peer-reviewed ; H.D.D., A.J.C., P.J.B. and B.J.H. would like to acknowledge the Dairy Futures Cooperative Research Centre for funding. H.P. and R.F. acknowledge funding from the German Federal Ministry of Education and Research (BMBF) within the AgroClustEr 'Synbreed—Synergistic Plant and Animal Breeding' (grant 0315527B). H.P., R.F., R.E. and K.-U.G. acknowledge the Arbeitsgemeinschaft Süddeutscher Rinderzüchter, the Arbeitsgemeinschaft Österreichischer Fleckviehzüchter and ZuchtData EDV Dienstleistungen for providing genotype data. A. Bagnato acknowledges the European Union (EU) Collaborative Project LowInputBreeds (grant agreement 222623) for providing Brown Swiss genotypes. Braunvieh Schweiz is acknowledged for providing Brown Swiss phenotypes. H.P. and R.F. acknowledge the German Holstein Association (DHV) and the Confederación de Asociaciones de Frisona Española (CONCAFE) for sharing genotype data. H.P. was financially supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (DFG) (grant PA 2789/1-1). D.B. and D.C.P. acknowledge funding from the Research Stimulus Fund (11/S/112) and Science Foundation Ireland (14/IA/2576). M.S. and F.S.S. acknowledge the Canadian Dairy Network (CDN) for providing the Holstein genotypes. P.S. acknowledges funding from the Genome Canada project entitled 'Whole Genome Selection through Genome Wide Imputation in Beef Cattle' and acknowledges WestGrid and Compute/Calcul Canada for providing computing resources. J.F.T. was supported by the National Institute of Food and Agriculture, US Department of Agriculture, under awards 2013-68004-20364 and 2015-67015-23183. A. Bagnato, F.P., M.D. and J.W. acknowledge EU Collaborative Project Quantomics (grant 516 agreement 222664) for providing Brown Swiss and Finnish Ayrshire sequences and genotypes. A.C.B. and R.F.V. acknowledge funding from the public–private partnership 'Breed4Food' (code BO-22.04-011- 001-ASG-LR) and EU FP7 IRSES SEQSEL (grant 317697). A.C.B. and R.F.V. acknowledge CRV (Arnhem, the Netherlands) for providing data on Dutch and New Zealand Holstein and Jersey bulls. ; Stature is affected by many polymorphisms of small effect in humans1. In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P < 5 × 10−8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP–seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals.
The genetic component of Immunoglobulin-A (IgA) vasculitis is still far to be elucidated. To increase the current knowledge on the genetic component of this vasculitis we performed the first genome-wide association study (GWAS) on this condition. 308 IgA vasculitis patients and 1,018 healthy controls from Spain were genotyped by Illumina HumanCore BeadChips. Imputation of GWAS data was performed using the 1000 Genomes Project Phase III dataset as reference panel. After quality control filters and GWAS imputation, 285 patients and 1,006 controls remained in the datasets and were included in further analysis. Additionally, the human leukocyte antigen (HLA) region was comprehensively studied by imputing classical alleles and polymorphic amino acid positions. A linkage disequilibrium block of polymorphisms located in the HLA class II region surpassed the genome-wide level of significance (OR = 0.56, 95% CI = 0.46–0.68). Although no polymorphic amino acid positions were associated at the genome-wide level of significance, P-values of potential relevance were observed for the positions 13 and 11 of HLA-DRB1 (P = 6.67E-05, P = 1.88E-05, respectively). Outside the HLA, potential associations were detected, but none of them were close to the statistical significance. In conclusion, our study suggests that IgA vasculitis is an archetypal HLA class II disease. ; This study was supported by European Union FEDER funds and "Fondo de Investigaciones Sanitarias" (grant PI12/00193) from 'Instituto de Salud Carlos III' (ISCIII, Health Ministry, Spain). RL-M was supported by the Miguel Servet I programme of the Spanish Ministry of Economy and Competitiveness through the grant CP16/00033. FDC was supported by the Ramón y Cajal programme of the Spanish Ministry of Economy and Competitiveness through the grant RYC-2014-16458. FG was recipient of a Sara Borrell postdoctoral fellowship from the "Instituto Carlos III de Salud" at the Spanish Ministry of Health (Spain) (CD15/00095). SR-M and BU were supported by funds from the RETICS Program (RIER) (RD16/0012/0009 and RD12/0009/0013, respectively).
Objective To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk. DESIGN Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach. Setting 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data. Participants A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a twosample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor. Results Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian randomisation analyses showed a clear effect of bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P=1.5×10?68). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture. Con clusions This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk. ; Funding: This research and the Genetic Factors for Osteoporosis (GEFOS) consortium have been funded by the European Commission (HEALTH-F2-2008-201865-GEFOS). AGES: NIH contract N01- AG-12100 and NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and Althingi (the Icelandic Parliament). Icelandic Heart Association. Anglo-Australasian Osteoporosis Genetics Consortium (AOGC): National Health and Medical Research Council (Australia) (grant reference 511132). Australian Cancer Research Foundation and Rebecca Cooper Foundation (Australia). National Health and Medical Research Council (Australia). National Health and Medical Research Council (Australia) Career Development Award (569807). Medical Research Council New Investigator Award (MRC G0800582). Health Research Council of New Zealand. Sanofi-Aventis, Eli Lilly, Novartis, Pfizer, Proctor & Gamble Pharmaceuticals and Roche. National Health and Medical Research Council, Australia. Australian National Health and Medical Research Council, MBF Living Well foundation, the Ernst Heine Family Foundation and from untied educational grants from Amgen, Eli Lilly International, GE-Lunar, Merck Australia, Novartis, Sanofi-Aventis Australia and Servier. Medical Research Council UK and Arthritis Research UK. The Victorian Health Promotion Foundation and the Geelong Region Medical Research Foundation, and the National Health and Medical Research Council, Australia (project grant 628582). Action Research UK. DME is supported by an Australian Research Council Future Fellowship (FT130101709). This work was supported by a Medical Research Council programme grant (MC_UU_12013/4). B-Vitamins for the PRevention Of Osteoporotic Fractures (BPROOF) study: supported and funded so far by The Netherlands Organisation for Health Research and Development (ZonMw, grant 6130.0031), The Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; Netherlands Consortium Healthy Ageing (NCHA) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), The Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam. Cardiovascular Health Study (CHS): National Heart Lung and Blood Institute (NHLBI) contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Ageing (NIA). Genotyping supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Genetics. EPIC-Norfolk: Medical Research Council G9321536 and G9800062, MAFF AN0523, EU FP5 (QLK6-CT-2002-02629), Food Standards Agency N05046, GEFOS EU FP7 Integrated Project Grant Reference: 201865, The UK's National Institute for Health Research (NIHR) Biomedical Research Centre Grant to Cambridge contributed to the costs of genotyping. Estonian Genome Center University of Tartu (EGCUT): This study was supported by EU H2020 grants 692145, 676550, 654248, Estonian Research Council Grant IUT20-60, NIASC and EIT—Health and EU through the European Regional Development Fund (project No 2014-2020.4.01.15-0012 GENTRANSMED). Erasmus Rucphen Family Study (ERF): Netherlands Organisation for Scientific Research (NWO), Erasmus University Medical Centre, the Centre for Medical Systems Biology (CMSB1 and CMSB2) of the Netherlands Genomics Initiative (NGI). Framingham Osteoporosis Study (FOS): National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Ageing (R01 AR41398; DPK and R01 AR 050066; DK National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix for genotyping services (N02-HL-6-4278). The Gothenburg Osteoporosis and Obesity Determinan Study (GOOD): Swedish Research Council (K2010-54X-09894-19-3, 2006-3832 and K2010-52X-20229-05-3), Swedish Foundation for Strategic Research, ALF/LUA research grant in Gothenburg, Lundberg Foundation, Torsten and Ragnar Söderberg's Foundation, Västra Götaland Foundation, Göteborg Medical Society, Novo Nordisk Foundation, and European Commission grant HEALTH-F2-2008- 201865-GEFOS. Health Aging and Body Composition Study (HealthABC): the Intramural Research Program of the National Institute of Health (NIH), National Institute on Ageing. US National Institute of Ageing (NIA) contracts N01AG62101, N01AG62103, and N01AG62106. NIA grant 1R01AG032098. The Center for Inherited Disease Research (CIDR). National Institutes of Health contract number HHSN268200782096C. Hong Kong Osteoporosis Study (HKOS): Hong Kong Research Grant Council (HKU 768610M); Bone Health Fund of HKU Foundation; KC Wong Education Foundation; Small Project Funding (201007176237); Matching Grant, Committee on research and conference (CRCG) Grant and Osteoporosis and Endocrine Research Fund; and the Genomics Strategic Research Theme of the University of Hong Kong. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Ageing (NIA), National Center for Research Resources (NCRR), and National Institute of Health (NIH) Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, and UL1 RR024140. Prospective study of pravastatin in the elderly at risk (PROSPER): European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement No HEALTH-F2-2009-223004 PHASE. Rotterdam study I, Rotterdam study II, Rotterdam study III: Netherlands Organisation of Scientific Research (NWO) Investments (No 175.010.2005.011, 911-03-012); Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Ageing (050-060-810); German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G. the Netherlands Organisation for Health Research and Development ZonMw VIDI 016.136.367 (funding FR, CM-G, KT). Study of Osteoporotic Fractures (SOF): supported by National Institutes of Health funding. The National Institute on Ageing (NIA) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, and R01 AG026720. TwinsUK1, TwinsUK2: NIHR Biomedical Research Centre (grant to Guys' and St Thomas' Hospitals and King's College London); Chronic Disease Research Foundation; Wellcome Trust; Canadian Institutes of Health Research, Canadian Foundation for Innovation, Fonds de la Recherche en Santé Québec, Lady Davis Institute, Jewish General Hospital, and Ministère du Développement économique, de l'Innovation et de l'Exportation du Quebec. UK Biobank: This research has been conducted using the UK Biobank Resource (application No 12703). Access to the UK Biobank study data was funded by a University of Queensland Early Career Researcher Grant (2014002959). Access to the UK Biobank study data was funded by University of Queensland Early Career Researcher Grant (2014002959) and University of Western Australia-University of Queensland Bilateral Research Collaboration Award (2014001711). NMW is supported by a National Health and Medical Research Council Early Career Fellowship (APP1104818). Women's Genome Health Study (WGHS): HL 043851 and HL69757 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W Reynolds Foundation, and the Fondation Leducq Amgen. Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Young Finns study (YFS): has been financially supported by the Academy of Finland: grants 286284 (TL), 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Tampere, Turku and Kuopio University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association; and EU Horizon 2020 (grant 755320 for TAXINOMISIS). Barcelona cohort osteoporosis (BARCOS): Red de Envejecimiento y fragilidad RETICEF, CIBERER, Instituto Carlos III. Fondos FEDER. Fondo de Investigación Sanitaria (FIS PI13/00116). Spanish MINECO (SAF2014-56562-R), Catalan Government (2014SGR932). Austrios-A, Austrios-B: was supported by BioPersMed (COMET K project 825329), and the Competence Center CBmed (COMET K1 centre 844609), funded by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT) and the Austrian Federal Ministry of Economics and Labour/ the Federal Ministry of Economy, Family and Youth (BMWA/BMWFJ) and the Styrian Business Promotion Agency (SFG). Cantabria-Camargo study (Cabrio-C), Cantabria osteoporosis case-control study (Cabrio-CC): Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias Grants PI 06/34,PI09/539, PI12/615 and PI15/521 (that could be cofunded by European Union-FEDER funds). Calcium Intake Fracture Outcome Study (CAIFOS): Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grant (254627, 303169 and 572604). Canadian Multicentre Osteoporosis Study (CaMos): was supported by a grant from the Canadian Institutes for Health Research (CIHR) (grant No MOP111103). JBR and JAM are funded by the Canadian Institutes of Health Research, Fonds du Recherche Québec Santé, and Jewish General Hospital. Edinburgh Osteoporosis Study (EDOS): was supported by a grant from Arthritis Research UK (grant number 15389). European Prospective Osteoporosis Study (EPOS): EU Biomed 1 (BMHICT920182, CIPDCT925012, ERBC1PDCT 940229, ERBC1PDCT930105), Medical Research Council G9321536 and G9800062, Wellcome Trust Collaborative Research Initiative 1995, MAFF AN0523,EU FP5 (QLK6-CT-2002-02629), Food Standards Agency N05046, GEFOS EU FP7 Integrated Project Grant Reference: 201865. The UK's National Institute for Health Research (NIHR) Biomedical Research Centre Grant to Cambridge contributed to the costs of genotyping. Geelong Osteoporosis Study (GEOS): Canadian Institutes for health research operating grant funding reference #86748. Genetic analysis of osteoporosis in Greece (GROS): University of Athens, Greece (Kapodistrias 2009). Hertfordshire Cohort Study (HCS): supported by Medical Research Council UK; Arthritis Research UK; National Institute for Health Research (NIHR) Musculoskeletal BRU Oxford; National Institute for Health Research (NIHR) Nutrition BRC Southampton. Hong Kong: The projects have been supported by The Hong Kong Jockey Club Charities Trust, VC discretionary fund of The Chinese University of Hong Kong, and Research Grants Council Earmarked Grant CUHK4101/02M. Korean osteoporosis study in Asan Medical Center (KorAMC): a grant of the Korea Health Technology R&D Project, the Ministry of Health and Welfare, Republic of Korea (project No HI14C2258); a grant of the Korea Health Technology R&D Project, the Ministry of Health and Welfare, Republic of Korea (project No HI15C0377). Longitudinal Aging Study Amsterdam (LASA): largely supported by a grant from the Netherlands Ministry of Health Welfare and Sports, Directorate of Long term Care. MINOS study was supported by a grant from the Merck-Sharp-Dohme Chibret company. Malta osteoporotic fracture study (MOFS): financial support was received from the European Union Strategic Educational Pathways Scholarhip scheme (STEPS). The Osteoporotic Fractures in Men (MrOS) Sweden: financial support was received from the Swedish Research Council (K2010- 54X-09894-19-3, 2006-3832), Swedish Foundation for Strategic Research, ALF/LUA research grant in Gothenburg, Lundberg Foundation, Torsten and Ragnar Söderberg's Foundation, Västra Götaland Foundation, Göteborg Medical Society, Novo Nordisk foundation, and European Commission grant HEALTH-F2-2008- 201865-GEFOS. Odense androgen study (OAS): World Anti-Doping Agency, Danish Ministry of Culture, Institute of Clinical Research of the University of Southern Denmark. Prevalence of osteoporosis in Slovenia (Slo-preval): was created as part of projects financially supported by the Slovenian research agency: P3-298 Geni, Hormoni in osebnostne spremembe pri hormonskih motnjah; Z1-3238: Genski in okoljski dejavniki tveganja za razvoj motnje pri remodellaciji kosti; J2-3314 Genetski faktorji in hormoni pri presnovnih boleznih; and J3-2330 Genetski dejavniki pri osteoporozi. TWINGENE: supported in part by the Ragnar Söderberg Foundation (E9/11); the National Science Foundation (EArly Concept Grants for Exploratory Research: "Workshop for the Formation of a Social Science Genetic Association Consortium," SES-1064089) as supplemented by the National Institutes of Health's (NIH) Office of Behavioural and Social Sciences Research; and the National Institute on Ageing/NIH through Grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to the National Bureau of Economic Research. The Swedish Twin Registry is supported by the Swedish Department of Higher Education, European Commission European Network for Genetic and Genomic Epidemiology (ENGAGE: 7th Framework Program (FP7/2007-2013)/Grant agreement HEALTH-F4-2007-201413; and GenomEUtwin: 5th Framework program "Quality of Life and Management of the Living Resources" Grant QLG2-CT-2002-01254); NIH (DK U01-066134); Swedish Research Council (M-2005-1112 and 2009-2298); Swedish Foundation for Strategic Research (ICA08-0047); Jan Wallander and Tom Hedelius Foundation; and Swedish Council for Working Life and Social Research. The Umeå Fracture and Osteoporosis Study (UFO) is supported by the Swedish Research Council (K20006- 72X-20155013), Swedish Sports Research Council (87/06), Swedish Society of Medicine, Kempe-Foundation (JCK-1021), and by grants from the Medical Faculty of Umeå University (ALFVLL:968:22-2005, ALFVL:-937-2006, ALFVLL:223:11-2007, ALFVLL:78151-2009) and county council of Västerbotten (SpjutspetsanslagVLL:159:33-2007). GRW and JHDB were funded by the Wellcome Trust (Strategic Award grant No 101123; Joint Investigator Award No 110141; project grant No 094134). DPK was funded by a grant from the National Institute on Arthritis Musculoskeletal and Skin Diseases R01 AR041398. The funding agencies had no role in the study design, analysis, or interpretation of data; the writing of the manuscript; or in the decision to submit the article for publication.
The Welcome Trust Case Control Consortium project was funded by the Wellcome Trust (awards 076113 and 085475). The New Zealand project was funded by the Health Research Council of New Zealand (08–75, 14–155). Recruitment of abdominal aortic aneurysm patients and controls in Belgium, Canada, and Pittsburgh, USA, was funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health (HL064310 and HL044682). The Geisinger sample collection was funded in part by the Pennsylvania Commonwealth Universal Research Enhancement program, the Geisinger Clinical Research Fund, the American Heart Association, and the Ben Franklin Technology Development Fund of Pennsylvania. The Barts and the Leicester Cardiovascular Biomedical Research Units are funded by the National Institute for Health Research. The eMERGE (electronic Medical Records and Genomics) Network is funded by the National Human Genome Research Institute, with additional funding from the National Institute of General Medical Sciences through the following grants: U01HG004438 to Johns Hopkins University; U01HG004424 to The Broad Institute; U01HG004438 to CIDR; U01HG004610 and U01HG006375 to Group Health Cooperative; U01HG004608 to Marshfield Clinic; U01HG006389 to Essentia Institute of Rural Health; U01HG04599 and U01HG006379 to Mayo Clinic; U01HG004609 and U01HG006388 to Northwestern University; U01HG04603 and U01HG006378 to Vanderbilt University; U01HG006385 to the Coordinating Center; U01HG006382 to Geisinger Health System; U01HG006380 to Icahn School of Medicine Mount Sinai. The generation and management of genome-wide association study (GWAS) data for the Rotterdam Study (control samples for the Dutch GWAS) is supported by the Netherlands Organization of Scientific Research (NWO) Investments (175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative/NWO project nr. 050-060-810. The Italian sample collection were funded by grants from Ente Cassa di Risparmio di Firenze to Fiorgen Foundation, Florence, Italy, and from the Italian Ministry of Health. Sample collections from Poland were funded in part by the National Science Centre in Poland (6P05A03921, NN403250440). The Mayo Vascular Disease Biorepository was funded by a Marriot Award for Individualized Medicine and an Award from the Mayo Center of Individualized Medicine. The Vanderbilt data set(s) were obtained from Vanderbilt University Medical Center's BioVU supported by institutional funding and by the National Center for Research Resources (UL1 RR024975-01, which is now at the National Center for Advancing Translational Sciences, UL1 TR000445-06). The ASAP study (Advanced Study of Aortic Pathology) was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Leducq Foundation (MIBAVA), and a donation by Fredrik Lundberg. S.E. Humphries holds a Chair funded by the British Heart Foundation, and is supported by the British Heart Foundation (BHF; PG08/008) and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The Cardiogenics project was supported by the European Union 6th Framework Programme (LSHM-CT-2006–037593). S.C. Harrison was funded by a BHF clinical training fellowship (FS/11/16/28696). The Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task biobank and the generation of the RNASeq data set was funded by Astra-Zeneca Translational Science Centre-Karolinska Institutet, the University of Tartu (SP1GVARENG), the Estonian Research Council (ETF 8853), the Torsten and Ragnar Söderberg Foundation, the Knut and Alice Wallenberg Foundation, the American Heart Association (A14SFRN20840000) and by the National Institute of Health (R01HL71207).
Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes. ; Artika Nath was supported by an Australian Postgraduate Award. This research was supported in part by the Victorian Government's OIS Program. Michael Inouye was supported by an NHMRC and Australian Heart Foundation Career Development Fellowship (no. 1061435). Gad Abraham was supported by an NHMRC Early Career Fellowship (no. 1090462). Qin Qin Huang is supported by the Melbourne International Research Scholarship. The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; and EU Horizon 2020 (grant 755320 for TAXINOMISIS); and European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation. Peter Würtz is supported by the Novo Nordisk Foundation (15998) and Academy of Finland (312476 and 312477).
Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and 90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I2 statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways ('Aromatic amine metabolism' [PGSEA = 0.0100, PARTP = 0.0020], 'NAD biosynthesis' [PGSEA = 0.0018, PARTP = 0.0086], 'NAD salvage' [PARTP = 0.0068], 'Clathrin derived vesicle budding' [PARTP = 0.0018], 'Lysosome vesicle biogenesis' [PGSEA = 0.0023, PARTP<0.00012], 'Retrograde neurotrophin signaling' [PGSEA = 0.00840], and 'Mitotic metaphase/anaphase transition' [PGSEA = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder ; This project has been funded in part with federal funds from the Natio nal Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Support for individual studies that participated in the effort is as follows: SBCS (Dr. Silverman) - Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-11015. FIS/Spain 98/1274, FIS/Spain 00/0745, PI061614, and G03/174 Fundació Marató TV3, Red Temática Investigación Cooperativa en Cáncer (RTICC), Consolider ONCOBIO, EU-FP7-201663; and RO1- CA089715 and CA34627. NEBCS (Dr. Silverman) - Intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-01037 PLCO (Dr. Purdue) - The National Institutes of Health (NIH) Genes, Environment and Health Initiative(GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C), and study coordination at the GENEVA (Dr. Caporaso)- The NIH Genes, Environment and Health Initiative [GEI] partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01HG004446) for EAGLE and part of PLCO studies. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. ATBC (Dr. Albanes) - This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services
Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.
National Commission of Scientific and Technologic Research (CONICYT) ; Government of Canada ; U-Inicia grant, from the Vicerrectoria de Investigacion y Desarrollo, Universidad de Chile ; grant FON-DEF NEWTON-PICARTE - CONICYT (Government of Chile) ; Newton Fund - The British Council (Government of United Kingdom) ; Nucleo Milenio INVASAL from Iniciativa Cientifica Milenio (Ministerio de Economia, Fomento y Turismo, Gobierno de Chile) ; government of Canada through Genome Canada ; Genome British Columbia ; Genome Quebec ; grant FON-DEF NEWTON-PICARTE - CONICYT (Government of Chile): IT14I10100 ; Piscirickettsia salmonis is one of the main infectious diseases affecting coho salmon (Oncorhynchus kisutch) farming, and current treatments have been ineffective for the control of this disease. Genetic improvement for P. salmonis resistance has been proposed as a feasible alternative for the control of this infectious disease in farmed fish. Genotyping by sequencing (GBS) strategies allow genotyping of hundreds of individuals with thousands of single nucleotide polymorphisms (SNPs), which can be used to perform genome wide association studies (GWAS) and predict genetic values using genome-wide information. We used double-digest restriction-site associated DNA (ddRAD) sequencing to dissect the genetic architecture of resistance against P. salmonis in a farmed coho salmon population and to identify molecular markers associated with the trait. We also evaluated genomic selection (GS) models in order to determine the potential to accelerate the genetic improvement of this trait by means of using genome-wide molecular information. A total of 764 individuals from 33 full-sib families (17 highly resistant and 16 highly susceptible) were experimentally challenged against P. salmonis and their genotypes were assayed using ddRAD sequencing. A total of 9,389 SNPs markers were identified in the population. These markers were used to test genomic selection models and compare different GWAS methodologies for resistance measured as day of death (DD) and binary survival (BIN). Genomic selection models showed higher accuracies than the traditional pedigree-based best linear unbiased prediction (PBLUP) method, for both DD and BIN. The models showed an improvement of up to 95% and 155% respectively over PBLUP. One SNP related with B-cell development was identified as a potential functional candidate associated with resistance to P. salmonis defined as DD.
The PGC was funded by National Institute of Mental Health (NIMH) Grant Nos. MH085520 (to PFS) and MH080403. Statistical analyses were carried out on the Genetic Cluster Computer (http://www. geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization Grant No. NWO 480-05-003 (to D. Posthuma) and the department of Psychology, Vrije Universiteit Amsterdam along with a supplement from the Dutch Brain Foundation. The Bonn/Mannheim GWAS was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia Grant Nos. 01GS08144 and 01GS08147, under the auspices of the National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders, under the auspices of the e:Med Programme Grant Nos. 01ZX1314A and 01ZX1314G. The Bonn/Mannheim GWAS was also supported by the German Research Foundation (DFG) Grant Nos. FOR2107, RI908/11-1, and NO246/10-1. The GenRED GWAS project was supported by NIMH R01 Grant Nos. MH061686 (to DFL), MH059542 (to W.H. Coryell), MH075131 (W.B. Lawson), MH059552 (JBP), MH059541 (W.A. Scheftner), and MH060912 (MMW). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression by Grant No. 01ES0811. Genotyping was supported by the Bavarian Ministry of Commerce, and the BMBF in the framework of the National Genome Research Network by Grant Nos. NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145. The Netherlands Study of Depression and Anxiety and the Netherlands Twin Register contributed to Genetic Association Information Network (GAIN)-MDD and to MDD2000. Funding for NTR/NESDA was from the following: the Netherlands Organization for Scientific Research (MagW/ZonMW Grant Nos. 904-61-090, 985-10-002, 904-61-193, 480-04004, 400-05-717, 912-100-20; Spinozapremie Grant No. 56-464-14192; Geestkracht program Grant No. 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, Vrije Universiteit's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, BIC/BioAssist/RK (Grant No. 2008.024); the European Science Foundation (Grant No. EU/QLRT-200101254); the European Community's Seventh Framework Program (Grant No. FP7/2007-2013); ENGAGE (Grant No. HEALTH-F4-2007-201413); and the European Science Council (Grant No. ERC 230374). Genotyping was funded in part by the GAIN of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (Grant No. MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (Grant Nos. 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (Grant Nos. FT0991360, FT0991022), the FP-5 GenomEUtwin Project (Grant No. QLG2-CT-2002-01254), and the US National Institutes of Health (Grant Nos. AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD). RADIANT was funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (Grant No. r G0701420); the National Institute for Health Research Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and the Institute of Psychiatry, King's College London; the UK Medical Research Council (Grant No. G0000647), and the Marie Curie Industry-Academia Partnership and Pathways (Grant No. 286213). The GENDEP study was funded by a European Commission Framework 6 grant (EC Contract Ref.: LSHB-CT2003- 503428). Genotyping of STAR* D was supported by NIMH Grant No. MH072802 (to SPH). STAR* D was funded by NIMH Grant No. N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (to A.J. Rush). The CoLaus/PsyCoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grant Nos. 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401) and two grants from GlaxoSmithKline Clinical Genetics. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. SHIP-LEGEND is funded by the DFG (Grant No. GR 1912/5-1). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (Grant No. M-2005-1112), GenomEUtwin (Grant Nos. EU/QLRT2001-01254,QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (Grant No. U01 DK066134). The collection of PRISME control subjects and genotyping of the 883 Danish control subjects was supported by grants from The Danish Strategic Research Council, The Stanley Research Foundation, and H. Lundbeck A/S. The Muenster Depression cohorts were supported by the European Union (Grant No. N Health-F2-2008-222963) and by grants from the DFG (Grant Nos. FOR 2107 and DA1151/5-1 [ to UD]), Innovative Medizinische Forschung of the Medical Faculty of Munster (Grant Nos. DA120903, DA111107, and DA211012 [ all to UD]). Generation Scotland is supported by a Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" (Reference No.: 104036/Z/14/Z) and core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6) and the Scottish Funding Council (Grant No. HR03006).r The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant No. U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control dataset were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression.r We acknowledge the contributions of Dr. George S Zubenko and Dr. Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. We are grateful to Knowledge Networks (Menlo Park, CA) for assistance in collecting the control dataset. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. We thank V. Mooser, G. Weaber, and P. Vollenweider who initiated the CoLaus project. We express our gratitude to the Lausanne inhabitants who volunteered to participate in the PsyCoLaus study. We would like to acknowledge the PRISME-study group, Denmark, for collection of the PRISME samples. We thank David M. Hougaard, Section of Neonatal Screening and Hormones, Statens Serum Institute, Copenhagen, Denmark; Preben Bo Mortensen, National Centre for Register-based Research, Aarhus University, Denmark; Merete Nordentoft, Mental Health Centre, Copenhagen, Denmark; and The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark. Funding from the BBSRC and MRC is gratefully acknowledged.r Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer's disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report.r SS, HS, KS, and TET are employees of deCODE Genetics/Amgen. VA received funds from the German Federal Ministry of Education and Research, from the European Union (FP 7), and from the Interdisciplinary Center for Clinical Research Munster, and he has served on the advisory boards of, or has given presentations on behalf of the following companies: Astra-Zeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer, Otsuka, and Trommsdorff. BTB has received funding from the National Health and Medical Research Council Australia and honoraria from Lundbeck, BristolMeyers Squibb, Sanofi, Servier, Astra-Zeneca, Pfizer. IJD is supported by the MRC-BBSRC, Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (Grant No. MR/K026992/1). HJG has received funding from German Research Foundation and Federal Ministry of Education and Research Germany and speakers honoraria from Eli Lilly and Servier. CH acknowledges support from the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC). DJM is supported by an , funded by the Chief Scientist Office. AMM is supported by a Scottish Funding Council Senior Clinical Fellowship and by the Dame Theresa and Mortimer Sackler Foundation and has received research support from Pfizer, Janssen, and Lilly. CMM was supported by the Netherlands Organization for Scientific Research (Grant No. NOW VENI 916-76-125). BM- M has consulted for Affectis Pharmaceuticals. MP has served on the advisory boards of Lundbeck and Eli Lilly ; BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (.27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11–1.21, p 5 5.2 3 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder. ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) MH085520 MH080403 ; SURFsara ; Netherlands Scientific Organization NWO 480-05-003 ; Department of Psychology, Vrije Universiteit Amsterdam ; Dutch Brain Foundation ; Federal Ministry of Education & Research (BMBF) 01GS08144 01GS08147 ; National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders ; e:Med Programme 01ZX1314A 01ZX1314G ; German Research Foundation (DFG) FOR2107 RI908/11-1 NO246/10-1 ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) MH061686 MH059542 MH075131 MH059552 MH059541 MH060912 ; Federal Ministry of Education & Research (BMBF) 01ES0811 ; Bavarian Ministry of Commerce ; Federal Ministry of Education & Research (BMBF) NGFN2 NGFN-Plus FKZ 01GS0481 01GS08145 ; Netherlands Organization for Scientific Research (MagW/ZonMW) 904-61-090 985-10-002 904-61-193 480-04004 400-05-717 912-100-20 ; Spinozapremie 56-464-14192 ; Geestkracht program 10-000-1002 ; Center for Medical Systems Biology (NWO Genomics) ; Biobanking and Biomolecular Resources Research Infrastructure ; Vrije Universiteit's Institutes for Health and Care Research and Neuroscience Campus Amsterdam ; BIC/BioAssist/RK 2008.024 ; European Science Foundation (ESF) EU/QLRT-200101254 ; European Union (EU) FP7/2007-2013 ; ENGAGE HEALTH-F4-2007-201413 ; European Science Council ERC 230374 ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA ; GAIN ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) MH081802 MH072802 N01MH90003 ; National Health and Medical Research Council of Australia 241944 339462 389927 389875 389891 389892 389938 442915 442981 496675 496739 552485 552498 613602 613608 613674 619667 ; Australian Research Council FT0991360 FT0991022 ; FP-5 GenomEUtwin Project QLG2-CT-2002-01254 ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA AA07535 AA10248 AA13320 AA13321 AA13326 AA14041 MH66206 DA12854 DA019951 U01 DK066134 ; Center for Inherited Disease Research (Baltimore, MD) ; UK Medical Research Council and GlaxoSmithKline G0701420 ; National Institute for Health Research (NIHR) ; Maudsley National Health Service Foundation Trust ; Institute of Psychiatry, King's College London ; Medical Research Council UK (MRC) G0000647 ; European Union (EU) 286213 ; European Commission Framework 6 grant (EC) LSHB-CT2003- 503428 ; GlaxoSmithKline ; Faculty of Biology and Medicine of Lausanne ; Swiss National Science Foundation (SNSF) 3200B0-105993 3200B0-118308 33CSCO-122661 33CS30-139468 33CS30-148401 ; GlaxoSmithKline Clinical Genetics ; Federal Ministry of Education & Research (BMBF) 01ZZ9603 01ZZ0103 01ZZ0403 03ZIK012 ; Ministry of Cultural Affairs ; Social Ministry of the Federal State of Mecklenburg-West Pomerania ; Siemens Healthcare, Erlangen, Germany ; German Research Foundation (DFG) GR 1912/5-1 FOR 2107 DA1151/5-1 ; Swedish Ministry for Higher Education ; Swedish Research Council M-2005-1112 ; GenomEUtwin QLG2-CT-2002-01254 EU/QLRT2001-01254 ; Swedish Foundation for Strategic Research ; Danske Strategiske Forskningsrad (DSF) ; Stanley Research Foundation ; European Union (EU) N Health-F2-2008-222963 ; Innovative Medizinische Forschung of the Medical Faculty of Munster DA120903 DA111107 DA211012 ; Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" 104036/Z/14/Z ; Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 ; Scottish Funding Council HR03006 ; Broad Institute Center for Genotyping and Analysis U54 RR020278 ; NARSAD ; Biotechnology and Biological Sciences Research Council (BBSRC) ; Medical Research Council UK (MRC) ; Federal Ministry of Education & Research (BMBF) ; Interdisciplinary Center for Clinical Research Munster ; National Health and Medical Research Council of Australia ; MRC-BBSRC, Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative MR/K026992/1 ; German Research Foundation (DFG) ; Federal Ministry of Education ; Research Germany and speakers honoraria from Eli Lilly and Servier ; Medical Research Council UK (MRC) ; Biotechnology and Biological Sciences Research Council (BBSRC) ; NRS Career Fellowship - Chief Scientist Office ; Scottish Funding Council Senior Clinical Fellowship ; Dame Theresa and Mortimer Sackler Foundation ; Netherlands Organization for Scientific Research (NWO) NOW VENI 916-76-125 ; Lundbeckfonden R155-2014-1724 ; Medical Research Council UK (MRC) MR/K026992/1 MC_PC_U127561128 1292844 ; Chief Scientist Office CZD/16/6/4
Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.
Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.
PUBLISHED ; Export Date: 13 January 2017 ; Background Bovine tuberculosis (bTB) infection in cattle is a significant economic concern in many countries, with annual costs to the UK and Irish governments of approximately ?190 million and ?63 million, respectively, for bTB control. The existence of host additive and non-additive genetic components to bTB susceptibility has been established. Methods Two approaches i.e. single-SNP (single nucleotide polymorphism) regression and a Bayesian method were applied to genome-wide association studies (GWAS) using high-density SNP genotypes (n = 597,144 SNPs) from 841 dairy artificial insemination (AI) sires. Deregressed estimated breeding values for bTB susceptibility were used as the quantitative dependent variable. Network analysis was performed using the quantitative trait loci (QTL) that were identified as significant in the single-SNP regression and Bayesian analyses separately. In addition, an identity-by-descent analysis was performed on a subset of the most prolific sires in the dataset that showed contrasting prevalences of bTB infection in daughters. Results A significant QTL region was identified on BTA23 (P value >1 ? 10?5, Bayes factor >10) across all analyses. Sires with the minor allele (minor allele frequency = 0.136) for this QTL on BTA23 had estimated breeding values that conferred a greater susceptibility to bTB infection than those that were homozygous for the major allele. Imputation of the regions that flank this QTL on BTA23 to full sequence indicated that the most significant associations were located within introns of the FKBP5 gene. Conclusions A genomic region on BTA23 that is strongly associated with host susceptibility to bTB infection was identified. This region contained FKBP5, a gene involved in the TNF?/NF?-B signalling pathway, which is a major biological pathway associated with immune response. Although there is no study that validates this region in the literature, our approach represents one of the most powerful studies for the analysis of bTB susceptibility to date. ; This work was supported by Science Foundation Ireland Principal Investigator award grant number 09/IN.1/B2642, and the Irish Research Stimulus Fund 11/S/112. The authors would also like to acknowledge Dr. Karin Meyer for altering the Wombat software for our analysis. We gratefully acknowledge the 1000 Bull Genomes Consortium for providing accessibility to whole-genome sequence data which was used in this study.
We are grateful to the families and individuals who took part in the GS:SFHS and UKB studies, and to all those involved in participant recruitment, data collection, sample processing and QC, including academic researchers, clinical staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. This work is supported by the Wellcome Trust through a Strategic Award, reference 104036/Z/ 14/Z. We acknowledge with gratitude the financial support received from the Dr Mortimer and Theresa Sackler Foundation. This research has been conducted using the GS:SFHS and UK Biobank (project #4844) resources. GS:SFHS received core funding from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. UKB was established using funding from the Wellcome Trust, Medical Research Council, the Scottish Government Department of Health, and the Northwest Regional Development Agency. DJP, IJD, TCR and AMM are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). TCR is supported by Alzheimer's Scotland, through the Marjorie MacBeath bequest. Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council is gratefully acknowledged. We are grateful for the use of summary data from the International Genomics of Alzheimer's Project and the Major Depressive Disorder working group of the Psychiatric Genomics Consortium. ; Peer reviewed ; Publisher PDF
Abstract Background Bovine tuberculosis (bTB) infection in cattle is a significant economic concern in many countries, with annual costs to the UK and Irish governments of approximately €190 million and €63 million, respectively, for bTB control. The existence of host additive and non-additive genetic components to bTB susceptibility has been established. Methods Two approaches i.e. single-SNP (single nucleotide polymorphism) regression and a Bayesian method were applied to genome-wide association studies (GWAS) using high-density SNP genotypes (n = 597,144 SNPs) from 841 dairy artificial insemination (AI) sires. Deregressed estimated breeding values for bTB susceptibility were used as the quantitative dependent variable. Network analysis was performed using the quantitative trait loci (QTL) that were identified as significant in the single-SNP regression and Bayesian analyses separately. In addition, an identity-by-descent analysis was performed on a subset of the most prolific sires in the dataset that showed contrasting prevalences of bTB infection in daughters. Results A significant QTL region was identified on BTA23 (P value >1 × 10 −5 , Bayes factor >10) across all analyses. Sires with the minor allele (minor allele frequency = 0.136) for this QTL on BTA23 had estimated breeding values that conferred a greater susceptibility to bTB infection than those that were homozygous for the major allele. Imputation of the regions that flank this QTL on BTA23 to full sequence indicated that the most significant associations were located within introns of the FKBP5 gene. Conclusions A genomic region on BTA23 that is strongly associated with host susceptibility to bTB infection was identified. This region contained FKBP5 , a gene involved in the TNFα / NFκ-B signalling pathway, which is a major biological pathway associated with immune response. Although there is no study that validates this region in the literature, our approach represents one of the most powerful studies for the analysis of bTB susceptibility to date.