. Finally, using pseudotyped SARS-CoV-2 viruses, we demonstrate that these residue substitutions are associated with dramatically improved entry-inhibition efficacy toward both wild-type and antibody-resistant viruses. Taken together, our biochemical and structural data have delineated the basis for the elevated S-RBD binding associated with S19W, T27W, and N330Y mutations in ACE2, paving the way for potential application of these mutants in clinical treatment of COVID-19.
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http://dx.doi.org/10.1038/s41392-021-00756-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444507PMC
September 2021

Novel DNA methylation loci and genes showing pleiotropic association with Alzheimer's dementia: a network Mendelian randomization analysis.

Epigenetics 2021 Aug 31:1-13. Epub 2021 Aug 31.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Previous genome-wide association studies (GWAS) have identified potential genetic variants involved in the risk of Alzheimer's dementia, but their underlying biological interpretation remains largely unclear. In addition, the effects of DNA methylation and gene expression on Alzheimer's dementia are not well understood. A network summary data-based Mendelian randomization (SMR) analysis was performed integrating cis- DNA methylation quantitative trait loci (mQTL) /cis- gene expression QTL (eQTL) data in the brain and blood, as well as GWAS summarized data for Alzheimer's dementia to evaluate the pleiotropic associations of DNA methylation and gene expression with Alzheimer's dementia and to explore the complex mechanisms underpinning Alzheimer's dementia. After correction for multiple testing (false discovery rate [FDR] < 0.05) and filtering using the heterogeneity in dependent instruments (HEIDI) test (>0.01), we identified dozens of DNA methylation sites and genes showing pleiotropic associations with Alzheimer's dementia. We found 22 and 16 potentially causal pathways of Alzheimer's dementia (i.e., SNP→DNA methylation→Gene expression→Alzheimer's dementia) in the brain and blood, respectively. Approximately two-thirds of the identified DNA methylation sites had an influence on gene expression and the expression of almost all the identified genes was regulated by DNA methylation. Our network SMR analysis provided evidence supporting the pleiotropic association of some novel DNA methylation sites and genes with Alzheimer's dementia and revealed possible causal pathways underlying the pathogenesis of Alzheimer's dementia. Our findings shed light on the role of DNA methylation in gene expression and in the development of Alzheimer's dementia.
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http://dx.doi.org/10.1080/15592294.2021.1959735DOI Listing
August 2021

Latent Cognitive Class at Enrollment Predicts Future Cognitive Trajectories of Decline in a Community Sample of Older Adults.

J Alzheimers Dis 2021 ;83(2):641-652

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Background: Methods that can identify subgroups with different trajectories of cognitive decline are crucial for isolating the biologic mechanisms which underlie these groupings.

Objective: This study grouped older adults based on their baseline cognitive profiles using a latent variable approach and tested the hypothesis that these groups would differ in their subsequent trajectories of cognitive change.

Methods: In this study we applied time-varying effects models (TVEMs) to examine the longitudinal trajectories of cognitive decline across different subgroups of older adults in the Rush Memory and Aging Project.

Results: A total of 1,662 individuals (mean age = 79.6 years, SD = 7.4, 75.4%female) participated in the study; these were categorized into five previously identified classes of older adults differing in their baseline cognitive profiles: Superior Cognition (n = 328, 19.7%), Average Cognition (n = 767, 46.1%), Mixed-Domains Impairment (n = 71, 4.3%), Memory-Specific Impairment (n = 274, 16.5%), and Frontal Impairment (n = 222, 13.4%). Differences in the trajectories of cognition for these five classes persisted during 8 years of follow-up. Compared with the Average Cognition class, The Mixed-Domains and Memory-Specific Impairment classes showed steeper rates of decline, while other classes showed moderate declines.

Conclusion: Baseline cognitive classes of older adults derived through the use of latent variable methods were associated with distinct longitudinal trajectories of cognitive decline that did not converge during an average of 8 years of follow-up.
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http://dx.doi.org/10.3233/JAD-210484DOI Listing
January 2021

Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine.

Signal Transduct Target Ther 2021 Jul 14;6(1):270. Epub 2021 Jul 14.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.

Mesenchymal stem cell (MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases, but its underlying mechanism has not been fully understood. Dead cells, including apoptotic cells have immunomodulatory properties. It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5~50% in the ongoing clinical trials. It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs. We found that the MSC therapeutic preparation in the present study had about 5% dead MSCs (DMSCs), characterized by apoptotic cells. Namely, 1 × 10 MSCs in the preparation contained about 5 × 10 DMSCs. We found that the treatment with even 5 × 10 DMSCs alone had the equal therapeutic effects as with 1 × 10 MSCs. This protective effect of the dead MSCs alone was confirmed in four mouse models, including concanavalin A (ConA)- and carbon tetrachloride (CCl)-induced acute liver injury, LPS-induced lung injury and spinal cord injury. We also found that the infused MSCs died by apoptosis in vivo. Furthermore, the therapeutic effect was attributed to the elevated level of phosphatidylserine (PS) upon the injection of MSCs or DMSCs. The direct administration of PS liposomes (PSLs) mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs. The Mer tyrosine kinase (MerTK) deficiency or the knockout of chemokine receptor C-C motif chemokine receptor 2 (CCR2) reversed these protective effects of MSCs or DMSCs. These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the "living MSCs preparation" through releasing PS, which was further recognized by MerTK and participated in modulating immune cells.
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http://dx.doi.org/10.1038/s41392-021-00688-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280232PMC
July 2021

Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness.

BMC Genomics 2021 Jul 7;22(1):517. Epub 2021 Jul 7.

Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China.

Objective: To prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT).

Methods: We applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analyses were done for participants of European and East Asian ancestries, separately.

Results: We identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; P = 4.15 × 10), PTGDS (ILMN_1664464; P = 6.88 × 10) and C9orf142 (ILMN_1761138; P = 8.09 × 10) were the top three genes using the CAGE eQTL data, and RP11-458F8.4 (ENSG00000273142.1; P = 5.89 × 10), LCNL1 (ENSG00000214402.6; P = 5.67 × 10), and PTGDS (ENSG00000107317.7; P = 1.92 × 10) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing.

Conclusion: We identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.
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http://dx.doi.org/10.1186/s12864-021-07860-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263012PMC
July 2021

A bivalent recombinant vaccine targeting the S1 protein induces neutralizing antibodies against both SARS-CoV-2 variants and wild-type of the virus.

MedComm (Beijing) 2021 May 17. Epub 2021 May 17.

Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics West China Hospital, Sichuan University Chengdu China.

The emerging variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in pandemic call for the urgent development of universal corona virus disease 2019 (COVID-19) vaccines which could be effective for both wild-type SARS-CoV-2 and mutant strains. In the current study, we formulated protein subunit vaccines with AS03 adjuvant and recombinant proteins of S1 subunit of SARS-CoV-2 (S1-WT) and S1 variant (K417N, E484K, N501Y, and D614G) subunit (S1-Mut), and immunized transgenic mice that express human angiotensin-converting enzyme 2 (hACE2). The S1 protein-specific antibody production and the neutralization capability for SARS-CoV-2 and B.1.351 variant were measured after immunization in mice. The results revealed that the S1-Mut antigens were more effective in inhibiting the receptor-binding domain and ACE2 binding in B.1.351 variant than in wild-type SARS-CoV-2. Furthermore, the development of a bivalent vaccine exhibited the ideal neutralization properties against wild-type and B.1.351 variant, as well as other variants. Our findings may provide a rationale for the development of a bivalent recombinant vaccine targeting the S1 protein that can induce the neutralizing antibodies against both SARS-CoV-2 variants and wild-type of the virus and may be of importance to explore the potential clinical use of bivalent recombinant vaccine in the future.
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http://dx.doi.org/10.1002/mco2.72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242662PMC
May 2021

Mendelian randomization analysis identified genes potentially pleiotropically associated with periodontitis.

Saudi J Biol Sci 2021 Jul 16;28(7):4089-4095. Epub 2021 Apr 16.

Department of Stomatology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.

Objective: To prioritize genes that were pleiotropically or potentially causally associated with periodontitis.

Methods: We applied the summary data-based Mendelian randomization (SMR) method integrating genome-wide association study (GWAS) for periodontitis and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with periodontitis. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analysis were done for participants of European and East Asian ancestries, separately.

Results: We identified multiple genes showing pleiotropic association with periodontitis in participants of European ancestry and participants of East Asian ancestry. (corresponding probe: ILMN_1758915) was the top hit showing pleotropic association with periodontitis in the participants of European ancestry using CAGE eQTL data, and (corresponding probe: ILMN_1899903) and (corresponding probe: ENSG00000204792.2) were the top hits in the participants of East Asian ancestry using CAGE eQTL data and GTEx eQTL data, respectively.

Conclusion: We identified multiple genes that may be involved in the pathogenesis of periodontitis in participants of European ancestry and participants of East Asian ancestry. Our findings provided important leads to a better understanding of the mechanisms underlying periodontitis and revealed potential therapeutic targets for the effective treatment of periodontitis.
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http://dx.doi.org/10.1016/j.sjbs.2021.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241609PMC
July 2021

Cognitive and brain cytokine profile of non-demented individuals with cerebral amyloid-beta deposition.

J Neuroinflammation 2021 Jul 4;18(1):147. Epub 2021 Jul 4.

Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.

Background: Brain inflammation has been increasingly associated with early amyloid accumulation in Alzheimer's disease models; however, evidence of its occurrence in humans remains scarce. To elucidate whether amyloid deposition is associated with neuroinflammation and cognitive deficits, we studied brain inflammatory cytokine expression and cognitive decline in non-demented elderly individuals with and without cerebral amyloid-beta deposition.

Methods: Global cognition, episodic, working, and semantic memory, perceptual speed, visuospatial ability, and longitudinal decline (5.7 ± 3.6 years) in each cognitive domain were compared between elderly individuals (66-79 years) with and without cerebral amyloid-beta deposition. The expression of 20 inflammatory cytokines was analyzed in frozen temporal, parietal, and frontal cortices and compared between older individuals with and without amyloid-beta deposition in each brain region. Correlation analyses were performed to analyze associations between amyloid-beta load, cytokine expression, and cognitive decline.

Results: Individuals with cortical amyloid-beta deposition displayed deficits and a faster rate of cognitive decline in perceptual speed as compared with those individuals without amyloid-beta. This decline was positively associated with cortical amyloid-beta levels. Elderly individuals with amyloid-beta deposition had higher levels of IL-1β, IL-6, and eotaxin-3 in the temporal cortex accompanied by an increase in MCP-1 and IL-1β in the parietal cortex and a trend towards higher levels of IL-1β and MCP-1 in the frontal cortex as compared with age-matched amyloid-free individuals. Brain IL-1β levels displayed a positive association with cortical amyloid burden in each brain region. Finally, differential cytokine expression in each cortical region was associated with cognitive decline.

Conclusions: Elderly individuals with amyloid-beta neuropathology but no symptomatic manifestation of dementia, exhibit cognitive decline and increased brain cytokine expression. Such observations suggest that increased cytokine expression might be an early event in the Alzheimer's continuum.
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http://dx.doi.org/10.1186/s12974-021-02169-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254948PMC
July 2021

Antitumor and Radiosensitization Effects of a CXCR2 Inhibitor in Nasopharyngeal Carcinoma.

Front Cell Dev Biol 2021 26;9:689613. Epub 2021 May 26.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

CXCR2, a member of the G-protein-coupled cell surface chemokine receptor family, is commonly found on leukocytes, endothelial cells and tumor cells including nasopharyngeal carcinoma cells. However, how the activity of CXCR2 and its ligand CXCL8 affects the development of nasopharyngeal carcinoma (NPC) remains unknown. Here, we found that CXCR2 and CXCL8 were both predicted poor prognosis in NPC patients. Furthermore, we identified that treatment with CXCR2 antagonist SB225002 of nasopharyngeal carcinoma cell lines resulted tumorigenesis inhibition and . In addition, we found that SB225002 could enhance NPC cells radiosensitivity through regulating cell circle distribution and interfering with cellular DNA damage repair. SB225002 also exhibited an efficient radiosensitization effect in C666-1 and HONE-1 bearing mice. Functionally, we showed that SB225002 reduced microvessel density and proliferation and induced tumor apoptosis. Furthermore, changes in the tumor microenvironment were also observed in this study. We observed that SB225002 reduced tumor-associated neutrophils (TANs) in the tumors tissue which were recruited especially after irradiation. Taken together, our results suggested that targeting the CXCL8-CXCR2 pathway is a promising therapeutic strategy for comprehensive NPC treatment.
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http://dx.doi.org/10.3389/fcell.2021.689613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188356PMC
May 2021

Bootstrap approach for meta-synthesis of MRI findings from multiple scanners.

J Neurosci Methods 2021 08 27;360:109229. Epub 2021 May 27.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, United States; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, United States; Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL 60612, United States.

Background: Neuroimaging data from large epidemiologic cohort studies often come from multiple scanners. The variations of MRI measurements due to differences in magnetic field strength, image acquisition protocols, and scanner vendors can influence the interpretation of aggregated data. The purpose of the present study was to compare methods that meta-analyze findings from a small number of different MRI scanners.

Methods: We proposed a bootstrap resampling method using individual participant data and compared it with two common random effects meta-analysis methods, DerSimonian-Laird and Hartung-Knapp, and a conventional pooling method that combines MRI data from different scanners. We first performed simulations to compare the power and coverage probabilities of the four methods in the absence and presence of scanner effects on measurements. We then examined the association of age with white matter hyperintensity (WMH) volumes from 787 participants.

Results: In simulations, the bootstrap approach performed better than the other three methods in terms of coverage probability and power when scanner differences were present. However, the bootstrap approach was consistent with pooling, the optimal approach, when scanner differences were absent. In the association of age with WMH volume, we observed that age was significantly associated with WMH volumes using the bootstrap approach, pooling, and the DerSimonian-Laird method, but not using the Hartung-Knapp method (p < 0.0001 for the bootstrap approach, DerSimonian-Laird, and pooling but p = 0.1439 for the Hartung-Knapp approach).

Conclusion: The bootstrap approach using individual participant data is suitable for integrating outcomes from multiple MRI scanners regardless of absence or presence of scanner effects on measurements.
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http://dx.doi.org/10.1016/j.jneumeth.2021.109229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324567PMC
August 2021

Mendelian randomization integrating GWAS and eQTL data revealed genes pleiotropically associated with major depressive disorder.

Transl Psychiatry 2021 04 17;11(1):225. Epub 2021 Apr 17.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Previous genome-wide association studies (GWAS) have identified potential genetic variants associated with the risk of major depressive disorder (MDD), but the underlying biological interpretation remains largely unknown. We aimed to prioritize genes that were pleiotropically or potentially causally associated with MDD. We applied the summary data-based Mendelian randomization (SMR) method integrating GWAS and gene expression quantitative trait loci (eQTL) data in 13 brain regions to identify genes that were pleiotropically associated with MDD. In addition, we repeated the analysis by using the meta-analyzed version of the eQTL summary data in the brain (brain-eMeta). We identified multiple significant genes across different brain regions that may be involved in the pathogenesis of MDD. The prime-specific gene BTN3A2 (corresponding probe: ENSG00000186470.9) was the top hit showing pleiotropic association with MDD in 9 of the 13 brain regions and in brain-eMeta, after correction for multiple testing. Many of the identified genes are located in the human major histocompatibility complex (MHC) region on chromosome 6 and are mainly involved in the immune response. Our SMR analysis indicated that multiple genes showed pleiotropic association with MDD across the brain regions. These findings provided important leads to a better understanding of the mechanism of MDD and revealed potential therapeutic targets for the prevention and effective treatment of MDD.
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http://dx.doi.org/10.1038/s41398-021-01348-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053199PMC
April 2021

Association of genetic variants in enamel-formation genes with dental caries: A meta- and gene-cluster analysis.

Saudi J Biol Sci 2021 Mar 1;28(3):1645-1653. Epub 2020 Dec 1.

Department of Stomatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Previous studies have reported the association between multiple genetic variants in the enamel-formation genes and the risk of dental caries with inconsistent results. We performed a systematic literature search of the PubMed, Cochrane Library, HuGE and Google Scholar databases for studies published before March 21, 2020 and conducted meta-, gene-based and gene-cluster analysis on the association between genetic variants in the enamel-formation genes and the risk of dental caries. We identified 21 relevant publications including a total of 24 studies for analysis. The genetic variant rs17878486 in was significantly associated with dental caries risk (OR = 1.40, 95% CI: 1.02-1.93,  = 0.037). We found no significant association between the risk of dental caries with rs12640848 in (OR = 1.15, 95% CI: 0.88-1.52,  = 0.310), rs1784418 in (OR = 1.07, 95% CI: 0.76-1.49,  = 0.702) and rs3796704 in (OR = 1.06, 95% CI: 0.96-1.17,  = 0.228). Gene-based analysis indicated that multiple genetic variants in showed joint association with the risk of dental caries (6 variants;  < 10), so did genetic variants in (3 variants;  = 0.004), (3 variants;  < 10), (2 variants;  < 10) and (2 variants;  < 10). The gene-cluster analysis indicated a significant association between the genetic variants in this enamel-formation gene cluster and the risk of dental caries ( < 10). The present meta-analysis revealed that genetic variant rs17878486 in was associated with dental caries, and multiple genetic variants in the enamel-formation genes jointly contributed to the risk of dental caries, supporting the role of genetic variants in the enamel-formation genes in the etiology of dental caries.
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http://dx.doi.org/10.1016/j.sjbs.2020.11.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938150PMC
March 2021

Monitoring Recessions: A Bayesian Sequential Quickest Detection Method.

Int J Forecast 2021 Apr-Jun;37(2):500-510. Epub 2020 Aug 18.

Rush University Medical Center.

Monitoring business cycles faces two potentially conflicting objectives: accuracy and timeliness. To strike a balance between the dual objectives, we develop a Bayesian sequential quickest detection method to identify turning points in real time and propose a sequential stopping time as a solution. Using four monthly indexes of real economic activity in the US, we evaluate the method's real-time ability to date the past five recessions. The proposed method identifies similar turning point dates as the National Bureau of Economic Research (NBER), with no false alarms, but on average dates peaks 4 months faster and troughs 10 months faster relative to the NBER announcement. The timeliness of our method is also notable compared to the dynamic factor Markov-switching model - the average lead time is about 5 months in dating peaks and 2 months in dating troughs.
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http://dx.doi.org/10.1016/j.ijforecast.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944410PMC
August 2020

Deep learning-based detection and stage grading for optimising diagnosis of diabetic retinopathy.

Diabetes Metab Res Rev 2021 05 13;37(4):e3445. Epub 2021 Mar 13.

Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Aims: To establish an automated method for identifying referable diabetic retinopathy (DR), defined as moderate nonproliferative DR and above, using deep learning-based lesion detection and stage grading.

Materials And Methods: A set of 12,252 eligible fundus images of diabetic patients were manually annotated by 45 licenced ophthalmologists and were randomly split into training, validation, and internal test sets (ratio of 7:1:2). Another set of 565 eligible consecutive clinical fundus images was established as an external test set. For automated referable DR identification, four deep learning models were programmed based on whether two factors were included: DR-related lesions and DR stages. Sensitivity, specificity and the area under the receiver operating characteristic curve (AUC) were reported for referable DR identification, while precision and recall were reported for lesion detection.

Results: Adding lesion information to the five-stage grading model improved the AUC (0.943 vs. 0.938), sensitivity (90.6% vs. 90.5%) and specificity (80.7% vs. 78.5%) of the model for identifying referable DR in the internal test set. Adding stage information to the lesion-based model increased the AUC (0.943 vs. 0.936) and sensitivity (90.6% vs. 76.7%) of the model for identifying referable DR in the internal test set. Similar trends were also seen in the external test set. DR lesion types with high precision results were preretinal haemorrhage, hard exudate, vitreous haemorrhage, neovascularisation, cotton wool spots and fibrous proliferation.

Conclusions: The herein described automated model employed DR lesions and stage information to identify referable DR and displayed better diagnostic value than models built without this information.
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http://dx.doi.org/10.1002/dmrr.3445DOI Listing
May 2021

Systemic brain derived neurotrophic factor but not intestinal barrier integrity is associated with cognitive decline and incident Alzheimer's disease.

PLoS One 2021 4;16(3):e0240342. Epub 2021 Mar 4.

Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America.

The inflammatory hypothesis posits that sustained neuroinflammation is sufficient to induce neurodegeneration and the development of Alzheimer's disease (AD) and Alzheimer's dementia. One potential source of inflammation is the intestine which harbors pro-inflammatory microorganisms capable of promoting neuroinflammation. Systemic inflammation is robustly associated with neuroinflammation as well as low levels of brain derived neurotrophic factor (BDNF) in the systemic circulation and brain. Thus, in this pilot study, we tested the hypothesis that intestinal barrier dysfunction precedes risk of death, incident AD dementia and MCI, cognitive impairment and neuropathology. Serum BDNF was associated with changes in global cognition, working memory, and perceptual speed but not risk of death, incident AD dementia, incident MCI, or neuropathology. Neither of the markers of intestinal barrier integrity examined, including lipopolysaccharide binding protein (LBP) nor intestinal fatty acid binding protein (IFABP), were associated with risk of death, incident AD dementia, incident mild cognitive impairment (MCI), change in cognition (global or domains), or neuropathology. Taken together, the data in this pilot study suggest that intestinal barrier dysfunction does not precede diagnosis of AD or MCI, changes in cognition, or brain pathology. However, since MCI and AD are related to global cognition, the findings with BDNF and the contiguous cognitive measures suggest low power with the trichotomous cognitive status measures. Future studies with larger sample sizes are necessary to further investigate the results from this pilot study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240342PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932071PMC
August 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

Publisher Correction: A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2021 Feb;590(7844):E23

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41586-020-03108-4DOI Listing
February 2021

A mouse model for SARS-CoV-2-induced acute respiratory distress syndrome.

Signal Transduct Target Ther 2021 01 1;6(1). Epub 2021 Jan 1.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China.

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http://dx.doi.org/10.1038/s41392-020-00451-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775436PMC
January 2021

Cationic nanocarriers as potent adjuvants for recombinant S-RBD vaccine of SARS-CoV-2.

Signal Transduct Target Ther 2020 12 11;5(1):291. Epub 2020 Dec 11.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, 610041, Sichuan, Chengdu, China.

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http://dx.doi.org/10.1038/s41392-020-00434-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729145PMC
December 2020

Mendelian randomization analysis identified genes pleiotropically associated with the risk and prognosis of COVID-19.

J Infect 2021 01 28;82(1):126-132. Epub 2020 Nov 28.

Emergency Department, Xuanwu Hospital, Capital Medical University, Beijing, China. Electronic address:

Objectives: COVID-19 has caused a large global pandemic. Patients with COVID-19 exhibited considerable variation in disease behavior. Pervious genome-wide association studies have identified potential genetic variants involved in the risk and prognosis of COVID-19, but the underlying biological interpretation remains largely unclear.

Methods: We applied the summary data-based Mendelian randomization (SMR) method to identify genes that were pleiotropically associated with the risk and various outcomes of COVID-19, including severe respiratory confirmed COVID-19 and hospitalized COVID-19.

Results: In blood, we identified 2 probes, ILMN_1765146 and ILMN_1791057 tagging IFNAR2, that showed pleiotropic association with hospitalized COVID-19 (β [SE]=0.42 [0.09], P = 4.75 × 10 and β [SE]=-0.48 [0.11], P = 6.76 × 10, respectively). Although no other probes were significant after correction for multiple testing in both blood and lung, multiple genes as tagged by the top 5 probes were involved in inflammation or antiviral immunity, and several other tagged genes, such as PON2 and HPS5, were involved in blood coagulation.

Conclusions: We identified IFNAR2 and other potential genes that could be involved in the susceptibility or prognosis of COVID-19. These findings provide important leads to a better understanding of the mechanisms of cytokine storm and venous thromboembolism in COVID-19 and potential therapeutic targets for the effective treatment of COVID-19.
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http://dx.doi.org/10.1016/j.jinf.2020.11.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698677PMC
January 2021

Association of sleep disturbance and freezing of gait in Parkinson disease: prevention/delay implications.

J Clin Sleep Med 2021 04;17(4):779-789

Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Study Objectives: Freezing of gait (FOG) severely impairs life quality of Parkinson disease (PD) patients. The relationship between sleep disturbance and FOG in PD remains unclear, so in this study, we aimed to investigate that relationship.

Methods: First, we assessed clinical characteristics of freezers and nonfreezers among PD patients. Next, we assessed clinical characteristics of PD patients with different PDSS1 scores (score on first item of Parkinson's Disease Sleep Scale). Finally, we prospectively followed a cohort of nonfreezers from a baseline clinical visit and to a maximum of 18 months and performed a Cox regression analysis to further investigate the relationship between PDSS1 score and FOG in PD.

Results: A total of 163 participants with PD were included in the baseline analysis. The freezers had significantly worse sleep compared with the nonfreezers. The proportion of freezers in the patients with low PDSS1 score (PDSS1 < 6) was significantly higher than that in the patients with high PDSS1 score (PDSS1 ≥ 6). A total of 52 nonfreezers were prospectively followed. During a maximum 18-month follow-up, FOG incidence (73%) in the PDSS1 < 6 group was significantly higher than that (24%) in the PDSS1 ≥ 6 group (P = .008). Low PDSS1 score (hazard ratio = 4.23, 95% CI 1.64-10.92, P = .003) and high levodopa equivalent daily dose (hazard ratio = 4.18, 95% CI 1.62-10.75, P = .003) were significantly associated with an increased hazard of FOG.

Conclusions: Our study indicated that low PDSS1 score may be a risk indicator for the development of FOG and provided important insights into potential targets for the prevention/delay of FOG in PD.
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http://dx.doi.org/10.5664/jcsm.9022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020700PMC
April 2021

Mendelian randomization integrating GWAS and mQTL data identified novel pleiotropic DNA methylation loci for neuropathology of Alzheimer's disease.

Neurobiol Aging 2021 01 1;97:18-27. Epub 2020 Oct 1.

Division of Statistics, School of Economics, Shanghai University, Shanghai, China; Research Center of Financial Information, Shanghai University, Shanghai, China; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. Electronic address:

The pathogenesis of Alzheimer's disease (AD) remains largely unclear. Exploring the genetic/epigenetic loci showing pleiotropic association with the neuropathologies of AD may greatly enhance understanding of the mechanisms underlying the development of AD. In this study, using data from the Religious Orders Study and the Rush Memory and Aging Project, we undertook a Mendelian randomization approach integrating genome-wide association studies (GWASs) and DNA methylation quantitative trait locus data to explore pleiotropic epigenetic loci for AD neuropathologies, including amyloid-β (Aβ) load and tau-containing neurofibrillary tangle density. We performed GWASs of DNA methylation in brain tissues from 592 participants and mapped 60,595 cis-SNP-CpG pairs after correction for multiple testing. By linking cis-DNA methylation quantitative trait locus with GWAS results for Aβ load and tau tangles, we identified 47 CpGs showing pleiotropic association with Aβ load by the Mendelian randomization analysis. We then used gene expression data from 537 individuals and performed quantitative trait methylation analysis. We found that 18 of the 47 CpGs were in cis associated with 25 mRNAs/genes, comprising 41 unique CpG-mRNA/gene pairs. Our findings shed light on the role of DNA methylation in the pathogenesis of Aβ.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736197PMC
January 2021

Mendelian randomization analysis identified genes pleiotropically associated with the risk and prognosis of COVID-19.

medRxiv 2020 Sep 4. Epub 2020 Sep 4.

Objectives: COVID-19 has caused a large global pandemic. Patients with COVID-19 exhibited considerable variation in disease behavior. Pervious genome-wide association studies have identified potential genetic variants involved in the risk and prognosis of COVID-19, but the underlying biological interpretation remains largely unclear.

Methods: We applied the summary data-based Mendelian randomization (SMR) method to identify genes that were pleiotropically associated with the risk and various outcomes of COVID-19, including severe respiratory confirmed COVID-19 and hospitalized COVID-19.

Results: In blood, we identified 2 probes, ILMN_1765146 and ILMN_1791057 tagging IFNAR2, that showed pleiotropic association with hospitalized COVID-19 (Beta; [SE]=0.42 [0.09], P=4.75E-06 and Beta; [SE]=-0.48 [0.11], P=6.76E-06, respectively). Although no other probes were significant after correction for multiple testing in both blood and lung, multiple genes as tagged by the top 5 probes were involved in inflammation or antiviral immunity, and several other tagged genes, such as PON2 and HPS5, were involved in blood coagulation.

Conclusions: We identified IFNAR2 and other potential genes that could be involved in the susceptibility or prognosis of COVID-19. These findings provide important leads to a better understanding of the mechanisms of cytokine storm and venous thromboembolism in COVID-19 and potential therapeutic targets for the effective treatment of COVID-19.
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http://dx.doi.org/10.1101/2020.09.02.20187179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480052PMC
September 2020

Pharmacological Activation of Estrogen Receptor Beta Overcomes Tumor Resistance to Immune Checkpoint Blockade Therapy.

iScience 2020 Aug 12;23(9):101458. Epub 2020 Aug 12.

Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China. Electronic address:

The emerging immune checkpoint blockade (ICB) therapy has ushered the cancer therapeutics field into an era of immunotherapy. Although ICB treatment provides remarkable clinical responses in a subset of patients with cancer, this regimen fails to extend survival in a large proportion of patients. Here, we found that a combined treatment of estrogen receptor beta (ERβ) agonist and PD-1 antibody treatment improved therapeutic efficacy in mouse tumor models, compared with monotherapies, by reducing infiltration of myeloid-derived suppressor cells (MDSCs) and increasing CD8 T cells in tumors. Mechanistically, LY500307 treatment reduced tumor-derived CSF1 and decreased infiltration of CSF1R MDSCs in the tumor bed. CSF1 released by tumor cells induced CSF1R MDSC chemotaxis in vitro and blockade of CSF1R demonstrated similar therapeutic effects as ERβ activation in vivo. Collectively, our study proved combined treatment of ERβ agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy.
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http://dx.doi.org/10.1016/j.isci.2020.101458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476860PMC
August 2020

A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2020 10 29;586(7830):572-577. Epub 2020 Jul 29.

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.
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http://dx.doi.org/10.1038/s41586-020-2599-8DOI Listing
October 2020

Efficacy of conbercept combined with panretinal photocoagulation in the treatment of proliferative diabetic retinopathy.

Sci Rep 2020 05 29;10(1):8778. Epub 2020 May 29.

Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

This prospective clinical study was to compare the effect of panretinal photocoagulation (PRP) associated with intravitreal conbercept injections versus PRP alone in the treatment of proliferative diabetic retinopathy (PDR). For each of 15 patients included, one eye was randomly assigned to receive treatment with PRP, and the other eye received conbercept combined PRP. Ophthalmic examinations, optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) were performed at baseline and at each monthly visit until 6 months. Fluorescein angiography (FA) was acquired at baseline, 3 months and 6 months. Between group and within group analysis was done by using generalized estimating equations (GEE). The combination group had a significant decrease of neovascularization (NV) leakage area than the PRP group at month 3 and month 6 after treatment, and a better best-corrected visual acuity (BCVA) during the first three months. Within-group analysis indicated a significant decrease in NV leakage at month 3 and month 6 in both groups, and a significant increase in BCVA at 1 month in the combination group. In summary, the combination of intravitreal injection of conbercept and PRP can significantly reduce the NV of PDR patients and achieve better BCVA during the drug's lifespan compared with PRP alone.
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http://dx.doi.org/10.1038/s41598-020-65833-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260229PMC
May 2020

The association between genetic variants in lactotransferrin and dental caries: a meta- and gene-based analysis.

BMC Med Genet 2020 05 27;21(1):114. Epub 2020 May 27.

Division of Statistics, School of Economics, Shanghai University, 99 Shangda Rd, Baoshan Dist, Shanghai, 200444, China.

Background: The pathogenesis of dental caries remains unclear, with increasing evidence suggesting that genetic susceptibility plays an essential role. Previous studies have reported the association between genetic polymorphisms in lactotransferrin (LTF) and the risk of dental caries with inconsistent results.

Methods: A systematic literature search of the PubMed, Cochrane Library, HuGE and Google Scholar databases was performed by two authors independently for papers published before December 5, 2019 on the association between genetic variants in LTF and the risk of dental caries. We adopted the subsequent inclusion criteria to assess study eligibility: 1) The studies were based on human subjects; 2) the presence of dental caries should be screened for in both the case group and the control group; and 3) genotype data on variants in LTF were available in both the case group and the control group. We calculated odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) by using random-effects models to assess the association of genetic variants in LTF with the risk of dental caries. We also performed a gene-based analysis to explore the joint association of multiple genetic variants in LTF with the risk of dental caries.

Results: Our systematic literature search identified six relevant papers for analysis. We found no significant association between rs1126478 and the risk of dental caries when meta-analysing the genotype distribution between subjects with dental caries and those without dental caries (additive model: OR = 1.41; 95% CI = 0.98-2.02; P = 0.065). However, further analysis indicated that rs1126478 was associated with dental risk in subjects who had moderate or severe dental caries compared to those without dental caries (P < 0.0001). The gene-based analysis indicated that multiple genetic variants in LTF were jointly associated with the risk of dental caries (P = 0.002).

Conclusions: The present meta-analysis revealed some evidence of the association between rs1126478 and dental caries and that multiple genetic variants in LTF are jointly associated with the risk of dental caries. Our findings need to be validated by larger studies that adjust for important confounding factors for the risk of dental caries.
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http://dx.doi.org/10.1186/s12881-020-01029-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251739PMC
May 2020

Genome-wide interaction analysis of pathological hallmarks in Alzheimer's disease.

Neurobiol Aging 2020 09 29;93:61-68. Epub 2020 Apr 29.

Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, Hubei, China. Electronic address:

Genome-wide association studies have identified many loci associated with Alzheimer's dementia. However, these variants only explain part of the heritability of Alzheimer's disease (AD). As genetic epistasis can be a major contributor to the "missing heritability" of AD, we conducted genome-wide epistasis screening for AD pathologies in 2 independent cohorts. First, we performed a genome-wide epistasis study of AD-related brain pathologies (N = 1318) in ROS/MAP. Candidate interactions were validated using cerebrospinal fluid biomarkers of AD in ADNI (N = 1128). Further functional analysis tested the association of candidate interactions with neuroimaging phenotypes. For tau and amyloid-β pathology, we identified 2803 and 464 candidate SNP-SNP interactions, respectively. Associations of candidate SNP-SNP interactions with brain volume and white matter changes from neuroimages provides additional insights into their molecular functions. Transcriptional analysis supported possible gene-gene interactions identified by statistical screening through their co-expression in the brain. In summary, we outlined an exhaustive epistasis analysis to identify novel genetic interactions with potential roles in AD pathologies. We further delved into the functional relevance of candidate interactions by association with neuroimaging phenotypes and analysis of co-expression between corresponding gene pairs.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.025DOI Listing
September 2020
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