Test for rare variants by environment interactions in sequencing association studies

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142484/1/biom12368_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142484/2/biom12368.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142484/3/biom12368-sup-0001-SuppData.pd

Intratumoral Delivery of a PD-1-blocking scFv encoded in Oncolytic HSV-1 Promotes Antitumor Immunity and Synergizes with TIGIT Blockade

恶性肿瘤已严重威胁人类健康和生命，现有的治疗手段远远未能满足临床需求。厦门大学研究团队联合浙江养生堂生物科技有限公司、养生堂有限公司进行协同攻关，研制出新一代肿瘤免疫治疗药物——“注射用重组人PD-1抗体单纯疱疹病毒”。研究发现，重组表达PD-1单链抗体的溶瘤病毒具有“双药合一”抗肿瘤的突出优势，提高肿瘤治愈率。相关成果于2020年3月3日以研究论文形式在线发表于Cancer Immunology Research（《癌症免疫学研究》）期刊，为指导新型溶瘤病毒的升级改造和突破肿瘤免疫耐受提供了新的思路，为重组表达PD-1单链抗体的溶瘤病毒药物运用于肿瘤临床治疗奠定了坚实的理论基础。 厦门大学公共卫生学院夏宁邵教授和黄承浩助理教授为该论文的共同通讯作者，博士生林超龙和任文峰为该论文的共同第一作者。【Abstract】Oncolytic virotherapy can lead to systemic antitumor immunity, but the therapeutic potential of oncolytic viruses (OVs) in humans is limited due to their insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). Here, we showed that locoregional oncolytic virotherapy upregulated the expression of PD-L1 in the TME, which was mediated by virus-induced type I and type II interferons (IFNs). To explore PD-1/PD-L1 signaling as a direct target in tumor tissue, we developed a novel immunotherapeutic herpes simplex virus (HSV), OVH-aMPD-1, that expressed a single-chain variable fragment (scFv) against PD-1 (aMPD-1 scFv). The virus was designed to locally deliver aMPD-1 scFv in the TME to achieve enhanced antitumor effects. This virus effectively modified the TME by releasing damage associated molecular patterns (DAMPs), promoting antigen cross-presentation by dendritic cells, and enhancing the infiltration of activated T cells; these alterations resulted antitumor T cell activity which led to reduced tumor burdens in a liver cancer model. Compared with OVH, OVH-aMPD-1 promoted the infiltration of myeloid-derived suppressor cells (MDSCs),resulting in significantly higher percentages of CD155+ G-MDSCs and M-MDSCs in tumors. In combination with TIGIT blockade, this virus enhanced tumor-specific immune responses in mice with implanted subcutaneous tumors or invasive tumors. These findings highlighted that intratumoral immunomodulation with an OV expressing aMPD-1 scFv could be an effective standalone strategy to treat cancers or drive maximal efficacy of a combination therapy with other immune checkpoint inhibitors.This work was supported by grant 2018ZX10301404-001-002 from the National Science and Technology Major Project and grant 81571990 from the National Natural Science Foundation of China.该研究获得了国家自然科学基金、国家科技重大专项的资助

Intravenous Injections of a Rationally Selected Oncolytic Herpes Virus as a Potent Virotherapy for Hepatocellular Carcinoma

As a clinical setting in which novel treatment options are urgently needed, hepatocellular carcinoma (HCC) exhibits intriguing opportunities for oncolytic virotherapy. Here we report the rational generation of a novel herpes simplex virus type 1 (HSV-1)-based oncolytic vector for targeting HCC, named Ld0-GFP, which was derived from oncolytic ICP0-null virus (d0-GFP), had a fusogenic phenotype, and was a novel killer against HCC as well as other types of cancer cells. Compared with d0-GFP, Ld0-GFP exhibited superior cancer cell-killing ability in vitro and in vivo . Ld0-GFP targets a broad spectrum of HCC cells and can result in significantly enhanced immunogenic tumor cell death. Intratumoral and intravenous injections of Ld0-GFP showed effective antitumor capabilities in multiple tumor models, leading to increased survival. We speculated that more active cell-killing capability of oncolytic virus and enhanced immunogenic cell death may lead to better tumor regression. Additionally, Ld0-GFP had an improved safety profile, showing reduced neurovirulence and systemic toxicity. Ld0-GFP virotherapy could offer a potentially less toxic, more effective option for both local and systemic treatment of HCC. This approach also provides novel insights toward ongoing efforts to develop an optimal oncolytic vector for cancer therapy

Interethnic analyses of blood pressure loci in populations of East Asian and European descent

AbstractBlood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.AcknowledgementsMarie Loh71,72 (Institute of Health Sciences, University of Oulu, P.O.Box 5000FI-90014 Oulu, Finland and Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK),Niek Verweij73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Weihua Zhang72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK),Benjamin Lehne72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK),Irene Mateo Leach73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Alexander Drong75 (Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK),James Abbott76 (Bioinformatics Support Service, Imperial College London, South Kensington, London SW7 2AZ, UK),Sian-Tsung Tan74,77 (Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK and National Heart and Lung Institute, Imperial College London, London W12 0NN, UK),William R. Scott72,77 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Lung Institute, Imperial College London, London W12 0NN, UK),Gianluca Campanella72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK),Marc Chadeau-Hyam72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK),Uzma Afzal72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK),Tõnu Esko78,79,80,81 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia and Division of Endocrinology, Children’s Hospital Boston, Longwood 300, Boston, MA 02115, USA and Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA),Sarah E. Harris82,83 (Medical Genetics Section, University of Edinburgh Molecular Medicine Centre and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK and Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK),Jaana Hartiala84,85 (Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA and Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA),Marcus E. Kleber86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany),Richa Saxena87 (Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA),Alexandre F.R. Stewart88,89 (University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ontario K1Y 4W7, Canada and Ruddy Canadian Cardiovascular Genetics Centre, Ontario K1Y 4W7, Canada),Tarunveer S. Ahluwalia90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark),Imke Aits91 (Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany),Alexessander Da Silva Couto Alves92 (Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK),Shikta Das92 (Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK),Jemma C. Hopewell93 (Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK),Robert W. Koivula94 (Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, SE-205 02 Malmö, Sweden),Leo-Pekka Lyytikäinen95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland),Iris Postmus97,98 (Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, Netherlands and Netherlands Consortium for Healthy Ageing, Leiden 2333 ZC, Netherlands),Olli T. Raitakari99,100 (Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, FI-20521 Turku, Finland and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, FI-20520 Turku, Finland),Robert A. Scott101 (MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK),Rossella Sorice102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy),Vinicius Tragante103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands),Michela Traglia104,105 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy and Institute for Maternal and Child Health—IRCCS ‘‘Burlo Garofolo’’—Trieste, 34137 Trieste, Italy),Jon White106 (UCL Genetics Institute, Department of Genetics, Environment and Evolution, UCL, London WC1E 6BT, UK),Inês Barroso107,108,109 (Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK),Andrew Bjonnes87 (Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA),Rory Collins103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands),Gail Davies110 (Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK),Graciela Delgado86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany),Pieter A. Doevendans103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands),Lude Franke111 (Department of Genetics, University Medical Center, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Ron T. Gansevoort112 (Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Tanja B. Grammer86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany),Niels Grarup86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany),Jagvir Grewal72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK),Anna-Liisa Hartikainen113,114 (Department of Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, Oulu FI-90014, Finland and Department of Clinical Sciences/Obsterics and Gynecology, University of Oulu, Oulu FI-90014, Finland),Stanley L. Hazen115,116 (Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA),Chris Hsu117 (Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA),Lise L.N. Husemoen118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark),Johanne M. Justesen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark),Meena Kumari119 (Department of Epidemiology and Public Health, UCL, London WC1E 6BT, UK),Wolfgang Lieb91 (Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany),David C.M. Liewald110 (Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK),Evelin Mihailov78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia),Lili Milani78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia),Rebecca Mills74 (Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK),Nina Mononen95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland),Kjell Nikus120 (Heart Centre, Department of Cardiology, Tampere University Hospital, and University of Tampere School of Medicine, FI-33521 Tampere, Finland),Teresa Nutile102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy),Sarah Parish93 (Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK),Olov Rolandsson121 (Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, SE-901 85 Umeå, Sweden),Daniela Ruggiero102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy),Cinzia F. Sala104 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy),Harold Snieder122 (Department of Epidemiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Thomas H.W. Spasø90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark),Wilko Spiering123 (Department of Vascular Medicine, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands),John M. Starr83,124 (Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK and Alzheimer Scotland Dementia Research Centre, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK),David J. Stott125 (Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G4 0SF, UK),Daniel O. Stram117 (Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA),Silke Szymczak126 (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany),W.H.Wilson Tang115,116 (Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA),Stella Trompet127 (Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands),Väinö Turjanmaa128,129 (Department of Clinical Physiology, Tampere University Hospital, FI-33521 Tampere, Finland and Department of Clinical Physiology, University of Tampere School of Medicine, FI-33014 Tampere, Finland),Marja Vaarasmaki130 (Department of Obstetrics and Gynecology, Oulu University Hospital, PO Box 23FI-90029 Oulu, Finland),Wiek H. van Gilst73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Dirk J. van Veldhuisen73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Jorma S. Viikari131,132 (Department of Medicine, Turku University Hospital, FI-20521 Turku, Finland and Department of Medicine, University of Turku, FI-20014 Turku, Finland),Folkert W. Asselbergs103,133,134 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, Netherlands and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London WC1E 6BT, UK),Marina Ciullo102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy),Andre Franke126 (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany),Paul W. Franks94,121,135 (Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, SE-205 02 Malmö, Sweden and Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, SE-901 85 Umeå, Sweden and Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA),Steve Franks136 (Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W120HS, UK),Myron D. Gross137 (School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA),Torben Hansen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark),Marjo-Riitta Jarvelin72,92,138,139,140 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK and Biocenter Oulu, University of Oulu, P.O. Box 5000 Aapistie 5A, FI-90014 Oulu, Finland and Unit of Primary Care, Oulu University Hospital, Kajaanintie 50 P.O.Box 20FI-90220 Oulu, Finland and Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, FI-90101 Oulu, Finland),Torben Jørgensen118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark),Wouter J. Jukema127,133,141 (Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht 3511 EP, Netherlands),Mika Kähönen128,129 (Department of Clinical Physiology, Tampere University Hospital, FI-33521 Tampere, Finland and Department of Clinical Physiology, University of Tampere School of Medicine, FI-33014 Tampere, Finland),Mika Kivimaki119 (Department of Epidemiology and Public Health, UCL, London WC1E 6BT, UK),Terho Lehtimäki95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland),Allan Linneberg118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark),Oluf Pedersen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark),Nilesh J. Samani142,143 (Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK),Daniela Toniolo104,144 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy and Institute of Molecular GeneticsCNR, 27100 Pavia, Italy),Hooman Allayee84,85 (Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA and Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA),Ian J. Deary83,110 (Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK and Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK),Winfried März86,145,146 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria and Synlab Academy, Synlab Services GmbH, Gottlieb-Daimler-Straße 25, 68165 Mannheim, Germany),Andres Metspalu78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia),Cisca Wijmenga111 (Department of Genetics, University Medical Center, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Bruce H.W. Wolffenbuttel147 (Department of Endocrinology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Paolo Vineis72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK),Soterios A. KyrtopoulosNational Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens 116 35, Greece),Jos C.S. Kleinjans149 (Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, 6229ER Maastricht, Netherlands),Mark I. McCarthy75,150 (Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK),James Scott77 (National Heart and Lung Institute, Imperial College London, London W12 0NN, UK)Abstract Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.Acknowledgements Marie Loh71,72 (Institute of Health Sciences, University of Oulu, P.O.Box 5000FI-90014 Oulu, Finland and Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK),Niek Verweij73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands),Weihua Zhang72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK),Benjamin Lehne72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK),Irene Mateo Leach73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groning

X-chromosome and kidney function:evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.</p

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research

The Trans-Ancestral Genomic Architecture of Glycemic Traits

Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To 462 date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, 463 we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% 464 non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and 465 fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; 466 P&lt;5x10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted 467 to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. 468 Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of 469 estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression 470 and gene-set analyses revealed distinct biological signatures for each trait, highlighting different 471 underlying biological pathways. Our results increase understanding of diabetes pathophysiology by 472 use of trans-ancestry studies for improved power and resolution

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe