medRxiv : the preprint server for health sciences最新文献

{"title":"The Genetic Architecture of Biological Age in Nine Human Organ Systems.","authors":"Junhao Wen, Ye Ella Tian, Ioanna Skampardoni, Zhijian Yang, Yuhan Cui, Filippos Anagnostakis, Elizabeth Mamourian, Bingxin Zhao, Arthur W Toga, Andrew Zaleskey, Christos Davatzikos","doi":"10.1101/2023.06.08.23291168","DOIUrl":"10.1101/2023.06.08.23291168","url":null,"abstract":"<p><p>Understanding the genetic basis of biological aging in multi-organ systems is vital for elucidating age-related disease mechanisms and identifying therapeutic interventions. This study characterized the genetic architecture of the biological age gap (BAG) across nine human organ systems in 377,028 individuals of European ancestry from the UK Biobank. We discovered 393 genomic loci-BAG pairs (P-value<5×10^-8) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We observed BAG-organ specificity and inter-organ connections. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system while exerting pleiotropic effects on traits linked to multiple organ systems. A gene-drug-disease network confirmed the involvement of the metabolic BAG-associated genes in drugs targeting various metabolic disorders. Genetic correlation analyses supported Cheverud's Conjecture¹ - the genetic correlation between BAGs mirrors their phenotypic correlation. A causal network revealed potential causal effects linking chronic diseases (e.g., Alzheimer's disease), body weight, and sleep duration to the BAG of multiple organ systems. Our findings shed light on promising therapeutic interventions to enhance human organ health within a complex multi-organ network, including lifestyle modifications and potential drug repositioning strategies for treating chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5e/d9/nihpp-2023.06.08.23291168v3.PMC10312870.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10122271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International Multi-Specialty Expert Physician Preoperative Identification of Extranodal Extension n Oropharyngeal Cancer Patients using Computed Tomography: Prospective Blinded Human Inter-Observer Performance Evaluation.","authors":"Onur Sahin, Serageldin Kamel, Kareem A Wahid, Cem Dede, Nicolette Taku, Renjie He, Mohamed A Naser, Setareh Sharafi, Antti Mäkitie, Benjamin H Kann, Kimmo Kaski, Jaakko Sahlsten, Joel Jaskari, Moran Amit, Gregory M Chronowski, Eduardo M Diaz, Adam S Garden, Ryan P Goepfert, Jeffrey P Guenette, G Brandon Gunn, Jussi Hirvonen, Frank Hoebers, Katherine A Hutcheson, Nandita Guha-Thakurta, Jason Johnson, Diana Kaya, Shekhar D Khanpara, Kristofer Nyman, Stephen Y Lai, Miriam Lango, Kim O Learned, Anna Lee, Carol M Lewis, Anastasios Maniakas, Amy C Moreno, Jeffery N Myers, Jack Phan, Kristen B Pytynia, David I Rosenthal, Vlad C Sandulache, Dawid Schellingerhout, Shalin J Shah, Andrew G Sikora, Abdallah S R Mohamed, Melissa M Chen, Clifton D Fuller","doi":"10.1101/2023.02.25.23286432","DOIUrl":"10.1101/2023.02.25.23286432","url":null,"abstract":"<p><strong>Importance: </strong>Extranodal extension (pENE) is a critical prognostic factor in oropharyngeal cancer (OPC) that drives therapeutic disposition. Determination of pENE from radiological imaging has been associated with high inter-observer variability. However, the impact of clinician specialty on human observer performance of imaging-detected extranodal extension (iENE) remains poorly understood.</p><p><strong>Objective: </strong>To characterize the impact of clinician specialty on the accuracy of pre-operative iENE in human papillomavirus-positive (HPV+) OPC using computed tomography (CT) images.</p><p><strong>Design setting and participants: </strong>This prospective observational human performance study analyzed pre-therapy CT images from 24 HPV+ OPC patients, with duplication of 6 scans (n=30) of which 21 were pathologically confirmed pENE. Thirty-four expert observers, including 11 radiologists, 12 surgeons, and 11 radiation oncologists, independently assessed these scans for iENE and reported human-detected radiologic criteria and observer confidence.</p><p><strong>Main outcomes and measures: </strong>The primary outcomes included accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and Brier score for each physician, compared to ground-truth pENE. The significance of radiographic signs for prediction of pENE were determined through logistic regression analysis. Fleiss' kappa measured interobserver agreement, and Hanley-MacNeil AUC discrimination testing.</p><p><strong>Results: </strong>Median accuracy across all specialties was 0.57 (95%CI 0.39 to 0.73), with no specialty showing discriminate performance greater than random estimation (median AUC 0.64, 95%CI 0.44 to 0.83). Significant differences between radiologists and surgeons in Brier scores (0.33 vs. 0.26, p < 0.01), radiation oncologists and surgeons in sensitivity (0.48 vs. 0.69, p > 0.1), and radiation oncologists and radiologists/surgeons in specificity (0.89 vs. 0.56, p > 0.1). Indistinct capsular contour and nodal necrosis were significant predictors of correct pENE status among all specialties. Interobserver agreement was weak for all the radiographic criteria, regardless of specialty (<i>κ</i><0.6).</p><p><strong>Conclusions and relevance: </strong>Multiobserver testing shows physician discrimination of HPV+OPC pENE on pre-operative CT remains non-different than blind guessing, with high interrater variability and low diagnostic accuracy, regardless of clinician specialty. While minor differences in diagnostic performance among specialties are noted, they do not significantly affect the overall poor agreement and discrimination rates observed. The findings underscore the need for further research into automated detection systems or enhanced imaging techniques to improve the accuracy and reliability of iENE assessments in clinical practice.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9115355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-1 latency reversal agent boosting is not limited by opioid use.","authors":"Tyler Lilie, Jennifer Bouzy, Archana Asundi, Jessica Taylor, Samantha Roche, Alex Olson, Kendyll Coxen, Heather Corry, Hannah Jordan, Kiera Clayton, Nina Lin, Athe Tsibris","doi":"10.1101/2023.05.26.23290576","DOIUrl":"10.1101/2023.05.26.23290576","url":null,"abstract":"<p><p>The opioid epidemic may impact the HIV-1 reservoir and its reversal from latency in virally suppressed people with HIV (PWH). We studied forty-seven PWH and observed that lowering the concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that do not reverse latency, synergistically increases the magnitude of HIV-1 re-activation <i>ex vivo</i>, regardless of opioid use. This LRA boosting, which combines a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, can generate significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation in CD4⁺ T cells and modulated T cell activation-induced markers and intracellular cytokine production; Smac mimetic-based boosting was less likely to induce immune activation. We found that HIV-1 reservoirs in PWH contain unspliced and polyadenylated (polyA) virus mRNA, the ratios of which are greater in resting than total CD4⁺ T cells and can correct to 1:1 with PMAi exposure. Latency reversal results in greater fold-change increases to HIV-1 poly(A) mRNA than unspliced message. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe the mechanisms of an effective cellular HIV-1 latency reversal program.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bd/94/nihpp-2023.05.26.23290576v1.PMC10312897.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10122263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Associations with Placental Proteins in Maternal Serum Identify Biomarkers for Hypertension in Pregnancy.","authors":"Qi Yan, Nathan R Blue, Buu Truong, Yu Zhang, Rafael F Guerrero, Nianjun Liu, Michael C Honigberg, Samuel Parry, Rebecca B McNeil, Hyagriv N Simhan, Judith Chung, Brian M Mercer, William A Grobman, Robert Silver, Philip Greenland, George R Saade, Uma M Reddy, Ronald J Wapner, David M Haas","doi":"10.1101/2023.05.25.23290460","DOIUrl":"10.1101/2023.05.25.23290460","url":null,"abstract":"<p><strong>Background: </strong>Preeclampsia is a complex syndrome that accounts for considerable maternal and perinatal morbidity and mortality. Despite its prevalence, no effective disease-modifying therapies are available. Maternal serum placenta-derived proteins have been in longstanding use as markers of risk for aneuploidy and placental dysfunction, but whether they have a causal contribution to preeclampsia is unknown.</p><p><strong>Objective: </strong>We aimed to investigate the genetic regulation of serum placental proteins in early pregnancy and their potential causal links with preeclampsia and gestational hypertension.</p><p><strong>Study design: </strong>This study used a nested case-control design with nulliparous women enrolled in the nuMoM2b study from eight clinical sites across the United States between 2010 and 2013. The first- and second-trimester serum samples were collected, and nine proteins were measured, including vascular endothelial growth factor (VEGF), placental growth factor, endoglin, soluble fms-like tyrosine kinase-1 (sFlt-1), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM-12), pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, inhibin A, and alpha-fetoprotein. This study used genome-wide association studies to discern genetic influences on these protein levels, treating proteins as outcomes. Furthermore, Mendelian randomization was used to evaluate the causal effects of these proteins on preeclampsia and gestational hypertension, and their further causal relationship with long-term hypertension, treating proteins as exposures.</p><p><strong>Results: </strong>A total of 2,352 participants were analyzed. We discovered significant associations between the pregnancy zone protein locus and concentrations of ADAM-12 (rs6487735, <i>P=</i> 3.03×10 ^-22 ), as well as between the vascular endothelial growth factor A locus and concentrations of both VEGF (rs6921438, <i>P=</i> 7.94×10 ^-30 ) and sFlt-1 (rs4349809, <i>P=</i> 2.89×10 ^-12 ). Our Mendelian randomization analyses suggested a potential causal association between first-trimester ADAM-12 levels and gestational hypertension (odds ratio=0.78, <i>P=</i> 8.6×10 ^-4 ). We also found evidence for a potential causal effect of preeclampsia (odds ratio=1.75, <i>P</i> =8.3×10 ^-3 ) and gestational hypertension (odds ratio=1.84, <i>P</i> =4.7×10 ^-3 ) during the index pregnancy on the onset of hypertension 2-7 years later. The additional mediation analysis indicated that the impact of ADAM-12 on postpartum hypertension could be explained in part by its indirect effect through gestational hypertension (mediated effect=-0.15, <i>P=</i> 0.03).</p><p><strong>Conclusions: </strong>Our study discovered significant genetic associations with placental proteins ADAM-12, VEGF, and sFlt-1, offering insights into their regulation during pregnancy. Mendelian randomization analys","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10105557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pivotal role of the X-chromosome in the genetic architecture of the human brain.","authors":"Zhiwen Jiang, Patrick F Sullivan, Tengfei Li, Bingxin Zhao, Xifeng Wang, Tianyou Luo, Shuai Huang, Peter Y Guan, Jie Chen, Yue Yang, Jason L Stein, Yun Li, Dajiang Liu, Lei Sun, Hongtu Zhu","doi":"10.1101/2023.08.30.23294848","DOIUrl":"10.1101/2023.08.30.23294848","url":null,"abstract":"<p><p>Genes on the X-chromosome are extensively expressed in the human brain. However, little is known for the X-chromosome's impact on the brain anatomy, microstructure, and functional network. We examined 1,045 complex brain imaging traits from 38,529 participants in the UK Biobank. We unveiled potential autosome-X-chromosome interactions, while proposing an atlas outlining dosage compensation (DC) for brain imaging traits. Through extensive association studies, we identified 72 genome-wide significant trait-locus pairs (including 29 new associations) that share genetic architectures with brain-related disorders, notably schizophrenia. Furthermore, we discovered unique sex-specific associations and assessed variations in genetic effects between sexes. Our research offers critical insights into the X-chromosome's role in the human brain, underscoring its contribution to the differences observed in brain structure and functionality between sexes.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b7/4e/nihpp-2023.08.30.23294848v1.PMC10491353.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10267568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with an alcohol use disorder.","authors":"Peter B Barr, Zoe Neale, Chris Chatzinakos, Jessica Schulman, Niamh Mullins, Jian Zhang, David B Chorlian, Chella Kamarajan, Sivan Kinreich, Ashwini K Pandey, Gayathri Pandey, Stacey Saenz de Viteri, Laura Acion, Lance Bauer, Kathleen K Bucholz, Grace Chan, Danielle M Dick, Howard J Edenberg, Tatiana Foroud, Alison Goate, Victor Hesselbrock, Emma C Johnson, John Kramer, Dongbing Lai, Martin H Plawecki, Jessica E Salvatore, Leah Wetherill, Arpana Agrawal, Bernice Porjesz, Jacquelyn L Meyers","doi":"10.1101/2023.04.28.23289173","DOIUrl":"10.1101/2023.04.28.23289173","url":null,"abstract":"<p><p>Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; mean age: 38). Within participants with an AUD diagnosis, we explored risk across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning for lifetime suicide attempt. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22 - 1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with an AUD who report a lifetime suicide attempt appear to experience greater levels of trauma, have more severe comorbidities, and carry polygenic risk for a variety of psychiatric problems. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8d/e6/nihpp-2023.04.28.23289173v1.PMC10168504.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9500281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel longitudinal rank-sum test for multiple primary endpoints in clinical trials: Applications to neurodegenerative disorders.","authors":"Xiaoming Xu, Dhrubajyoti Ghosh, Sheng Luo","doi":"10.1101/2023.06.24.23291858","DOIUrl":"10.1101/2023.06.24.23291858","url":null,"abstract":"<p><p>Neurodegenerative disorders such as Alzheimer's disease (AD) present a significant global health challenge, characterized by cognitive decline, functional impairment, and other debilitating effects. Current AD clinical trials often assess multiple longitudinal primary endpoints to comprehensively evaluate treatment efficacy. Traditional methods, however, may fail to capture global treatment effects, require larger sample sizes due to multiplicity adjustments, and may not fully exploit multivariate longitudinal data. To address these limitations, we introduce the Longitudinal Rank Sum Test (LRST), a novel nonparametric rank-based omnibus test statistic. The LRST enables a comprehensive assessment of treatment efficacy across multiple endpoints and time points without multiplicity adjustments, effectively controlling Type I error while enhancing statistical power. It offers flexibility against various data distributions encountered in AD research and maximizes the utilization of longitudinal data. Extensive simulations and real-data applications demonstrate the LRST's performance, underscoring its potential as a valuable tool in AD clinical trials. Nonparametrics, Global test, rank-sum-type test, U-Statistics.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9813576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning.","authors":"Randy L Parrish, Aron S Buchman, Shinya Tasaki, Yanling Wang, Denis Avey, Jishu Xu, Philip L De Jager, David A Bennett, Michael P Epstein, Jingjing Yang","doi":"10.1101/2023.06.20.23291605","DOIUrl":"10.1101/2023.06.20.23291605","url":null,"abstract":"<p><p>Multiple reference panels of a given tissue or multiple tissues often exist, and multiple regression methods could be used for training gene expression imputation models for TWAS. To leverage expression imputation models (i.e., base models) trained with multiple reference panels, regression methods, and tissues, we develop a Stacked Regression based TWAS (SR-TWAS) tool which can obtain optimal linear combinations of base models for a given validation transcriptomic dataset. Both simulation and real studies showed that SR-TWAS improved power, due to increased effective training sample sizes and borrowed strength across multiple regression methods and tissues. Leveraging base models across multiple reference panels, tissues, and regression methods, our real application studies identified 6 independent significant risk genes for Alzheimer's disease (AD) dementia for supplementary motor area tissue and 9 independent significant risk genes for Parkinson's disease (PD) for substantia nigra tissue. Relevant biological interpretations were found for these significant risk genes.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ce/5a/nihpp-2023.06.20.23291605v1.PMC10327185.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis.","authors":"Marcos Chiñas, Daniela Fernandez-Salinas, Vitor R C Aguiar, Victor E Nieto-Caballero, Micah Lefton, Peter A Nigrovic, Joerg Ermann, Maria Gutierrez-Arcelus","doi":"10.1101/2023.09.21.23295912","DOIUrl":"10.1101/2023.09.21.23295912","url":null,"abstract":"<p><strong>Objective: </strong>Multiple lines of evidence indicate that ankylosing spondylitis (AS) is a lymphocyte-driven disease. However, which lymphocyte populations are critical in AS pathogenesis is not known. In this study, we aimed to identify the key cell types mediating the genetic risk in AS using an unbiased functional genomics approach.</p><p><strong>Methods: </strong>We integrated genome-wide association study (GWAS) data with epigenomic and transcriptomic datasets of human immune cells. To quantify enrichment of cell type-specific open chromatin or gene expression in AS risk loci, we used three published methods that have successfully identified relevant cell types in other diseases. We performed co-localization analyses between GWAS risk loci and genetic variants associated with gene expression (eQTL) to find putative target genes.</p><p><strong>Results: </strong>Natural killer (NK) cell-specific open chromatin regions are significantly enriched in heritability for AS, compared to other immune cell types such as T cells, B cells, and monocytes. This finding was consistent between two AS GWAS. Using RNA-seq data, we validated that genes in AS risk loci are enriched in NK cell-specific gene expression. Using the human Space-Time Gut Cell Atlas, we also found significant upregulation of AS-associated genes predominantly in NK cells. Co-localization analysis revealed four AS risk loci affecting regulation of candidate target genes in NK cells: two known loci, <i>ERAP1 and TNFRSF1A</i>, and two under-studied loci, <i>ENTR1</i> (aka <i>SDCCAG3</i>) and <i>B3GNT2</i>.</p><p><strong>Conclusion: </strong>Our findings suggest that NK cells may play a crucial role in AS development and highlight four putative target genes for functional follow-up in NK cells.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/28/77/nihpp-2023.09.21.23295912v1.PMC10557806.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41150986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the genetic heterogeneity of Alzheimer's disease: Evidence for genetic subtypes.","authors":"Jeremy A Elman, Nicholas J Schork, Aaditya V Rangan","doi":"10.1101/2023.05.02.23289347","DOIUrl":"10.1101/2023.05.02.23289347","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins.</p><p><strong>Objective: </strong>We investigated genetic heterogeneity in AD risk through a multi-step analysis.</p><p><strong>Methods: </strong>We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases=2,739, controls=5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (AD cases=500, controls=470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n=399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories.</p><p><strong>Results: </strong>PCA revealed three distinct clusters (\"constellations\") driven primarily by different correlation patterns in a region of strong LD surrounding the <i>MAPT</i> locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased CSF p-tau and cognitive decline over time.</p><p><strong>Conclusions: </strong>This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ca/50/nihpp-2023.05.02.23289347v1.PMC10187457.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9850113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}