Rare copy number variation in posttraumatic stress disorder

Funding Information: This work was supported by the National Institute of Mental Health/U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, MBS, KJRe, and KCK]), and National Institutes of Health (Grant No. 5U01MH109539 [to the Psychiatric Genomics Consortium] and Grant No. U19 MH069056 [to BWD])). Financial support for the PTSD PGC was provided by the Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, and One Mind. Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209).Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10−8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.publishersversionepub_ahead_of_prin

Recombinant Haplotypes Narrow the ARMS2/HTRA1 Association Signal for Age-Related Macular Degeneration

The authors thank Paul N. Baird (Ocular Genetics Unit, Centre for Eye Research, Australia) for critically reading the manuscript. The work was funded in part by grants from the German Federal Ministry of Education and Research (BMBF 01ER1206 and 01ER1507) to I.M.H., by the institutional budget for Research and Teaching from the Freestate of Bavaria and the German Research Foundation (WE 1259/19-2) to BHFW.Peer reviewedPublisher PD

A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration

Peer reviewedPublisher PD

HEALTHINESS Participant Information Sheet V2.0 (10.07.2024)

Title of Study HEALTHINESS (Health Inequalities in Diabetes Mellitus) Study Researchers Chief Investigator: Prof John Dillon Principal Investigator: Dr Rachael Barrett We are inviting you to take part in a study You are being invited to participate in the HEALTHINESS research study. The study takes the form of a questionnaire, and your responses will be linked to some of your medical information such as blood test results. Before you choose whether or not to take part, we want you to understand why we are doing the study. We also want to tell you what it will involve if you agree to take part. Please take time to read this information carefully. You can ask us any questions you have and talk to other people about it if you want (such as with friends and family). We will do our best to answer your questions and provide you with any more information you ask for. You do not have to decide straight away. Why are we doing this study? We are testing a new way of organising diabetes treatment in NHS Tayside. This is called iDiabetes, and uses information such as a person’s blood test results, height and weight and medical history to automatically make recommendations to their doctor or nurse on the best treatment option for them. The patients will also be able to see these recommendations on an app, called MyDiabetesMyWay. As part of the overall testing of the iDiabetes system, some GP surgeries will provide the same care that they have always done, and others will use the new iDiabetes system, so that these two groups can be compared. However, it will be important to make sure that not only does iDiabetes improve diabetes care but improves diabetes outcomes for everyone. Many researchers have found that “social determinants of health” impact on the likelihood of having type 2 diabetes, and on blood sugar control and the risk of complications in both type 1 and type 2 diabetes. Social determinants of health mean the conditions and environment where people are born, grow, live, work and age. These circumstances are often a result of distribution of resources at a worldwide, national, or local level and beyond an individual's control. This can result in “health inequalities” which is when people (with the same conditions) have different health outcomes due to certain characteristics such as sex, ethnicity, income level, education level and many more. We are performing the HEALTHINESS survey study alongside, but separately, to iDiabetes so we can see how social determinants of health are related to diabetes outcomes in NHS Tayside. We will then use the responses to make sure iDiabetes benefits all people with diabetes and to ensure it does not have less benefit in particular groups of people who may have less money, lower education level or certain ethnic groups. Why have I been contacted? We are contacting potential participants in NHS Tayside who have diabetes mellitus (any subtype). You may have been contacted because you are registered with either SHARE (The Scottish Health Research Register and Biobank) or the NRS (NHS Research Scotland) Diabetes Register and have indicated you are happy to be contacted to participate in research studies. You may also have been asked to take part during an iDiabetes study visit, diabetes clinic appointment or inpatient stay. You may have also heard about the study from posters or the iDiabetes website. We have deliberately made lots of options because we are looking to speak to as many different people as possible including people who may not normally use or receive emails. Do I have to take part? No. It is up to you to choose, taking part in this study is entirely up to you. You can choose to take part or choose not to take part. If you choose not to take part, then simply don’t complete the survey. You do not have to give a reason for not taking part. If you do not want to take part or want to stop the study the medical care you receive and your relationship with the medical or nursing staff looking after you will not be affected. What will happen if I take part? The study is a survey made up of two sets of questions. After finishing reading this information sheet you will be asked to review and agree to some statements making sure you understand and are happy to take part in the HEALTHINESS study. What if I’m unable to complete an online survey? We wish to hear from people who are not able, or do not have the facilities to complete this survey online. If this is the case for you, please contact the study team (contact details at the bottom of this sheet) and we will happily provide a paper copy or go through the survey with you over the telephone. The survey information below will be the same, just in paper format or over the telephone. What does the survey involve? If you take part, you will be transferred to an electronic survey page. You will be asked questions about your circumstances, quality of life, access to the internet and health literacy (how you find, read and understand health information in order to make decisions about your health). Your responses will be collected via our survey partner Jisc. When we have enough responses, the information will be downloaded to the NHS Tayside server. Your DOB (date of birth), name and postcode will be used to find your community health index number (CHI) to allow us to link your responses to your medical information. At this point we will anonymise your responses, by giving your responses a code (sometimes called a unique identifier). Your name, date of birth and CHI number will be removed from the responses at this stage. We will keep your postcode to allow us to look up the Scottish Index of Multiple Deprivation code for where you live. After around one year we will invite you to repeat some parts of the survey to see if your understanding of healthcare or wellbeing has changed. How long will the study take? The survey should take around 10 minutes to complete, but may take slightly longer or slightly less time from person to person. The study will run until we have collected enough responses and have 1 year follow-up of participants’ medical records since enrolment in iDiabetes. Will taking part in the study affect my usual care? No, there will be no alteration to your usual care as a result of taking part in the study. The study is a survey only and we will not be making any changes to your medical care. What are the possible benefits of taking part? There are no direct health benefits to you from taking part. It is hoped that your responses will allow the study team to assess the impact of iDiabetes on health inequalities. Results gathered from this study may guide any alterations to the iDiabetes platform to ensure those from all backgrounds and circumstances can benefit. Results may also inform those making decisions about healthcare in Scotland to make health outcomes more equal across the whole population of Scotland. What are the possible disadvantages and risks of taking part? There are no disadvantages and risks of taking part as the study will not alter your usual medical care. Who is organising and funding this research? The study is being organised by the University of Dundee. It is being funded by the Chief Scientist’s Office. It is being organised by Prof John Dillon and team. How will my survey data be used? We will link the responses from your survey data to the medical data (such as blood test results, information on hospital admissions, prescription information) that is being collected as part of the iDiabetes study and some other routinely available medical data. We will use the information in your survey responses to see if there any patterns in those who have better diabetes control compared to those who have worse diabetes control. This will hopefully allow us to identify any groups of people who may require further help or assistance in getting the most out of iDiabetes and their diabetes care. Study results The results from the study will be made available through the development of reports, peer-reviewed research papers, and presentations. You will not be identifiable in any of the results or any of the publications. If you wish to receive details of how the study is progressing and research outputs, there will be an option to opt-in to this at the end of the study. How will my data be collected? Data will be collected via an online survey. If you wish to complete the survey over the telephone or paper, your answers will be entered into the online survey by the trial team. How will my survey response data be stored? Your study responses will initially be stored by the University of Dundee’s survey partner, Jisc. The Jisc security policy can be accessed here https://onlinesurveys.jisc.ac.uk/security/. Following completion of the survey, data will be downloaded to the NHS Tayside secure server to allow identification of your CHI number. The survey responses will then be stored within the University of Dundee’s, Health Informatics Centre (HIC) Trusted Research Environment (TRE). Your responses will only be accessible by the research team. How long will my survey response data be stored for? Data will be stored for 5 years after the study is completed. What measures are in place to protect the security and confidentiality of my data? Storage and usage of all data is governed by University of Dundee data protection policies, which are aligned to the General Data Protection Regulation (GDPR) and associated Standard Operation Procedures (SOP). Further information is available at: https://www.dundee.ac.uk/information-governance/data-protection. Will my data be anonymised? We will pseudo-anonymise your data which means you will be given a unique identifier (numerical code) which will be linked to your CHI. Your data will be stored with the unique identifier separately from your CHI, name and date of birth. Who will have access to my data? The research team and members of the NRS diabetes register team will have access to the survey responses. This is to allow linkage with your medical records and blood test results so we can analyse the results of the study. Will my data be archived for use in other research projects in the future? Your data may be used in some further analysis for the iDiabetes project but will not be used in any other projects. How will my data be destroyed? The survey data will be securely destroyed 5 years after the results of the HEALTHINESS study have been published. How will we use information about you? We will need to use information from your survey responses and from your medical records for this research project. This information will include your: • Name • Postcode • Community Health Index Number • Date of Birth We will use this information to link your survey responses with the information from your medical records. Your data will have a code number and your personal identifiers will be kept separately. We will ask you to enter your preferred contact details (email, telephone, address) at the end of the survey so we can contact you about the second set of questions after one year. We will also ask your consent to contact you to discuss participating in interviews we are planning in the future. This is entirely optional. We will keep all information about you safe and secure. Once we have finished the study, we will keep some of the data so we can check the results. We will write our reports in a way that no-one can work out that you took part in the study. What are your choices about how your information is used? • You can stop being part of the study at any time, without giving a reason. We will keep information about you that we already have but will not ask you to complete any further surveys. • If you choose to stop taking part in the study, we would like to continue collecting information about your health from central NHS records. If you do not want this to happen, tell us and we will stop. • We need to manage your records in specific ways for the research to be reliable. This means that we won’t be able to let you see or change the data we hold about you. Where can you find out more about how your information is used? You can find out more about how we use your information at https://www.hra.nhs.uk/information-about-patients/ or by asking one of the research team by sending an email to [email protected]. What if I am unhappy or there is a problem? If you are unhappy, or if there is a problem, please feel free to let us know by contacting us. Principal Investigator, Dr Rachael Barrett ([email protected]) and we will try to help. If you are not satisfied, you can make a formal complaint to a senior member of the research team or to the Complaints Officer for NHS Tayside. Patient Experience Team NHS Tayside Ninewells Hospital Dundee DD1 9SY Freephone: 0800 027 5507 Email: [email protected] If you think you have come to harm due to taking part in the study there are no automatic arrangements to get financial compensation.   Insurance The University of Dundee is Sponsoring the study. The University of Dundee holds Clinical Trials indemnity cover which covers the University’s legal liability for harm caused to patients/participants. Who has reviewed this trial/study? This trial/study has been reviewed and approved by Brent Research Ethics Committee who are responsible for reviewing research which is conducted in humans. The Research Ethics committee does not have any objections to this study going ahead. Contact details for further information. Principal Investigator Dr Rachael Barrett Ninewells Hospital and Medical School Dundee DD2 1SY Phone: 01382 383017 Email: [email protected] Thank you for taking time to read this information and for considering taking part in this study.  Information Governance – Data Protection How we use your information If you choose to provide personal data in response to any of our questions, you should understand that we will hold and process that information in the dataset we generate from the survey responses. We will retain the raw data from the survey responses until 5 years after the end of the study. We will retain our analysis and reporting. You are under no obligation to complete this survey. Personal data Personal data is explicitly asked for in this survey. Should you provide personal data in response to any of our questions, please consider whether your responses reveal circumstances which may identify you and whether you wish to include them. Any disclosure of personal data is at your own discretion. You should restrict your answers to the matter at hand and avoid disclosing the personal data of others. Special categories of personal data This survey will ask for special categories of personal data in the completion of this survey. These are required for they analysis of the results due to the nature of the study. Data controller Should you provide personal data in response to this survey the University of Dundee would be the data controller for this information. This data may be processed by the University’s nominated agents such as software or service providers. Data will be processed using the University’s business systems. These include Microsoft 365 and Microsoft OneDrive. The University uses an online survey run by JISC to collect this information. For information on how this service secures your data please see https://www.jisc.ac.uk/online-surveys. Lawful processing If you choose to provide personal data in response to our questions, it will be processed by the University on the basis that it is lawful for it to process your personal data, as the processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the University as data controller. Your rights The University respects your rights and preferences in relation to you. If you wish to update, access, erase, or limit the use of your information please let us know by emailing: Dr Rachael Barrett: [email protected]. If you wish to complain about the University’s use of your information, please contact the University’s Data Protection Officer in the first instance by emailing [email protected]. You may also wish to contact the Information Commissioner’s Office

Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects.

Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. Despite evidence of an inherited genetic contribution to CTDs, little is known about the specific genes that contribute to the development of CTDs. We performed gene-based genome-wide analyses using microarray-genotyped and imputed common and rare variants data from two large studies of CTDs in the United States. We performed two case-parent trio analyses (N = 640 and 317 trios), using an extension of the family-based multi-marker association test, and two case-control analyses (N = 482 and 406 patients and comparable numbers of controls), using a sequence kernel association test. We also undertook two meta-analyses to combine the results from the analyses that used the same approach (i.e. family-based or case-control). To our knowledge, these analyses are the first reported gene-based, genome-wide association studies of CTDs. Based on our findings, we propose eight CTD candidate genes (ARF5, EIF4E, KPNA1, MAP4K3, MBNL1, NCAPG, NDFUS1 and PSMG3). Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. In addition, our analyses provide additional evidence that genes involved in chromatin-modification and in ribonucleic acid splicing are associated with congenital heart defects

Massive dissemination of a SARS-CoV-2 Spike Y839 variant in Portugal

Funding This study is co-funded by Fundação para a Ciência e a Tecnologia and Agência de Investigação Clínica e Inovação Biomédica [grant number 234_596874175] on behalf of the Research 4 COVID-19 call. This work is also a result of the GenomePT project [grant number POCI-01-0145- FEDER-022184], supported by COMPETE 2020 – Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e a Tecnologia (FCT).Genomic surveillance of SARS-CoV-2 was rapidly implemented in Portugal by the National Institute of Health in collaboration with a nationwide consortium of >50 hospitals/laboratories. Here, we track the geotemporal spread of a SARS-CoV-2 variant with a mutation (D839Y) in a potential host-interacting region involving the Spike fusion peptide, which is a target motif of anti-viral drugs that plays a key role in SARS-CoV-2 infectivity. The Spike Y839 variant was most likely imported from Italy in mid-late February and massively disseminated in Portugal during the early epidemic, becoming prevalent in the Northern and Central regions of Portugal where it represented 22% and 59% of the sampled genomes, respectively, by 30 April. Based on our high sequencing sampling during the early epidemics [15.5% (1275/8251) and 6.0% (1500/24987) of all confirmed cases until the end of March and April, respectively], we estimate that, between 14 March and 9 April (covering the epidemic exponential phase) the relative frequency of the Spike Y839 variant increased at a rate of 12.1% (6.1%–18.2%, CI 95%) every three days, being potentially associated with 24.8% (20.8–29.7%, CI 95%; 3177–4542 cases, CI 95%) of all COVID-19 cases in Portugal during this period. Our data supports population/epidemiological (founder) effects contributing to the Y839 variant superspread. The potential existence of selective advantage is also discussed, although experimental validation is required. Despite huge differences in genome sampling worldwide, SARS-CoV-2 Spike D839Y has been detected in 13 countries in four continents, supporting the need for close surveillance and functional assays of Spike variants.publishersversionpublishe

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease : a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7.8 million single nucleotide polymorphisms in 37688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1.4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0 .0035 for intracranial volume, p=0.024 for putamen volume), smoking status (p=0.024), and educational attainment (p=0.038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8.00 x10 -7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Copyright (C) 2019 Elsevier Ltd. All rights reserved.Peer reviewe