Pub Date : 2024-09-10DOI: 10.1101/2024.09.08.24313284
Sihan Liu, Xiaoshu Feng, Fengxiao Bu
Improving the precision and accuracy of variant classification in clinical genetic testing involves further specification and stratification of the ACMG/AMP criteria. The Bayesian framework proposed by ClinGen has provided a mathematical foundation for evidence refinement, successfully quantifying, and extending the evidence strengths of PS1, PS4, PM5, and PP3/BP4. However, existing software and tools designed for quantifying the evidence strength and establishing corresponding thresholds to refine the ACMG/AMP criteria are lacking. To address this gap, we have developed BayesQuantify, an R package that aims to provide users with a unified resource for quantifying the strength of evidence for ACMG/AMP criteria using a naive Bayes classifier. By analyzing publicly available data, we demonstrate BayesQuantify's capability to offer objective and consistent refinement of the ACMG/AMP evidence. BayesQuantify is available from GitHub at https://github.com/liusihan/BayesQuantify.
{"title":"BayesQuantify: an R package utilized to refine the ACMG/AMP criteria according to the Bayesian framework","authors":"Sihan Liu, Xiaoshu Feng, Fengxiao Bu","doi":"10.1101/2024.09.08.24313284","DOIUrl":"https://doi.org/10.1101/2024.09.08.24313284","url":null,"abstract":"Improving the precision and accuracy of variant classification in clinical genetic testing involves further specification and stratification of the ACMG/AMP criteria. The Bayesian framework proposed by ClinGen has provided a mathematical foundation for evidence refinement, successfully quantifying, and extending the evidence strengths of PS1, PS4, PM5, and PP3/BP4. However, existing software and tools designed for quantifying the evidence strength and establishing corresponding thresholds to refine the ACMG/AMP criteria are lacking. To address this gap, we have developed BayesQuantify, an R package that aims to provide users with a unified resource for quantifying the strength of evidence for ACMG/AMP criteria using a naive Bayes classifier. By analyzing publicly available data, we demonstrate BayesQuantify's capability to offer objective and consistent refinement of the ACMG/AMP evidence. BayesQuantify is available from GitHub at https://github.com/liusihan/BayesQuantify.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1101/2024.08.25.24312558
Yixuan He, Wenhan Lu, Yon Ho Jee, Ying Wang, Kristin Tsuo, David Qian, Chirag J Patel, James A Diao, Hailiang Huang, Jinyoung J Byun, Bogdan Pasaniuc, Elizabeth Atkinson, Christopher Amos, Matthew Moll, Michael Cho, Alicia Martin
While respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross TRait and Ancestry), a multi-trait and -ancestry polygenic risk score approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD, and lung cancer compared to trait- and ancestry-matched PRS in a multi-ancestry cohort from the All of Us Research Program, especially in diverse populations. PRSxtra identified individuals in the top decile with over four-fold odds of asthma and COPD compared to the first decile. Our results present a new framework for multi-trait and -ancestry studies of respiratory diseases to improve genetic discovery and polygenic prediction.
虽然慢性阻塞性肺病和哮喘等呼吸系统疾病有许多共同的风险因素，但大多数研究都是在日照不足和以欧洲血统为主的人群中进行的。在这里，我们对呼吸系统疾病和辅助性状进行了迄今为止最强大的多性状和多祖先遗传分析。我们的方法提高了跨性状和祖先的遗传发现能力，在东亚祖先中发现了 44 个与肺功能相关的新位点。利用这些结果，我们开发了 PRSxtra（交叉 TRait 和 Ancestry），这是一种多性状和多血统多基因风险评分方法，它通过多向效应来利用遗传风险的共享成分。在 "我们所有人研究计划"（All of Us Research Program）的多血统队列中，与性状和血统匹配的 PRS 相比，PRSxtra 明显改善了对哮喘、慢性阻塞性肺病和肺癌的预测，尤其是在不同人群中。与第一十分位数相比，PRSxtra 发现了前十分位数中患哮喘和慢性阻塞性肺病几率超过四倍的个体。我们的研究结果为呼吸系统疾病的多性状和种系研究提供了一个新的框架，以改进基因发现和多基因预测。
{"title":"Multi-trait and multi-ancestry genetic analysis of comorbid lung diseases and traits improves genetic discovery and polygenic risk prediction","authors":"Yixuan He, Wenhan Lu, Yon Ho Jee, Ying Wang, Kristin Tsuo, David Qian, Chirag J Patel, James A Diao, Hailiang Huang, Jinyoung J Byun, Bogdan Pasaniuc, Elizabeth Atkinson, Christopher Amos, Matthew Moll, Michael Cho, Alicia Martin","doi":"10.1101/2024.08.25.24312558","DOIUrl":"https://doi.org/10.1101/2024.08.25.24312558","url":null,"abstract":"While respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross TRait and Ancestry), a multi-trait and -ancestry polygenic risk score approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD, and lung cancer compared to trait- and ancestry-matched PRS in a multi-ancestry cohort from the All of Us Research Program, especially in diverse populations. PRSxtra identified individuals in the top decile with over four-fold odds of asthma and COPD compared to the first decile. Our results present a new framework for multi-trait and -ancestry studies of respiratory diseases to improve genetic discovery and polygenic prediction.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-08DOI: 10.1101/2024.09.05.24313142
Mohamed Abdulkadir, Janne Tidselbak Larsen, Loa Clausen, Christopher Huebel, Clara Albinana, Laura Marie Thornton, Bjarni Johann Vilhjalmsson, Cynthia Bulik, Zeynep Yilmaz, Liselotte Vogdrup Petersen
Objective: Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort. Methods: The sample compromised of 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) with at least two registered hospital contacts between 1995 and 2018. Based on medical records, occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGS and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models. Results: A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Presumed remission ranged between 86.9%-89.8%. Higher (one SD increase) PGS for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGS on a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for health rating showed the opposite. Conclusions: The authors found that most ED patients did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have significant polygenic component.
目的：进食障碍（ED）是一种严重的精神疾病，据估计全世界每年损失 330 万健康生命年。了解饮食失调症的病程、诊断转变和缓解及其相关的遗传相关性可为饮食失调症的病因学和治疗提供依据。作者在丹麦的一个大型登记队列中调查了 ED 的转归和假定缓解及其遗传相关性，并通过多基因评分（PGS）进行了捕捉。研究方法样本包括 10,565 名被诊断为神经性厌食症（AN）、神经性贪食症（BN）或未另作规定的进食障碍（EDNOS）的个体，他们在 1995 年至 2018 年期间至少有两次登记的医院接触。根据医疗记录，确定了诊断转换和假定缓解期的发生情况。使用 Cox 比例危险模型评估了 422 例 PGS 与诊断转变和假定缓解之间的关联。结果显示少数 ED 病例（14.1%-23.1%）经历了诊断转变。推定缓解率介于 86.9%-89.8% 之间。重度抑郁障碍和多部位慢性疼痛的 PGS 较高（增加一个标准差）与从 AN 过渡到 BN 或 EDNOS 呈正相关。体脂百分比和经济困难的 PGS 较高与自闭症假定缓解呈正相关。情绪波动的 PGS 较高与 EDNOS 的假定缓解呈正相关，而健康评分的 PGS 较高则相反。结论：作者发现，大多数 ED 患者没有经历诊断转变，但更有可能经历一段假定缓解期。诊断转变和假定缓解都有重要的多基因成分。
{"title":"Descriptives and genetic correlates of eating disorder diagnostic transitions and presumed remission in the Danish registry.","authors":"Mohamed Abdulkadir, Janne Tidselbak Larsen, Loa Clausen, Christopher Huebel, Clara Albinana, Laura Marie Thornton, Bjarni Johann Vilhjalmsson, Cynthia Bulik, Zeynep Yilmaz, Liselotte Vogdrup Petersen","doi":"10.1101/2024.09.05.24313142","DOIUrl":"https://doi.org/10.1101/2024.09.05.24313142","url":null,"abstract":"<strong>Objective:</strong> Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort. <strong>Methods:</strong> The sample compromised of 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) with at least two registered hospital contacts between 1995 and 2018. Based on medical records, occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGS and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models. <strong>Results:</strong> A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Presumed remission ranged between 86.9%-89.8%. Higher (one SD increase) PGS for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGS on a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for health rating showed the opposite. <strong>Conclusions:</strong> The authors found that most ED patients did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have significant polygenic component.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.09.04.24312938
Laura Ivete Rudaks, Igor Stevanovski, Dennis Yeow, Andre L. M. Reis, Sanjog R. Chintalaphani, Pak Leng Cheong, Hasindu Gamaarachchi, Lisa Worgan, Kate Ahmad, Michael Hayes, Andrew Hannaford, Samuel Kim, Victor S. C. Fung, Michael Halmagyi, Andrew Martin, David Manser, Michel Tchan, Karl Ng, Marina L. Kennerson, Ira W. Deveson, Kishore Raj Kumar
The hereditary spastic-ataxia spectrum disorders are a group of rare disabling neurological diseases. The genetic testing process is complex, and often requires multiple different assays to evaluate the many potential causative genes and variant types, including short tandem repeat expansions, single nucleotide variants, insertions/deletions, structural variants and copy number variants. This can be a protracted process and, even after all avenues are exhausted, many individuals do not receive a genetic diagnosis.
{"title":"Targeted long-read sequencing as a single assay improves diagnosis of spastic-ataxia disorders","authors":"Laura Ivete Rudaks, Igor Stevanovski, Dennis Yeow, Andre L. M. Reis, Sanjog R. Chintalaphani, Pak Leng Cheong, Hasindu Gamaarachchi, Lisa Worgan, Kate Ahmad, Michael Hayes, Andrew Hannaford, Samuel Kim, Victor S. C. Fung, Michael Halmagyi, Andrew Martin, David Manser, Michel Tchan, Karl Ng, Marina L. Kennerson, Ira W. Deveson, Kishore Raj Kumar","doi":"10.1101/2024.09.04.24312938","DOIUrl":"https://doi.org/10.1101/2024.09.04.24312938","url":null,"abstract":"The hereditary spastic-ataxia spectrum disorders are a group of rare disabling neurological diseases. The genetic testing process is complex, and often requires multiple different assays to evaluate the many potential causative genes and variant types, including short tandem repeat expansions, single nucleotide variants, insertions/deletions, structural variants and copy number variants. This can be a protracted process and, even after all avenues are exhausted, many individuals do not receive a genetic diagnosis.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.09.06.24313191
James Luccarelli, Theresa V. Strong, Emily B. Rubin, Thomas H. McCoy
Background Prader-Willi syndrome (PWS) is a genetic disorder associated with baseline respiratory impairment caused by multiple contributing etiologies. While this may be expected to increase the risk of severe COVID-19 infections in PWS patients, survey studies have suggested paradoxically low disease severity. To better characterize the course of COVID-19 infection in patients with PWS, this study analyzes the outcomes of hospitalizations for COVID-19 among patients with and without PWS.
{"title":"Inpatient Hospitalizations for COVID-19 Among Patients with Prader-Willi Syndrome: a National Inpatient Sample Analysis","authors":"James Luccarelli, Theresa V. Strong, Emily B. Rubin, Thomas H. McCoy","doi":"10.1101/2024.09.06.24313191","DOIUrl":"https://doi.org/10.1101/2024.09.06.24313191","url":null,"abstract":"<strong>Background</strong> Prader-Willi syndrome (PWS) is a genetic disorder associated with baseline respiratory impairment caused by multiple contributing etiologies. While this may be expected to increase the risk of severe COVID-19 infections in PWS patients, survey studies have suggested paradoxically low disease severity. To better characterize the course of COVID-19 infection in patients with PWS, this study analyzes the outcomes of hospitalizations for COVID-19 among patients with and without PWS.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.09.02.24312951
Emma Short, Ian M. Adcock, Bilal Al-Sarireh, Ann Ager, Ramzi Ajjan, Naveed Akbar, Michael A. Akeroyd, Ghada Alsaleh, Ghada Al-Sharbatee, Kambiz Alavian, Winfried Amoaku, Julie Andersen, Chrystalina Antoniades, Mark J. Arends, Sue Astley, Denize Atan, Richard Attanoos, Johannes Attems, Steve Bain, Konstantinos Balaskas, Gabriel Balmus, Manohar Bance, Thomas M. Barber, Ajoy Bardhan, Karen Barker, Peter Barnes, Gemma Basatemur, Adrian Bateman, Moises Evandro Bauer, Christopher Bellamy, Edwin van Beek, Ilaria Bellantuono, Emyr Benbow, Sunil Bhandari, Rahul Bhatnagar, Philip Bloom, Dawn Bowdish, Melissa Bowerman, Melanie Burke, Roxana Carare, Emma Victoria Carrington, Jorge Iván Castillo-Quan, Peter Clegg, James Cole, Carlo Cota, Paul Chazot, Christopher Chen, Ying Cheong, Gary Christopher, George Church, David Clancy, Paul Cool, Francesco Del Galdo, Mayank Dalakoti, Soumit Dasgupta, Colleen Deane, Devesh Dhasmana, Stefan Dojcinov, Monia Di Prete, Huaidong Du, Niharika A Duggal, Toby Ellmers, Costanza Emanueli, Mark Emberton, Jorge D. Erusalimsky, Laurence Feldmeyer, Alexander Fleming, Karen Forbes, Thomas C. Foster, Daniela Frasca, Ian Frayling, Daniel Freedman, Tamas Fülöp, Georgina Ellison-Hughes, Gus Gazzard, Christopher George, Jesus Gil, Richard Glassock, Rob Goldin, John Green, Robyn Guymer, Hasan Haboubi, Lorna Harries, Simon Hart, Douglas Hartley, Sebri Hasaballa, Christin Henein, Maggie Helliwell, Emily Henderson, Rakesh Heer, Kristofer Holte, Iskander Idris, David Isenburg, Juulia Jylhävä, Ahmed Iqbal, Simon W. Jones, Rajesh Kalaria, Venkateswarlu Kanamarlapudi, Werner Kempf, Alexandra J. Kermack, Jemma Kerns, Albert Koulman, Adnan H. Khan, James Kinross, Katarina Klaucane, Yamini Krishna, Harinderjit Singh Gill, Edward Lakatta, Ezio Laconi, Alpar Lazar, Christiaan Leeuwenburgh, Samantha Leung, Xuan Li, Ian van der Linde, Luísa V. Lopes, Antonello Lorenzini, Andrew Lotery, Pedro Machado, Sarah Mackie, Paolo Madeddu, Andrea Maier, Krishna Mukkanna, Pinelopi Manousou, Oonagh Markey, Claudio Mauro, Barry McDonnell, Reinhold J. Medina, Soma Meran, Claudia Metzler-Baddeley, Ignor Meglinksi, Neta Milman, Christina Mitteldorf, Ruth Montgomery, Andrew Conway Morris, Beda Mühleisen, Abhik Mukherkee, Andrew Murray, Scott Nelson, Anna Nicolaou, Alexander Nirenberg, Simon Noble, Lisa S. Nolan, Meritxell Nus, Canh Van On, Victor Osei-Lah, Mandy Peffers, Antony Palmer, Donald Palmer, Laura Palmer, William Parry-Smith, Graham Pawelec, Shahaf Peleg, Ranmith Perera, Andrew Pitsillides, Christopher J. Plack, Franze Progatzsky, Sonja Pyott, Kaukab Rajput, Sameera Rashid, J. Arjuna Ratnayaka, Sudhira A.B. Ratnayake, Manuel Rodriguez-Justo, Arianna Carolina Rosa, Andrew Rule, Gareth J. Sanger, Ian Sayers, Andrew Saykin, Dinesh Selvarajah, Jaswinder Sethi, Cathy Shanahan, Shai Shen-Orr, Carl Sheridan, Paul Shiels, Kastytis Sidlauskas, Sobha Sivaprasad, Judith Sluimer, Gary Small, Peter Smith, Rebecca Smith, Sarah Snelling, Ioakim Spyridopoulos, Ramasamy Srinivasa Raghavan, David Steel, Karen P Steel, Claire Stewart, Keeron Stone, Selvarani Subbarayan, Mark Sussman, Jonas Svensson, Vyshnavi Tadanki, Ai Lyn Tan, Rudolph E. Tanzi, Amanda Tatler, Adriana A. S. Tavares, Tengku Amatullah Madeehah Tengku Mohd, Ana Tiganescu, James Timmons, Jeremy Tree, Drupad Trivedi, Emmanuel A. Tsochatzis, Dialechti Tsimpida, Elisabeth J Vinke, Anna Whittaker, Neeru A. Vallabh, Kristin Veighey, Zoe C. Venables, Venkat Reddy, Meike W. Vernooij, Chris Verschoor, Manlio Vinciguerra, Vesna Vukanovic, Vladyslav Vyazovskiy, James Walker, Richard Wakefield, Adam J. Watkins, Anthony Webster, Caroline Weight, Birgit Weinberger, Susan L. Whitney, Rosalind Willis, Jacek M. Witkowski, Leonard L.L. Yeo, Tham Yhi Chung, Emma Yu, Michael Zemel, Stuart R.G. Calimport, Barry L. Bentley
Background Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies.
{"title":"Defining an Ageing-Related Pathology, Disease or Syndrome: International Consensus Statement","authors":"Emma Short, Ian M. Adcock, Bilal Al-Sarireh, Ann Ager, Ramzi Ajjan, Naveed Akbar, Michael A. Akeroyd, Ghada Alsaleh, Ghada Al-Sharbatee, Kambiz Alavian, Winfried Amoaku, Julie Andersen, Chrystalina Antoniades, Mark J. Arends, Sue Astley, Denize Atan, Richard Attanoos, Johannes Attems, Steve Bain, Konstantinos Balaskas, Gabriel Balmus, Manohar Bance, Thomas M. Barber, Ajoy Bardhan, Karen Barker, Peter Barnes, Gemma Basatemur, Adrian Bateman, Moises Evandro Bauer, Christopher Bellamy, Edwin van Beek, Ilaria Bellantuono, Emyr Benbow, Sunil Bhandari, Rahul Bhatnagar, Philip Bloom, Dawn Bowdish, Melissa Bowerman, Melanie Burke, Roxana Carare, Emma Victoria Carrington, Jorge Iván Castillo-Quan, Peter Clegg, James Cole, Carlo Cota, Paul Chazot, Christopher Chen, Ying Cheong, Gary Christopher, George Church, David Clancy, Paul Cool, Francesco Del Galdo, Mayank Dalakoti, Soumit Dasgupta, Colleen Deane, Devesh Dhasmana, Stefan Dojcinov, Monia Di Prete, Huaidong Du, Niharika A Duggal, Toby Ellmers, Costanza Emanueli, Mark Emberton, Jorge D. Erusalimsky, Laurence Feldmeyer, Alexander Fleming, Karen Forbes, Thomas C. Foster, Daniela Frasca, Ian Frayling, Daniel Freedman, Tamas Fülöp, Georgina Ellison-Hughes, Gus Gazzard, Christopher George, Jesus Gil, Richard Glassock, Rob Goldin, John Green, Robyn Guymer, Hasan Haboubi, Lorna Harries, Simon Hart, Douglas Hartley, Sebri Hasaballa, Christin Henein, Maggie Helliwell, Emily Henderson, Rakesh Heer, Kristofer Holte, Iskander Idris, David Isenburg, Juulia Jylhävä, Ahmed Iqbal, Simon W. Jones, Rajesh Kalaria, Venkateswarlu Kanamarlapudi, Werner Kempf, Alexandra J. Kermack, Jemma Kerns, Albert Koulman, Adnan H. Khan, James Kinross, Katarina Klaucane, Yamini Krishna, Harinderjit Singh Gill, Edward Lakatta, Ezio Laconi, Alpar Lazar, Christiaan Leeuwenburgh, Samantha Leung, Xuan Li, Ian van der Linde, Luísa V. Lopes, Antonello Lorenzini, Andrew Lotery, Pedro Machado, Sarah Mackie, Paolo Madeddu, Andrea Maier, Krishna Mukkanna, Pinelopi Manousou, Oonagh Markey, Claudio Mauro, Barry McDonnell, Reinhold J. Medina, Soma Meran, Claudia Metzler-Baddeley, Ignor Meglinksi, Neta Milman, Christina Mitteldorf, Ruth Montgomery, Andrew Conway Morris, Beda Mühleisen, Abhik Mukherkee, Andrew Murray, Scott Nelson, Anna Nicolaou, Alexander Nirenberg, Simon Noble, Lisa S. Nolan, Meritxell Nus, Canh Van On, Victor Osei-Lah, Mandy Peffers, Antony Palmer, Donald Palmer, Laura Palmer, William Parry-Smith, Graham Pawelec, Shahaf Peleg, Ranmith Perera, Andrew Pitsillides, Christopher J. Plack, Franze Progatzsky, Sonja Pyott, Kaukab Rajput, Sameera Rashid, J. Arjuna Ratnayaka, Sudhira A.B. Ratnayake, Manuel Rodriguez-Justo, Arianna Carolina Rosa, Andrew Rule, Gareth J. Sanger, Ian Sayers, Andrew Saykin, Dinesh Selvarajah, Jaswinder Sethi, Cathy Shanahan, Shai Shen-Orr, Carl Sheridan, Paul Shiels, Kastytis Sidlauskas, Sobha Sivaprasad, Judith Sluimer, Gary Small, Peter Smith, Rebecca Smith, Sarah Snelling, Ioakim Spyridopoulos, Ramasamy Srinivasa Raghavan, David Steel, Karen P Steel, Claire Stewart, Keeron Stone, Selvarani Subbarayan, Mark Sussman, Jonas Svensson, Vyshnavi Tadanki, Ai Lyn Tan, Rudolph E. Tanzi, Amanda Tatler, Adriana A. S. Tavares, Tengku Amatullah Madeehah Tengku Mohd, Ana Tiganescu, James Timmons, Jeremy Tree, Drupad Trivedi, Emmanuel A. Tsochatzis, Dialechti Tsimpida, Elisabeth J Vinke, Anna Whittaker, Neeru A. Vallabh, Kristin Veighey, Zoe C. Venables, Venkat Reddy, Meike W. Vernooij, Chris Verschoor, Manlio Vinciguerra, Vesna Vukanovic, Vladyslav Vyazovskiy, James Walker, Richard Wakefield, Adam J. Watkins, Anthony Webster, Caroline Weight, Birgit Weinberger, Susan L. Whitney, Rosalind Willis, Jacek M. Witkowski, Leonard L.L. Yeo, Tham Yhi Chung, Emma Yu, Michael Zemel, Stuart R.G. Calimport, Barry L. Bentley","doi":"10.1101/2024.09.02.24312951","DOIUrl":"https://doi.org/10.1101/2024.09.02.24312951","url":null,"abstract":"<strong>Background</strong> Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.09.06.24313183
Elizabeth R. Feldman, Yunqi Li, David J. Cutler, Tracie C. Rosser, Stephanie B. Wechsler, Lauren Sanclemente, Angela L. Rachubinski, Natalina Elliott, Paresh Vyas, Irene Roberts, Karen R. Rabin, Michael Wagner, Bruce D. Gelb, Joaquin M. Espinosa, Philip J. Lupo, Adam J. de Smith, Stephanie L. Sherman, Elizabeth J. Leslie
Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n=886: atrioventricular septal defects (AVSD), n=438; atrial septal defects (ASD), n=122; ventricular septal defects (VSD), n=170; other types of CHD, n=156) and DS with a structurally normal heart (DS+NH, n=572). We performed four GWAS for common variants (MAF>0.05) comparing DS with CHD, stratified by CHD-subtype, to DS+NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p<2×10−6). Of these, the 1p35.1 locus (near RBBP4) was specifically associated with ASD risk and the 5q35.2 locus (near MSX2) was associated with any type of CHD. Each of the suggestive loci contained one or more plausible candidate genes expressed in the developing heart. While no SNP replicated (p<2×10−6) in an independent cohort of DS+CHD (DS+CHD: n=229; DS+NH: n=197), most SNPs that were suggestive in our GWASs remained suggestive when meta-analyzed with the GWASs from the replication cohort. These results build on previous work to identify genetic modifiers of DS-associated CHD.
先天性心脏缺陷（CHD）是最常见的结构性出生缺陷，40%-50%的唐氏综合征（DS）患儿都有这种缺陷。为了描述唐氏综合征相关先天性心脏缺损的遗传结构，我们对一组多种族唐氏综合征先天性心脏缺损患儿（n=886：房室间隔缺损（AVSD），n=438；房间隔缺损（ASD），n=122；室间隔缺损（VSD），n=170；其他类型的先天性心脏缺损，n=156）和心脏结构正常的唐氏综合征患儿（DS+NH，n=572）进行了基因组测序。我们针对常见变异（MAF>0.05）进行了四次全球基因组研究，将患有CHD的DS（按CHD亚型分层）与DS+NH对照进行比较。虽然没有 SNP 达到全基因组显著性，但每次分析中都有多个位点达到了提示性显著性（p<2×10-6）。其中，1p35.1位点（靠近RBBP4）与ASD风险特别相关，5q35.2位点（靠近MSX2）与任何类型的先天性心脏病相关。每个提示性位点都包含一个或多个在心脏发育过程中表达的可信候选基因。虽然没有 SNP 在 DS+CHD 的独立队列（DS+CHD：n=229；DS+NH：n=197）中得到重复（p<2×10-6），但在我们的 GWAS 中具有提示性的大多数 SNP 在与来自重复队列的 GWAS 进行元分析时仍具有提示性。这些结果建立在先前确定 DS 相关先天性心脏病遗传修饰因子的工作基础之上。
{"title":"Genome-wide association studies of Down syndrome associated congenital heart defects","authors":"Elizabeth R. Feldman, Yunqi Li, David J. Cutler, Tracie C. Rosser, Stephanie B. Wechsler, Lauren Sanclemente, Angela L. Rachubinski, Natalina Elliott, Paresh Vyas, Irene Roberts, Karen R. Rabin, Michael Wagner, Bruce D. Gelb, Joaquin M. Espinosa, Philip J. Lupo, Adam J. de Smith, Stephanie L. Sherman, Elizabeth J. Leslie","doi":"10.1101/2024.09.06.24313183","DOIUrl":"https://doi.org/10.1101/2024.09.06.24313183","url":null,"abstract":"Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n=886: atrioventricular septal defects (AVSD), n=438; atrial septal defects (ASD), n=122; ventricular septal defects (VSD), n=170; other types of CHD, n=156) and DS with a structurally normal heart (DS+NH, n=572). We performed four GWAS for common variants (MAF>0.05) comparing DS with CHD, stratified by CHD-subtype, to DS+NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p<2×10<sup>−6</sup>). Of these, the 1p35.1 locus (near <em>RBBP4</em>) was specifically associated with ASD risk and the 5q35.2 locus (near <em>MSX2</em>) was associated with any type of CHD. Each of the suggestive loci contained one or more plausible candidate genes expressed in the developing heart. While no SNP replicated (p<2×10<sup>−6</sup>) in an independent cohort of DS+CHD (DS+CHD: n=229; DS+NH: n=197), most SNPs that were suggestive in our GWASs remained suggestive when meta-analyzed with the GWASs from the replication cohort. These results build on previous work to identify genetic modifiers of DS-associated CHD.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.09.05.24313021
Mashiat Zaman, Julien L Marcadier, Amanda V Tyndall, Brenda McInnes, A Micheil Innes, Francois P Bernier, Timothy E. Shutt
Pathogenic variants in the mitochondrial fusion protein Mitofusin2 typically cause axonal Charcot-Marie- Tooth disease type 2A (CMT2A), a progressively degenerative peripheral neuropathy. Here, we present two siblings with a lethal disorder of neonatal onset who carried a novel homozygous MFN2 variant R334K. Given the severe clinical presentation, which is atypical of MFN2 variants, further functional investigations were warranted to confirm the pathogenicity of the R334K variant, which was deemed to be likely pathogenic. Characterization of patient fibroblasts showed severe disruptions all MFN2-related functions that were assayed, including reduced mitochondrial respiration, altered mito-ER contacts, decreased mtDNA copy number and size, as well as increased abundance of cellular lipid droplets. We also observed reduced Complex I activity, which is noted in cells lacking MFN2, but is not standard for pathogenic MFN2 variants that cause CMT2A. These functional deficits, combined with the fact that loss of MFN2 is lethal in model organisms (e.g. mice/fruit-flies), support the notion that the MFN2 R334K is a loss of function variant that is responsible for patient phenotype. Thus, we present a novel pathogenic MFN2 variant causing severe fatal neonatal disease.
{"title":"A novel variant in MFN2 linked to a lethal disorder of neonatal onset","authors":"Mashiat Zaman, Julien L Marcadier, Amanda V Tyndall, Brenda McInnes, A Micheil Innes, Francois P Bernier, Timothy E. Shutt","doi":"10.1101/2024.09.05.24313021","DOIUrl":"https://doi.org/10.1101/2024.09.05.24313021","url":null,"abstract":"Pathogenic variants in the mitochondrial fusion protein Mitofusin2 typically cause axonal Charcot-Marie- Tooth disease type 2A (CMT2A), a progressively degenerative peripheral neuropathy. Here, we present two siblings with a lethal disorder of neonatal onset who carried a novel homozygous MFN2 variant R334K. Given the severe clinical presentation, which is atypical of MFN2 variants, further functional investigations were warranted to confirm the pathogenicity of the R334K variant, which was deemed to be likely pathogenic. Characterization of patient fibroblasts showed severe disruptions all MFN2-related functions that were assayed, including reduced mitochondrial respiration, altered mito-ER contacts, decreased mtDNA copy number and size, as well as increased abundance of cellular lipid droplets. We also observed reduced Complex I activity, which is noted in cells lacking MFN2, but is not standard for pathogenic MFN2 variants that cause CMT2A. These functional deficits, combined with the fact that loss of MFN2 is lethal in model organisms (e.g. mice/fruit-flies), support the notion that the MFN2 R334K is a loss of function variant that is responsible for patient phenotype. Thus, we present a novel pathogenic MFN2 variant causing severe fatal neonatal disease.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.09.06.24313124
Raquel Puerta, Itziar de Rojas, Pablo García-González, Clàudia Olivé, Oscar Sotolongo-Grau, Ainhoa García-Sánchez, Fernando García-Gutiérrez, Laura Montrreal, Juan Pablo Tartari, Ángela Sanabria, Vanesa Pytel, Carmen Lage, Inés Quintela, Nuria Aguilera, Eloy Rodriguez-Rodriguez, Emilio Alarcón-Martín, Adelina Orellana, Pau Pastor, Jordi Pérez-Tur, Gerard Piñol-Ripoll, Adolfo López de Munian, Jose María García-Alberca, Jose Luís Royo, María Jesús Bullido, Victoria Álvarez, Luis Miguel Real, Arturo Corbatón Anchuelo, Dulcenombre Gómez-Garre, María Teresa Martínez Larrad, Emilio Franco-Macías, Pablo Mir, Miguel Medina, Raquel Sánchez-Valle, Oriol Dols- Icardo, María Eugenia Sáez, Ángel Carracedo, Lluís Tárraga, Montse Alegret, Sergi Valero, Marta Marquié, Mercè Boada, Pascual Sánchez Juan, Jose Enrique Cavazos, Alfredo Cabrera, Amanda Cano, Agustín Ruiz, Alzheimer’s Disease Neuroimaging Initiative
Background Alzheimer’s disease (AD) has a high heritable component characteristic of complex diseases, yet many of the genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may be helpful to understand the underlying biology of the disease.
{"title":"Connecting genomic and proteomic signatures of amyloid burden in the brain","authors":"Raquel Puerta, Itziar de Rojas, Pablo García-González, Clàudia Olivé, Oscar Sotolongo-Grau, Ainhoa García-Sánchez, Fernando García-Gutiérrez, Laura Montrreal, Juan Pablo Tartari, Ángela Sanabria, Vanesa Pytel, Carmen Lage, Inés Quintela, Nuria Aguilera, Eloy Rodriguez-Rodriguez, Emilio Alarcón-Martín, Adelina Orellana, Pau Pastor, Jordi Pérez-Tur, Gerard Piñol-Ripoll, Adolfo López de Munian, Jose María García-Alberca, Jose Luís Royo, María Jesús Bullido, Victoria Álvarez, Luis Miguel Real, Arturo Corbatón Anchuelo, Dulcenombre Gómez-Garre, María Teresa Martínez Larrad, Emilio Franco-Macías, Pablo Mir, Miguel Medina, Raquel Sánchez-Valle, Oriol Dols- Icardo, María Eugenia Sáez, Ángel Carracedo, Lluís Tárraga, Montse Alegret, Sergi Valero, Marta Marquié, Mercè Boada, Pascual Sánchez Juan, Jose Enrique Cavazos, Alfredo Cabrera, Amanda Cano, Agustín Ruiz, Alzheimer’s Disease Neuroimaging Initiative","doi":"10.1101/2024.09.06.24313124","DOIUrl":"https://doi.org/10.1101/2024.09.06.24313124","url":null,"abstract":"<strong>Background</strong> Alzheimer’s disease (AD) has a high heritable component characteristic of complex diseases, yet many of the genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may be helpful to understand the underlying biology of the disease.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1101/2024.09.03.24313025
Angela G. Jones, Guinevere G. Connelly, Trisha Dalapati, Liuyang Wang, Benjamin H. Schott, Adrianna K. San Roman, Dennis C. Ko
Humans display sexual dimorphism across many traits, but little is known about underlying genetic mechanisms and impacts on disease. We utilized single-cell RNA-seq of 480 lymphoblastoid cell lines to reveal that the vast majority (79%) of sex-biased genes are targets of transcription factors that display sex-biased expression. Further, we developed a two-step regression method that identified sex-biased expression quantitative trait loci (sb-eQTL) across the genome. In contrast to previous work, these sb-eQTL are abundant (n=10,754; FDR 5%) and reproducible (replication up to π1=0.56). These sb-eQTL are enriched in over 600 GWAS phenotypes, including 120 sb-eQTL associated with the female-biased autoimmune disease multiple sclerosis. Our results demonstrate widespread genetic impacts on sexual dimorphism and identify possible mechanisms and clinical targets for sex differences in diverse diseases.
{"title":"Biological sex affects functional variation across the human genome","authors":"Angela G. Jones, Guinevere G. Connelly, Trisha Dalapati, Liuyang Wang, Benjamin H. Schott, Adrianna K. San Roman, Dennis C. Ko","doi":"10.1101/2024.09.03.24313025","DOIUrl":"https://doi.org/10.1101/2024.09.03.24313025","url":null,"abstract":"Humans display sexual dimorphism across many traits, but little is known about underlying genetic mechanisms and impacts on disease. We utilized single-cell RNA-seq of 480 lymphoblastoid cell lines to reveal that the vast majority (79%) of sex-biased genes are targets of transcription factors that display sex-biased expression. Further, we developed a two-step regression method that identified sex-biased expression quantitative trait loci (sb-eQTL) across the genome. In contrast to previous work, these sb-eQTL are abundant (n=10,754; FDR 5%) and reproducible (replication up to π<sub>1</sub>=0.56). These sb-eQTL are enriched in over 600 GWAS phenotypes, including 120 sb-eQTL associated with the female-biased autoimmune disease multiple sclerosis. Our results demonstrate widespread genetic impacts on sexual dimorphism and identify possible mechanisms and clinical targets for sex differences in diverse diseases.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"182 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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