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1. Genome wide association study of clinical duration and age at onset of sporadic CJD.

Author

Hummerich H, Speedy H, Campbell T, Darwent L, Hill E, Collins S, Stehmann C, Kovacs GG, Geschwind MD, Frontzek K, Budka H, Gelpi E, Aguzzi A, van der Lee SJ, van Duijn CM, Liberski PP, Calero M, Sanchez-Juan P, Bouaziz-Amar E, Laplanche JL, Haïk S, Brandel JP, Mammana A, Capellari S, Poleggi A, Ladogana A, Pocchiari M, Zafar S, Booth S, Jansen GH, Areškevičiūtė A, Løbner Lund E, Glisic K, Parchi P, Hermann P, Zerr I, Appleby BS, Safar J, Gambetti P, Collinge J, and Mead S

Subjects
Humans, Aged, Middle Aged, Female, Male, Phenotype, Genotype, Creutzfeldt-Jakob Syndrome genetics, Creutzfeldt-Jakob Syndrome pathology, Age of Onset, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci., Competing Interests: Stéphane Haik reports grants from Santé Publique France, during the conduct of the study; grants from LFB Biomedicaments, grants from Institut de Recherche Servier, grants from MedDay Pharmaceuticals, outside the submitted work; In addition, Stéphane Haik has a patent Method for treating prion diseases (PCT/EP2019/070457) pending. Brian Appleby has received funding from CDC, NIH, CJD Foundation, Alector, and Ionis. He has served as a consultant for Ionis, Sangamo, and Gate Biosciences. He has received royalties from Wolter Kluwers. Karl Fronztek reports grants from Ono Pharmaceuticals outside the submitted work. Simon Mead reports grants from Medical Research Council (UK) and grants from National Institute of Health Research’s Biomedical Research Centre at University College London Hospitals NHS Foundation Trust during the conduct of the study. Gabor G Kovacs reports personal fees from Biogen, outside the submitted work. John Collinge reports grants from Medical Research Council, grants from NIHR UCLH Biomedical Research Centre, during the conduct of the study; and is a Director and shareholder of D-Gen Limited, an academic spinout in the field of prion disease diagnostics, decontamination and therapeutics. Inga Zerr reports grants from the Bundesministerium für Gesundheit via Robert Koch institute, JPND and personal fees (not related to the content of the manuscript) from Ferring Pharmaceuticals and IONIS, speaking honoraria for medical lectures from Lilly, Biogen, Medfora, DGLN (German Society for cerebrospinal fluid diagnostics in Neurology). Maurizio Pocchiari reports personal fees from Ferring Pharmaceuticals, personal fees from CNCCS (Collection of National Chemical Compounds and Screening Center), non-financial support from Fondazione Cellule Staminali, outside the submitted work. Michael D Geschwind has consulted for3D Communications, Adept Field Consulting, Advanced Medical Inc., Best Doctors Inc., Second Opinion Inc., Gerson Lehrman Group Inc., Guidepoint Global LLC, InThought Consulting Inc., Market Plus, Trinity Partners LLC, Biohaven Pharmaceuticals, Quest Diagnostics and various medical-legal consulting. He has received speaking honoraria for various medical center lectures and from Oakstone publishing. He has received past research support from Alliance Biosecure, CurePSP, the Tau Consortium, and Quest Diagnostics. Michael D Geschwind serves on the board of directors for San Francisco Bay Area Physicians for Social Responsibility and on the editorial board of Dementia & Neuropsychologia., (Copyright: © 2024 Hummerich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2024
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2. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study.

Author

Jones E, Hummerich H, Viré E, Uphill J, Dimitriadis A, Speedy H, Campbell T, Norsworthy P, Quinn L, Whitfield J, Linehan J, Jaunmuktane Z, Brandner S, Jat P, Nihat A, How Mok T, Ahmed P, Collins S, Stehmann C, Sarros S, Kovacs GG, Geschwind MD, Golubjatnikov A, Frontzek K, Budka H, Aguzzi A, Karamujić-Čomić H, van der Lee SJ, Ibrahim-Verbaas CA, van Duijn CM, Sikorska B, Golanska E, Liberski PP, Calero M, Calero O, Sanchez-Juan P, Salas A, Martinón-Torres F, Bouaziz-Amar E, Haïk S, Laplanche JL, Brandel JP, Amouyel P, Lambert JC, Parchi P, Bartoletti-Stella A, Capellari S, Poleggi A, Ladogana A, Pocchiari M, Aneli S, Matullo G, Knight R, Zafar S, Zerr I, Booth S, Coulthart MB, Jansen GH, Glisic K, Blevins J, Gambetti P, Safar J, Appleby B, Collinge J, and Mead S

Subjects
Creutzfeldt-Jakob Syndrome diagnosis, Creutzfeldt-Jakob Syndrome epidemiology, Genetic Predisposition to Disease epidemiology, Humans, Polymorphism, Single Nucleotide genetics, Risk Factors, Creutzfeldt-Jakob Syndrome genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods
Abstract

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms., Methods: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country., Findings: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10 -15 ; heterozygous model p=1·01 × 10 -135 ), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10 -9 ), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10 -10 ). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions., Interpretation: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders., Funding: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2020
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3. Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci.

Author

Law PJ, Sud A, Mitchell JS, Henrion M, Orlando G, Lenive O, Broderick P, Speedy HE, Johnson DC, Kaiser M, Weinhold N, Cooke R, Sunter NJ, Jackson GH, Summerfield G, Harris RJ, Pettitt AR, Allsup DJ, Carmichael J, Bailey JR, Pratt G, Rahman T, Pepper C, Fegan C, von Strandmann EP, Engert A, Försti A, Chen B, Filho MI, Thomsen H, Hoffmann P, Noethen MM, Eisele L, Jöckel KH, Allan JM, Swerdlow AJ, Goldschmidt H, Catovsky D, Morgan GJ, Hemminki K, and Houlston RS

Subjects
Adaptor Proteins, Signal Transducing genetics, Adult, Aged, Female, Genetic Predisposition to Disease, HLA-DQ beta-Chains genetics, HLA-DRB1 Chains genetics, Hodgkin Disease pathology, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Multiple Myeloma pathology, Oncogene Proteins genetics, Polymorphism, Single Nucleotide genetics, Risk Factors, Genetic Pleiotropy genetics, Genome-Wide Association Study, Hodgkin Disease genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Multiple Myeloma genetics
Abstract

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10 -9 ) with opposing effects between CLL (P = 1.97 × 10 -8 ) and HL (P = 3.31 × 10 -3 ). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10 -12 ) was associated with increased CLL and HL risk (P = 4.68 × 10 -12 ), and reduced MM risk (P = 1.12 × 10 -2 ), and Gly70 in HLA-DQB1 (P = 3.15 × 10 -10 ) showed opposing effects between CLL (P = 3.52 × 10 -3 ) and HL (P = 3.41 × 10 -9 ). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

Published
2017
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4. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia.

Author

Speedy HE, Di Bernardo MC, Sava GP, Dyer MJ, Holroyd A, Wang Y, Sunter NJ, Mansouri L, Juliusson G, Smedby KE, Roos G, Jayne S, Majid A, Dearden C, Hall AG, Mainou-Fowler T, Jackson GH, Summerfield G, Harris RJ, Pettitt AR, Allsup DJ, Bailey JR, Pratt G, Pepper C, Fegan C, Rosenquist R, Catovsky D, Allan JM, and Houlston RS

Subjects
Aged, Case-Control Studies, Chromosomes, Human, Pair 3, Humans, Male, Membrane Proteins genetics, Middle Aged, Neoplasm Proteins genetics, Recombination, Genetic, Shelterin Complex, Telomere-Binding Proteins genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Polymorphism, Single Nucleotide
Abstract

Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10(-9)), 4q26 (rs6858698, P = 3.07 × 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10(-10)) and 8q22.3 (rs2511714, P = 2.90 × 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.

Published
2014
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6. Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

Author

Went, Molly, Sud, Amit, Speedy, Helen, Sunter, Nicola J., Försti, Asta, Law, Philip J., Johnson, David C., Mirabella, Fabio, Holroyd, Amy, Li, Ni, Orlando, Giulia, Weinhold, Niels, van Duin, Mark, Chen, Bowang, Mitchell, Jonathan S., Mansouri, Larry, Juliusson, Gunnar, Smedby, Karin E, Jayne, Sandrine, Majid, Aneela, Dearden, Claire, Allsup, David J., Bailey, James R., Pratt, Guy, Pepper, Chris, Fegan, Chris, Rosenquist, Richard, Kuiper, Rowan, Stephens, Owen W., Bertsch, Uta, Broderick, Peter, Einsele, Hermann, Gregory, Walter M., Hillengass, Jens, Hoffmann, Per, Jackson, Graham H., Jöckel, Karl-Heinz, Nickel, Jolanta, Nöthen, Markus M., da Silva Filho, Miguel Inacio, Thomsen, Hauke, Walker, Brian A., Broyl, Annemiek, Davies, Faith E., Hansson, Markus, Goldschmidt, Hartmut, Dyer, Martin J. S., Kaiser, Martin, Sonneveld, Pieter, Morgan, Gareth J., Hemminki, Kari, Nilsson, Björn, Catovsky, Daniel, Allan, James M., Houlston, Richard S., and Hematology

Subjects
Cancer och onkologi, Genetic Linkage, Quantitative Trait Loci, Medizin, Hematology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Leukemia, Lymphocytic, Chronic, B-Cell, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Organ Specificity, Cancer and Oncology, hemic and lymphatic diseases, Case-Control Studies, Databases, Genetic, Humans, Genetic Predisposition to Disease, Hematologi, Multiple Myeloma, Alleles, Genetic Association Studies, Genome-Wide Association Study
Abstract

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R g = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

Published
2018

7. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

Law, Philip J, Berndt, Sonja I, Speedy, Helen E, Camp, Nicola J, Sava, Georgina P, Skibola, Christine F, Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J, Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R, Clot, Guillem, Teras, Lauren R, Quintela, Inés, Birmann, Brenda M, Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E, Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G, Purdue, Mark P, Mainou-Fowler, Tryfonia, Vajdic, Claire M, Jackson, Graham H, Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G, Lawrence, Charles, Call, Timothy G, Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W Ryan, Link, Brian K, Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A, Jackson, Rebecca D, Tinker, Lesley F, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E., Morton, Lindsay M, Severson, Richard K, Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C H, Southey, Melissa C, Milne, Roger L., Clavel, Jacqueline, Topka, Sabine, Spinelli, John J, Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M, Harris, Robert J, Miligi, Lucia, Pettitt, Andrew R, North, Kari E, Allsup, David J, Fraumeni, Joseph F, Bailey, James R, Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Christopher, Chanock, Stephen J, Fegan, Chris, Rosenquist, Richard, de Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J S, Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M, Rothman, Nathanial, Houlston, Richard, Slager, Susan, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Microsoft Research [Redmond], Microsoft Corporation [Redmond, Wash.], Department of Physics, Loyola College, Nungambakkam, Chennai – 600 034, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Aleppo [Aleppo], Sea Mammal Research Unit [University of St Andrews] (SMRU), School of Biology [University of St Andrews], University of St Andrews [Scotland]-University of St Andrews [Scotland]-Natural Environment Research Council (NERC), Department of Chemical Engineering, Imperial College London, De la Molécule aux Nanos-objets : Réactivité, Interactions et Spectroscopies (MONARIS), Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), The Cancer Council Victoria, University of Oulu, Uppsala Universitet [Uppsala], Université Paris Nanterre (UPN), University of Iowa [Iowa City], Registre des hémopathies malignes de Côte d'Or, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), B.B. Brodie Department of Neuroscience, Pennsylvania State University (Penn State), Penn State System, University of Newcastle [Australia] (UoN), Astrophysique Interprétation Modélisation (AIM (UMR_7158 / UMR_E_9005 / UM_112)), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Department of Haematology, School of Medicine, Cardiff University, CIBER de Enfermedades Raras (CIBERER), University of Leeds, Haemato-oncology, Institute of cancer research, Mayo Clinic [Rochester], Northern Institute for Cancer Research [Newcastle] (NICR), Newcastle University [Newcastle], Institute of Cancer Research, Belmont, Sutton, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Sea Mammal Research Unit, Scottish Oceans Institute, University of St Andrews [Scotland], Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), University of Cardiff, Équipe Instrumentation embarquée et systèmes de surveillance intelligents (LAAS-S4M), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), University of Newcastle [Callaghan, Australia] (UoN), Astrophysique Interprétation Modélisation (AIM (UMR7158 / UMR_E_9005 / UM_112)), LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, Université Toulouse 1 Capitole (UT1)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
Adult, Male, RM, Cancer och onkologi, B-Lymphocytes, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Science, Chromosome Mapping, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell, Polymorphism, Single Nucleotide, Article, Young Adult, Cancer and Oncology, Case-Control Studies, Antibody Formation, Chromosomes, Human, Humans, Female, Genetic Predisposition to Disease, RC, Genome-Wide Association Study
Abstract

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response., Chronic lymphocytic leukaemia has a hereditary component, much of which remains to be identified. Here, the authors perform a genome-wide association study and find new risk loci for the disease, which are associated with genes involved in immune function.

Published
2017
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8. Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

Author

Law, Philip J, Sud, Amit, Mitchell, Jonathan S, Henrion, Marc, Orlando, Giulia, Lenive, Oleg, Broderick, Peter, Speedy, Helen E, Johnson, David C, Kaiser, Martin, Weinhold, Niels, Cooke, Rosie, Sunter, Nicola J, Jackson, Graham H, Summerfield, Geoffrey, Harris, Robert J, Pettitt, Andrew R, Allsup, David J, Carmichael, Jonathan, Bailey, James R, Pratt, Guy, Rahman, Thahira, Pepper, Christopher, Fegan, Chris, von Strandmann, Elke Pogge, Engert, Andreas, Försti, Asta, Chen, Bowang, da Silva Filho, Miguel Inacio, Thomsen, Hauke, Hoffmann, Per, Noethen, Markus M, Eisele, Lewin, Jöckel, Karl-Heinz, Allan, James M, Swerdlow, Anthony J, Goldschmidt, Hartmut, Catovsky, Daniel, Morgan, Gareth J, Hemminki, Kari, and Houlston, Richard S

Subjects
Adult, Male, Oncogene Proteins, Medizin, Genetic Pleiotropy, Middle Aged, R1, Hodgkin Disease, Leukemia, Lymphocytic, Chronic, B-Cell, Polymorphism, Single Nucleotide, Article, R852, Risk Factors, HLA-DQ beta-Chains, Humans, Female, Genetic Predisposition to Disease, Multiple Myeloma, Adaptor Proteins, Signal Transducing, Aged, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10−9) with opposing effects between CLL (P = 1.97 × 10−8) and HL (P = 3.31 × 10−3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10−12) was associated with increased CLL and HL risk (P = 4.68 × 10−12), and reduced MM risk (P = 1.12 × 10−2), and Gly70 in HLA-DQB1 (P = 3.15 × 10−10) showed opposing effects between CLL (P = 3.52 × 10−3) and HL (P = 3.41 × 10−9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

Published
2017

9. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Schmidt, Amand F, Holmes, Michael V, Preiss, David, Swerdlow, Daniel I, Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, Van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M, Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F, Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G, Onland-Moret, N Charlotte, Van Der Schouw, Yvonne T, Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J, Langenberg, Claudia, Scott, Robert A, Luan, Jian'an, Bobak, Martin, Malyutina, Sofia, Pająk, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E, Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S, McCarty, Catherine A, Lester, Kirchner H, Larson, Eric B, Crosslin, David R, De Andrade, Mariza, Roden, Dan M, Denny, Joshua C, Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Van Der Harst, Pim, Said, M Abdullah, Eppinga, Ruben N, Verweij, Niek, Snieder, Harold, Lifelines Cohort Authors, Christen, Tim, Mook-Kanamori, DO, ICBP Consortium, Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M, Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P, Meade, Tom, Christophersen, Ingrid E, Maitland-Van Der Zee, Anke H, Baranova, Ekaterina V, Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L, Grobbee, Diederick E, Froguel, Philippe, Thuillier, Dorothée, Roussel, Ronan, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C, Seshadri, Sudha, METASTROKE Consortium Of The ISGC, Dale, Caroline, Costa, Rui Providencia E, Ridker, Paul M, Chasman, Daniel I, Reiner, Alex P, Ritchie, Marylyn D, Lange, Leslie A, Cornish, Alex J, Dobbins, Sara E, Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Björn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W, Patel, Riyaz S, Keating, Brendan J, Sattar, Naveed, Houlston, Richard, Casas, Juan P, and Hingorani, Aroon D

Subjects
Genetic association studies, Serine Proteinase Inhibitors, Anticholesteremic Agents, PCSK9 Inhibitors, Myocardial Infarction, Down-Regulation, Cholesterol, LDL, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Brain Ischemia, Stroke, Treatment Outcome, Risk Factors, LDL-cholesterol, Humans, Phenome-wide association scan, Proprotein Convertase 9, Mendelian randomisation, Biomarkers, Dyslipidemias, Genome-Wide Association Study, Randomized Controlled Trials as Topic
Abstract

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

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