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13. Germline selection shapes human mitochondrial DNA diversity

Author

Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

Published
2019
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14. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children

Author

French, CE, Delon, I, Dolling, H, Sanchis-Juan, A, Shamardina, O, Mégy, K, Abbs, S, Austin, T, Bowdin, S, Branco, RG, Firth, H, Tuna, S, Aitman, TJ, Ashford, S, Astle, WJ, Bennet, DL, Bleda, M, Carss, KJ, Chinnery, PF, Deevi, SVV, Fletcher, D, Gale, DP, Gräf, SF, Hu, F, James, R, Kasanicki, MA, Kingston, N, Koziell, AB, Allen, HL, Maher, ER, Markus, HS, Meacham, S, Morrell, NW, Penkett, CJ, Roberts, I, Smith, KGC, Stark, H, Stirrups, KE, Turro, E, Watkins, H, Williamson, C, Young, T, Bradley, JR, Ouwehand, WH, Raymond, FL, Agrawal, S, Armstrong, R, Beardsall, K, Belteki, G, Bohatschek, M, Broster, S, Campbell, R, Chaudhary, R, Costa, C, D’Amore, A, Fitzsimmons, A, Hague, J, Harley, J, Hoodbhoy, S, Kayani, R, Kelsall, W, Mehta, SG, O’Donnell, R, O’Hare, S, Ogilvy-Stuart, A, Papakostas, S, Park, SM, Parker, A, Pathan, N, Prapa, M, Sammut, A, Sandford, R, Schon, K, Singh, Y, Spike, K, Tavares, ALT, Wari-Pepple, D, Wong, HS, Woods, CG, Rowitch, DH, Raymond, F Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository

Subjects
Male, NICU, medicine.medical_specialty, Palliative care, Adolescent, PICU, Original, Critical Illness, Critically ill children, Genomics, Critical Care and Intensive Care Medicine, Intensive Care Units, Pediatric, State Medicine, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Anesthesiology, Intensive care, Intensive Care Units, Neonatal, Genetics, Medicine, Humans, Prospective Studies, Medical diagnosis, Intensive care medicine, Prospective cohort study, Child, Whole genome sequencing, Whole Genome Sequencing, business.industry, Genetic Diseases, Inborn, Infant, Newborn, Infant, 030208 emergency & critical care medicine, 030228 respiratory system, England, FOS: Biological sciences, Child, Preschool, Female, business, Genetic Background, Cohort study
Abstract

Purpose With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations. Methods We performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2–3 weeks of recruitment. Results A total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2–3 week turnaround was sufficient to impact most clinical decision-making. Conclusions The use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children. Electronic supplementary material The online version of this article (10.1007/s00134-019-05552-x) contains supplementary material, which is available to authorized users.

Published
2019

16. Assessing the effectiveness of upper-limb spasticity management using a structured approach to goal-setting and outcome measurement: First cycle results from the ULIS-III Study

Author

Turner-Stokes, L., Jacinto, J., Fheodoroff, K., Brashear, A., Maisonobe, P., Lysandropoulos, A., Ashford, S., Baguley, I., Aggarwal, A., Olver, J., Estell, J., Faux, S., Luk, E., Kotschet, K., Hughes, A., Nunan, R., Haslinger, B., Baum, P., Mobius, C., Fietzek, U., Chi Wang, Ip., Chung, T. M., Chueire, R. H., Moro, C. H. C., Schnitzler, A., Delleci, C., Ferrapie, A. -L., Isner-Horobeti, M. -E., Perennou, D., Leung, C. M., Cosma, M., Caltagirone, C., Diverio, M., Girlanda, P., Ianeri, G., Millevolte, M., Molteni, F., Franco, J. H., Hernandez, J. F. G., Aguilar, S. Q., de la Lanza Andrade, L. P., Rosales, R., Flordelis, J., Koziorowski, D., Potulska, A., Rudzinska, M., Afonso, E., Duarte, A. R., Khatkova, S., Korenko, A., Khasanova, D., Okhabov, D., Arefyeva, E., Karpov, D., Korolev, A., Lee, Y. -C., Tsai, S. -W., Tate, J., Davis, T. L., Marciniak, C., and Patel, A.

Subjects
Male, Longitudinal study, medicine.medical_specialty, Botulinum Toxins, Psychological intervention, Physical Therapy, Sports Therapy and Rehabilitation, RM1-950, Type A, Goal Attainment Scaling, Upper Extremity, Physical medicine and rehabilitation, medicine, Humans, goal attainment scaling, physical therapy, Longitudinal Studies, Spasticity, Botulinum Toxins, Type A, Goal setting, stroke rehabilitation, botulinum toxin-a, business.industry, Rehabilitation, General Medicine, Middle Aged, Botulinum toxin-A, Goal attainment scaling, Physical therapy, Post-stroke spasticity, Stroke rehabilitation, Female, Muscle Spasticity, Stroke, Stroke Rehabilitation, Treatment Outcome, Confidence interval, post-stroke spasticity, medicine.anatomical_structure, Concomitant, Upper limb, Therapeutics. Pharmacology, medicine.symptom, business
Abstract

Objective: To describe the utility of a structured approach to assessing effectiveness following injection with botulinum toxin-A alongside physical therapies, within the first cycle of the Upper Limb International Spasticity-III (ULIS-III) study. Methods: ULIS-III (registered at clinicaltrials.gov as NCT02454803) is a large international, observation-al, longitudinal study of adults treated for upper-limb spasticity. It introduces novel methods for the structured evaluation of person-centred goal attainment alongside targeted standardized outcome measures: the Upper limb Spasticity Index, and the Upper Limb Spasticity Therapy Recording Schedule. Results: A total of 953/1,004 enrolled patients (95%) completed cycle 1. Mean overall goal attainment scaling (GAS) T scores were 49.8 (95% confidence interval 49.2–50.3; 67.1% of patients met their primary goal, with highest achievement rates for goals related to involuntary movement, (75.6%) and range of movement (74.4%). Standardized measures of spasticity, pain, involuntary movements, active and passive function, all improved significantly over the treatment cycle. Overall, 59.7% of patients saw a therapist following botulinum toxin-A injection. Interventions varied, as expected, with the set treatment goals. After controlling for concomitant therapies using the upper limb spasticity therapy recording schedule, significant differences in injection intervals (p

Published
2021

17. Comprehensive cancer-predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

Author

Whitworth, J, Smith, PS, Martin, J-E, West, H, Luchetti, A, Rodger, F, Clark, G, Carss, K, Stephens, J, Stirrups, K, Penkett, C, Mapeta, R, Ashford, S, Megy, K, Shakeel, H, Ahmed, M, Adlard, J, Barwell, J, Brewer, C, Casey, RT, Armstrong, R, Cole, T, Evans, DG, Fostira, F, Greenhalgh, L, Hanson, H, Henderson, A, Hoffman, J, Izatt, L, Kumar, A, Kwong, A, Lalloo, F, Ong, KR, Paterson, J, Park, S-M, Chen-Shtoyerman, R, Searle, C, Side, L, Skytte, A-B, Snape, K, Woodward, ER, Tischkowitz, MD, Maher, ER, Aitman, T, Alachkar, H, Ali, S, Allen, L, Allsup, D, Ambegaonkar, G, Anderson, J, Antrobus, R, Arno, G, Arumugakani, G, Astle, W, Attwood, A, Austin, S, Bacchelli, C, Bakchoul, T, Bariana, TK, Baxendale, H, Bennett, D, Bethune, C, Bibi, S, Bitner-Glindzicz, M, Bleda, M, Boggard, H, Bolton-Maggs, P, Booth, C, Bradley, JR, Brady, A, Brown, M, Browning, M, Bryson, C, Burns, S, Calleja, P, Canham, N, Carmichael, J, Caulfield, M, Chalmers, E, Chandra, A, Chinnery, P, Chitre, M, Church, C, Clement, E, Clements-Brod, N, Clowes, V, Coghlan, G, Collins, P, Cookson, V, Cooper, N, Corris, P, Creaser-Myers, A, Dacosta, R, Daugherty, L, Davies, S, Davis, J, De Vries, M, Deegan, P, Deevi, SVV, Deshpande, C, Devlin, L, Dewhurst, E, Dixon, P, Doffinger, R, Dormand, N, Drewe, E, Edgar, D, Egner, W, Erber, WN, Erwood, M, Everington, T, Favier, R, Firth, H, Fletcher, D, Flinter, F, Frary, A, Freson, K, Furie, B, Furnell, A, Gale, D, Gardham, A, Gattens, M, Ghali, N, Ghataorhe, PK, Ghurye, R, Gibbs, S, Gilmour, K, Gissen, P, Goddard, S, Gomez, K, Gordins, P, Graf, S, Gräf, S, Greene, D, Greenhalgh, A, Greinacher, A, Grigoriadou, S, Grozeva, D, Hackett, S, Hadinnapola, C, Hague, R, Haimel, M, Halmagyi, C, Hammerton, T, Hart, D, Hayman, G, Heemskerk, JWM, Henderson, R, Hensiek, A, Henskens, Y, Herwadkar, A, Holden, S, Holder, M, Holder, S, Hu, F, Veld, A, Huissoon, A, Humbert, M, Hurst, J, James, R, Jolles, S, Josifova, D, Kazmi, R, Keeling, D, Kelleher, P, Kelly, AM, Kennedy, F, Kiely, D, Kingston, N, Koziell, A, Krishnakumar, D, Kuijpers, TW, Kuijpers, T, Kumararatne, D, Kurian, M, Laffan, MA, Lambert, MP, Allen, HL, Lango-Allen, H, Lawrie, A, Lear, S, Lees, M, Lentaigne, C, Liesner, R, Linger, R, Longhurst, H, Lorenzo, L, Louka, E, Machado, R, Ross, RM, Maclaren, R, Maher, E, Maimaris, J, Mangles, S, Manson, A, Markus, HS, Martin, J, Masati, L, Mathias, M, Matser, V, Maw, A, McDermott, E, McJannet, C, Meacham, S, Meehan, S, Mehta, S, Michaelides, M, Millar, CM, Moledina, S, Moore, A, Morrell, N, Mumford, A, Murng, S, Murphy, E, Nejentsev, S, Noorani, S, Nurden, P, Oksenhendler, E, Othman, S, Ouwehand, WH, Papadia, S, Parker, A, Pasi, J, Patch, C, Payne, J, Peacock, A, Peerlinck, K, Penkett, CJ, Pepke-Zaba, J, Perry, D, Perry, DJ, Pollock, V, Polwarth, G, Ponsford, M, Qasim, W, Quinti, I, Rankin, S, Rankin, J, Raymond, FL, Rayner-Matthews, P, Rehnstrom, K, Reid, E, Rhodes, CJ, Richards, M, Richardson, S, Richter, A, Roberts, I, Rondina, M, Rosser, E, Roughley, C, Roy, N, Rue-Albrecht, K, Samarghitean, C, Sanchis-Juan, A, Sandford, R, Santra, S, Sargur, R, Savic, S, Schotte, G, Schulman, S, Schulze, H, Scott, R, Scully, M, Seneviratne, S, Sewell, C, Shamardina, O, Shipley, D, Simeoni, I, Sivapalaratnam, S, Smith, KGC, Sohal, A, Southgate, L, Staines, S, Staples, E, Stark, H, Stauss, H, Stein, P, Stock, S, Suntharalingam, J, Talks, K, Tan, Y, Thachil, J, Thaventhiran, J, Thomas, E, Thomas, M, Thompson, D, Thrasher, A, Tischkowitz, M, Titterton, C, Toh, C-H, Toshner, M, Treacy, C, Trembath, R, Tuna, S, Turek, W, Turro, E, Van Geet, C, Veltman, M, Vogt, J, Von Ziegenweldt, J, Noordegraaf, AV, Wakeling, E, Wanjiku, I, Warner, TQ, Wassmer, E, Watkins, H, Watt, C, Webster, N, Welch, S, Westbury, S, Wharton, J, Whitehorn, D, Wilkins, M, Willcocks, L, Williamson, C, Woods, G, Wort, J, Yeatman, N, Yong, P, Young, T, and Yu, P

Abstract

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Published
2018

18. Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data

Author

Farmery, JHR, Smith, ML, Lynch, AG, Huissoon, A, Furnell, A, Mead, A, Levine, AP, Manzur, A, Thrasher, A, Greenhalgh, A, Parker, A, Sanchis-Juan, A, Richter, A, Gardham, A, Lawrie, A, Sohal, A, Creaser-Myers, A, Frary, A, Greinacher, A, Themistocleous, A, Peacock, AJ, Marshall, A, Mumford, A, Rice, A, Webster, A, Brady, A, Koziell, A, Manson, A, Chandra, A, Hensiek, A, In't Veld, AH, Maw, A, Kelly, AM, Moore, A, Noordegraaf, AV, Attwood, A, Herwadkar, A, Ghofrani, A, Houweling, AC, Girerd, B, Furie, B, Treacy, CM, Millar, CM, Sewell, C, Roughley, C, Titterton, C, Williamson, C, Hadinnapola, C, Deshpande, C, Toh, C-H, Bacchelli, C, Patch, C, Van Geet, C, Babbs, C, Bryson, C, Penkett, CJ, Rhodes, CJ, Watt, C, Bethune, C, Booth, C, Lentaigne, C, McJannet, C, Church, C, French, C, Samarghitean, C, Halmagyi, C, Gale, D, Greene, D, Hart, D, Allsup, D, Bennett, D, Edgar, D, Kiely, DG, Gosal, D, Perry, DJ, Keeling, D, Montani, D, Shipley, D, Whitehorn, D, Fletcher, D, Krishnakumar, D, Grozeva, D, Kumararatne, D, Thompson, D, Josifova, D, Maher, E, Wong, EKS, Murphy, E, Dewhurst, E, Louka, E, Rosser, E, Chalmers, E, Colby, E, Drewe, E, McDermott, E, Thomas, E, Staples, E, Clement, E, Matthews, E, Wakeling, E, Oksenhendler, E, Turro, E, Reid, E, Wassmer, E, Raymond, FL, Hu, F, Kennedy, F, Soubrier, F, Flinter, F, Kovacs, G, Polwarth, G, Ambegaonkar, G, Arno, G, Hudson, G, Woods, G, Coghlan, G, Hayman, G, Arumugakani, G, Schotte, G, Cook, HT, Alachkar, H, Allen, HL, Lango-Allen, H, Stark, H, Stauss, H, Schulze, H, Boggard, HJ, Baxendale, H, Dolling, H, Firth, H, Gall, H, Watson, H, Longhurst, H, Markus, HS, Watkins, H, Simeoni, I, Emmerson, I, Roberts, I, Quinti, I, Wanjiku, I, Gibbs, JSR, Thaventhiran, J, Whitworth, J, Hurst, J, Collins, J, Suntharalingam, J, Payne, J, Thachil, J, Martin, JM, Martin, J, Carmichael, J, Maimaris, J, Paterson, J, Pepke-Zaba, J, Heemskerk, JWM, Gebhart, J, Davis, J, Pasi, J, Bradley, JR, Wharton, J, Stephens, J, Rankin, J, Anderson, J, Vogt, J, Von Ziegenweldt, J, Rehnstrom, K, Megy, K, Talks, K, Peerlinck, K, Yates, K, Freson, K, Stirrups, K, Gomez, K, Smith, KGC, Carss, K, Rue-Albrecht, K, Gilmour, K, Masati, L, Scelsi, L, Southgate, L, Ranganathan, L, Ginsberg, L, Devlin, L, Willcocks, L, Ormondroyd, L, Lorenzo, L, Harper, L, Allen, L, Daugherty, L, Chitre, M, Kurian, M, Humbert, M, Tischkowitz, M, Bitner-Glindzicz, M, Erwood, M, Scully, M, Veltman, M, Caulfield, M, Layton, M, McCarthy, M, Ponsford, M, Toshner, M, Bleda, M, Wilkins, M, Mathias, M, Reilly, M, Afzal, M, Brown, M, Rondina, M, Stubbs, M, Haimel, M, Lees, M, Laffan, MA, Browning, M, Gattens, M, Richards, M, Michaelides, M, Lambert, MP, Makris, M, De Vries, M, Mahdi-Rogers, M, Saleem, M, Thomas, M, Holder, M, Eyries, M, Clements-Brod, N, Canham, N, Dormand, N, Van Zuydam, N, Kingston, N, Ghali, N, Cooper, N, Morrell, NW, Yeatman, N, Roy, N, Shamardina, O, Alavijeh, OS, Gresele, P, Nurden, P, Chinnery, P, Deegan, P, Yong, P, Yu-Wai-Man, P, Corris, PA, Calleja, P, Gissen, P, Bolton-Maggs, P, Rayner-Matthews, P, Ghataorhe, PK, Gordins, P, Stein, P, Collins, P, Dixon, P, Kelleher, P, Ancliff, P, Yu, P, Tait, RC, Linger, R, Doffinger, R, Machado, R, Kazmi, R, Sargur, R, Favier, R, Tan, R, Liesner, R, Antrobus, R, Sandford, R, Scott, R, Trembath, R, Horvath, R, Hadden, R, MackenzieRoss, RV, Henderson, R, MacLaren, R, James, R, Ghurye, R, DaCosta, R, Hague, R, Mapeta, R, Armstrong, R, Noorani, S, Murng, S, Santra, S, Tuna, S, Johnson, S, Chong, S, Lear, S, Walker, S, Goddard, S, Mangles, S, Westbury, S, Mehta, S, Hackett, S, Nejentsev, S, Moledina, S, Bibi, S, Meehan, S, Othman, S, Revel-Vilk, S, Holden, S, McGowan, S, Staines, S, Savic, S, Burns, S, Grigoriadou, S, Papadia, S, Ashford, S, Schulman, S, Ali, S, Park, S-M, Davies, S, Stock, S, Deevi, SVV, Graf, S, Ghio, S, Wort, SJ, Jolles, S, Austin, S, Welch, S, Meacham, S, Rankin, S, Seneviratne, S, Holder, S, Sivapalaratnam, S, Richardson, S, Kuijpers, T, Kuijpers, TW, Bariana, TK, Bakchoul, T, Everington, T, Renton, T, Young, T, Aitman, T, Warner, TQ, Vale, T, Hammerton, T, Pollock, V, Matser, V, Cookson, V, Clowes, V, Qasim, W, Wei, W, Erber, WN, Ouwehand, WH, Astle, W, Egner, W, Turek, W, Henskens, Y, Tan, Y, Lynch, Andy G [0000-0002-7876-7338], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and British Heart Foundation

Subjects
Whole genome sequencing, 0303 health sciences, Multidisciplinary, Science & Technology, lcsh:R, lcsh:Medicine, Computational biology, Biology, Telomere, Multidisciplinary Sciences, 03 medical and health sciences, 0302 clinical medicine, NIHR BioResource - Rare Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, lcsh:Q, Ploidy, lcsh:Science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-14403-y, published online 22 January 2018 The original version of this Article contained a typographical error in the spelling of the consortium member Patrick Yu-Wai-Man which was incorrectly given as Patrick Yu Wai Man. In addition, a supplementary file containing additional algorithms and analysis was omitted from the original version of this Article. These errors have now been corrected in the HTML and PDF versions of the Article.

Published
2018

21. Observations of the 3-D distribution of interplanetary electrons and ions from solar wind plasma to low energy cosmic rays

Author

Lin, R. P, Anderson, K. A, Ashford, S, Carlson, C, Curtis, D, Ergun, R, Larson, D, McFadden, J, McCarthy, M, and Parks, G. K

Subjects
Solar Physics
Abstract

The 3-D Plasma and Energetic Particle instrument on the GGS Wind spacecraft (launched November 1, 1994) is designed to make measurements of the full three-dimensional distribution of suprathermal electrons and ions from solar wind plasma to low energy cosmic rays, with high sensitivity, wide dynamic range, good energy and angular resolution, and high time resolution. Three pairs of double-ended telescopes, each with two or three closely sandwiched passivated ion implanted silicon detectors measure electrons and ions from approximately 20 keV to greater than or equal to 300 keV. Four top-hat symmetrical spherical section electrostatic analyzers with microchannel plate detectors, a large and a small geometric factor analyzer for electrons and a similar pair for ions, cover from approximately 3 eV to 30 keV. We present preliminary observations of the electron and ion distributions in the absence of obvious solar impulsive events and upstream particles. The quiet time electron energy spectrum shows a smooth approximately power law fall-off extending from the halo population at a few hundred eV to well above approximately 100 keV The quiet time ion energy spectrum also shows significant fluxes over this energy range. Detailed 3-D distributions and their temporal variations will be presented.

Published
1995

22. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

Hendricks, AE, Bochukova, EG, Marenne, G, Keogh, JM, Atanassova, N, Bounds, R, Wheeler, E, Mistry, V, Henning, E, Körner, A, Muddyman, D, McCarthy, S, Hinney, A, Hebebrand, J, Scott, RA, Langenberg, C, Wareham, NJ, Surendran, P, Howson, JM, Butterworth, AS, Danesh, J, Nordestgaard, BG, Nielsen, SF, Afzal, S, Papadia, S, Ashford, S, Garg, S, Millhauser, GL, Palomino, RI, Kwasniewska, A, Tachmazidou, I, O'Rahilly, S, Zeggini, E, Barroso, I, Farooqi, IS, Benzeval, M, Burton, J, Buck, N, Jäckle, A, Kumari, M, Laurie, H, Lynn, P, Pudney, S, Rabe, B, Wolke, D, Overvad, K, Tjønneland, A, Clavel-Chapelon, F, Kaaks, R, Boeing, H, Trichopoulou, A, Ferrari, P, Palli, D, Krogha, V, Panico, S, Tuminoa, R, Matullo, G, Boer, J, Van Der Schouw, Y, Weiderpass, E, Quiros, JR, Sánchez, MJ, Navarro, C, Moreno-Iribas, C, Arriola, L, Melander, O, Wennberg, P, Key, TJ, Riboli, E, Turki, SA, Anderson, CA, Anney, R, Antony, D, Soler Artigas, M, Ayub, M, Bala, S, Barrett, JC, Beales, P, Bentham, J, Bhattacharyaa, S, Birney, E, Blackwooda, D, Bobrow, M, Bolton, PF, Boustred, C, Breen, G, Calissanoa, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampia, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Coccaa, M, Collier, DA, Cosgrove, C, Coxa, T, and Crooks, Lucy

Abstract

© 2017 The Author(s). Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Published
2017

23. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

Hendricks, A., Bochukova, E., Marenne, G., Keogh, ., Atanassova, N., Bounds, R., Wheeler, E., Mistry, V., Henning, E., Körner, A., Muddyman, D., McCarthy, S., Hinney, A., Hebebrand, J., Scott, R., Langenberg, C., Wareham, N., Surendran, P., Howson, J., Butterworth, A., Danesh, J., Børge G , N., Nielse, S., Afzal, S., Papadia, S., Ashford, S., Garg, S., Palomino, R., Kwasniewska, A., Tachmazidou, I., O’Rahilly, S., Zeggini, E., Barroso, I., and Farooqi, I.

Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10−3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Published
2017

24. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

Hendricks, A.E. Bochukova, E.G. Marenne, G. Keogh, J.M. Atanassova, N. Bounds, R. Wheeler, E. Mistry, V. Henning, E. Körner, A. Muddyman, D. McCarthy, S. Hinney, A. Hebebrand, J. Scott, R.A. Langenberg, C. Wareham, N.J. Surendran, P. Howson, J.M. Butterworth, A.S. Danesh, J. Nordestgaard, Bø.G. Nielsen, S.F. Afzal, S. Papadia, S. Ashford, S. Garg, S. Millhauser, G.L. Palomino, R.I. Kwasniewska, A. Tachmazidou, I. O'Rahilly, S. Zeggini, E. Barroso, I. Farooqi, I.S. Benzeval, M. Burton, J. Buck, N. Jäckle, A. Kumari, M. Laurie, H. Lynn, P. Pudney, S. Rabe, B. Wolke, D. Overvad, K. Tjønneland, A. Clavel-Chapelon, F. Kaaks, R. Boeing, H. Trichopoulou, A. Ferrari, P. Palli, D. Krogha, V. Panico, S. Tuminoa, R. Matullo, G. Boer, J. Van Der Schouw, Y. Weiderpass, E. Quiros, J.R. Sánchez, M.-J. Navarro, C. Moreno-Iribas, C. Arriola, L. Melander, O. Wennberg, P. Key, T.J. Riboli, E. Turki, S.A. Anderson, C.A. Anney, R. Antony, D. Soler Artigas, M. Ayub, M. Bala, S. Barrett, J.C. Beales, P. Bentham, J. Bhattacharyaa, S. Birney, E. Blackwooda, D. Bobrow, M. Bolton, P.F. Boustred, C. Breen, G. Calissanoa, M. Carss, K. Charlton, R. Chatterjee, K. Chen, L. Ciampia, A. Cirak, S. Clapham, P. Clement, G. Coates, G. Coccaa, M. Collier, D.A. Cosgrove, C. Coxa, T. Craddock, N. Crooks, L. Curran, S. Curtis, D. Daly, A. Danecek, P. Day, I.N.M. Day-Williams, A. Dominiczak, A. Down, T. Du, Y. Dunham, I. Durbin, R. Edkins, S. Ekong, R. Ellis, P. Evansa, D.M. Fitzpatrick, D.R. Flicek, P. Floyd, J. Foley, A.R. Franklin, C.S. Futema, M. Gallagher, L. Gaunt, T.R. Geihs, M. Geschwind, D. Greenwood, C.M.T. Griffin, H. Grozeva, D. Guo, X. Guo, X. Gurling, H. Hart, D. Holmans, P. Howie, B. Huang, J. Huang, L. Hubbard, T. Humphries, S.E. Hurles, M.E. Hysi, P. Iotchkova, V. Jackson, D.K. Jamshidi, Y. Joyce, C. Karczewski, K.J. Kaye, J. Keane, T. Kemp, J.P. Kennedy, K. Kent, A. Khawaja, F. Van Kogelenberg, M. Kolb-Kokocinski, A. Lachance, G. Langford, C. Lawson, D. Lee, I. Lek, M. Li, R. Li, Y. Liang, J. Lin, H. Liu, R. Lönnqvist, J. Lopes, L.R. Lopes, M. MacArthur, D.G. Mangino, M. Marchini, J. Maslen, J. Mathieson, I. McGuffin, P. McIntosh, A.M. McKechanie, A.G. McQuillin, A. Memari, Y. Metrustry, S. Migone, N. Min, J.L. Mitchison, H.M. Moayyeri, A. Morris, A. Morris, J. Muntoni, F. Northstone, K. O'Donovan, M.C. Onoufriadis, A. Oualkacha, K. Owen, M.J. Palotie, A. Panoutsopoulou, K. Parker, V. Parr, J.R. Paternoster, L. Paunio, T. Payne, F. Payne, S.J. Perry, J.R.B. Pietilainen, O. Plagnol, V. Pollitt, R.C. Porteous, D.J. Povey, S. Quail, M.A. Quaye, L. Raymond, F.L. Rehnström, K. Richards, J.B. Ridout, C.K. Ring, S. Ritchie, G.R.S. Roberts, N. Robinson, R.L. Savage, D.B. Scambler, P. Schiffels, S. Schmidts, M. Schoenmakers, N. Scott, R.H. Semple, R.K. Serra, E. Sharp, S.I. Shaw, A. Shihab, H.A. Shin, S.-Y. Skuse, D. Small, K.S. Smee, C. Smith, B.H. Davey Smith, G. Soranzo, N. Southam, L. Spasic-Boskovic, O. Spector, T.D. St Clair, D. St Pourcain, B. Stalker, J. Stevens, E. Sun, J. Surdulescu, G. Suvisaari, J. Syrris, P. Taylor, R. Tian, J. Timpson, N.J. Tobin, M.D. Valdes, A.M. Vandersteen, A.M. Vijayarangakannan, P. Visscher, P.M. Wain, L.V. Walter, K. Walters, J.T.R. Wang, G. Wang, J. Wang, Y. Ward, K. Whyte, T. Williams, H.J. Williamson, K.A. Wilson, C. Wilson, S.G. Wong, K. Xu, C. Yang, J. Zhang, F. Zhang, P. Zheng, H.-F.

Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies. © 2017 The Author(s).

Published
2017

25. The future of planted forests.

Author

CARLE, J. B., DUVAL, A., and ASHFORD, S.

Subjects
FORESTS & forestry, FOREST products, GREEN technology, SPECIES diversity, ECOSYSTEM services, FOREST biodiversity, SUSTAINABILITY
Abstract

Copyright of International Forestry Review is the property of Commonwealth Forestry Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2020
Full Text
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26. Goal-setting and attainment in prolonged disorders of consciousness – development of a structured approach.

Author

Turner-Stokes, L., Rose, H., Lakra, C., Williams, H., Ashford, S. A., and Siegert, R. J.

Subjects
CONFIDENCE intervals, GOAL (Psychology), LONGITUDINAL method, MEDICAL protocols, MEDICAL practice, HEALTH outcome assessment, RETROSPECTIVE studies, REHABILITATION for brain injury patients
Abstract

Aims: To develop a structured goal-set for use in programs for the assessment and management of prolonged disorders of consciousness (PDOC). Methods: A retrospective analysis of goals from a consecutive cohort of patients (n = 162) admitted to a specialist in-patient PDOC program in the UK from 2007 to 2018. Overall goal attainment was examined with Goal Attainment Scaling (GAS) using the GAS-Light method. Rates of individual goal-setting and achievement were examined for both standardized objectives (n = 2959) and personalized goals (n = 661). Goal statements from the personalized goals were independently reviewed and mapped to the domains of the existing structured objective set to identify any missing goal areas. Results: Mean outcome GAS T-scores were 47.2 (95% CI: 46.7, 47.6) and 47.7 (95% CI: 46.7, 48.8), respectively, for the standardized and personally set goals. These were closely correlated (r = 0.482, p <.001) with no significant difference between them. Analysis of goal achievement within each domain identified goals that were/were not likely to be achieved. An initial structured set of 20 standardized objectives in 12 domains was expanded and re-organized to produce a final-structured goal-set of 36 objectives in 18 domains. Conclusions: Developed through real-life clinical practice, this first published structured goal-set for PDOC programs now requires testing in other services/settings. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

32. Common genetic variation drives molecular heterogeneity in human iPSCs

Author

Kilpinen, H, Goncalves, A, Leha, A, Afzal, V, Alasoo, K, Ashford, S, Bala, S, Bensaddek, D, Casale, FP, Ulley, OJC, Danecek, P, Faulconbridge, A, Harrison, PW, Kathuria, A, McCarthy, D, McCarthy, SA, Meleckyte, R, Memari, Y, Moens, N, Soares, F, Mann, A, Streeter, I, Agu, CA, Alderton, A, Nelson, R, Harper, S, Patel, M, White, A, Patel, SR, Clarke, L, Halai, R, Kirton, CM, Kolb-Kokocinski, A, Beales, P, Birney, E, Danovi, D, Lamond, AI, Ouwehand, WH, Vallier, L, Watt, FM, Durbin, R, Stegle, O, Gaffney, DJ, Kilpinen, H, Goncalves, A, Leha, A, Afzal, V, Alasoo, K, Ashford, S, Bala, S, Bensaddek, D, Casale, FP, Ulley, OJC, Danecek, P, Faulconbridge, A, Harrison, PW, Kathuria, A, McCarthy, D, McCarthy, SA, Meleckyte, R, Memari, Y, Moens, N, Soares, F, Mann, A, Streeter, I, Agu, CA, Alderton, A, Nelson, R, Harper, S, Patel, M, White, A, Patel, SR, Clarke, L, Halai, R, Kirton, CM, Kolb-Kokocinski, A, Beales, P, Birney, E, Danovi, D, Lamond, AI, Ouwehand, WH, Vallier, L, Watt, FM, Durbin, R, Stegle, O, and Gaffney, DJ

Abstract

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Published
2017

33. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation

Author

Pearce LR, Atanassova N, Banton MC, Bottomley B, van der Klaauw AA, Revelli JP, Hendricks A, Keogh JM, Henning E, Doree D, Jeter-Jones S, Garg S, Bochukova EG, Bounds R, Ashford S, Gayton E, Hindmarsh PC, Shield JP, Crowne E, Barford D, Wareham NJ, UK10K consortium, O'Rahilly S, Murphy MP, Powell DR, Barroso I, Farooqi IS, Pearce LR, Atanassova N, Banton MC, Bottomley B, van der Klaauw AA, Revelli JP, Hendricks A, Keogh JM, Henning E, Doree D, Jeter-Jones S, Garg S, Bochukova EG, Bounds R, Ashford S, Gayton E, Hindmarsh PC, Shield JP, Crowne E, Barford D, Wareham NJ, UK10K consortium, O'Rahilly S, Murphy MP, Powell DR, Barroso I, and Farooqi IS

Published
2013

34. Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

Author

Chen, L., Ge, B., Casale, F.P., Vasquez, L., Kwan, T., Garrido-Martin, D., Watt, S., Yan, Y., Kundu, K., Ecker, S., Datta, A., Richardson, D., Burden, F., Mead, D., Mann, A.L., Fernandez, J.M., Rowlston, S., Wilder, S.P., Farrow, S., Shao, X., Lambourne, J.J., Redensek, A., Albers, C.A., Amstislavskiy, V., Ashford, S., Berentsen, K., Bomba, L., Bourque, G., Bujold, D., Busche, S., Caron, M., Chen, S.H., Cheung, W., Delaneau, O., Dermitzakis, E.T., Elding, H., Colgiu, I., Bagger, F.O., Flicek, P., Habibi, E., Iotchkova, V., Janssen-Megens, E., Kim, B., Lehrach, H., Lowy, E., Mandoli, A., Matarese, F., Maurano, M.T., Morris, J.A., Pancaldi, V., Pourfarzad, F., Rehnstrom, K., Rendon, A., Risch, T., Sharifi, N., Simon, M.M., Sultan, M., Valencia, A., Walter, K., Wang, S.Y., Frontini, M., Antonarakis, S.E., Clarke, L., Yaspo, M.L., Beck, S., Guigo, R., Rico, D., Martens, J.H., Ouwehand, W.H., Kuijpers, T.W., Paul, D.S., Stunnenberg, H.G., Stegle, O., Downes, K., Pastinen, T., Soranzo, N., Chen, L., Ge, B., Casale, F.P., Vasquez, L., Kwan, T., Garrido-Martin, D., Watt, S., Yan, Y., Kundu, K., Ecker, S., Datta, A., Richardson, D., Burden, F., Mead, D., Mann, A.L., Fernandez, J.M., Rowlston, S., Wilder, S.P., Farrow, S., Shao, X., Lambourne, J.J., Redensek, A., Albers, C.A., Amstislavskiy, V., Ashford, S., Berentsen, K., Bomba, L., Bourque, G., Bujold, D., Busche, S., Caron, M., Chen, S.H., Cheung, W., Delaneau, O., Dermitzakis, E.T., Elding, H., Colgiu, I., Bagger, F.O., Flicek, P., Habibi, E., Iotchkova, V., Janssen-Megens, E., Kim, B., Lehrach, H., Lowy, E., Mandoli, A., Matarese, F., Maurano, M.T., Morris, J.A., Pancaldi, V., Pourfarzad, F., Rehnstrom, K., Rendon, A., Risch, T., Sharifi, N., Simon, M.M., Sultan, M., Valencia, A., Walter, K., Wang, S.Y., Frontini, M., Antonarakis, S.E., Clarke, L., Yaspo, M.L., Beck, S., Guigo, R., Rico, D., Martens, J.H., Ouwehand, W.H., Kuijpers, T.W., Paul, D.S., Stunnenberg, H.G., Stegle, O., Downes, K., Pastinen, T., and Soranzo, N.

Abstract

Contains fulltext : 167824.pdf (Publisher’s version ) (Open Access)

Published
2016

35. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Author

Wensley, F, Gao, P, Burgess, S, Kaptoge, S, Di Angelantonio, E, Shah, T, Engert, JC, Clarke, R, Davey-Smith, G, Nordestgaard, BG, Saleheen, D, Samani, NJ, Sandhu, M, Anand, S, Pepys, MB, Smeeth, L, Whittaker, J, Casas, JP, Thompson, SG, Hingorani, AD, Danesh, J, Eiriksdottir, G, Harris, TB, Launer, LJ, Gudnason, V, Folsom, AR, Andrews, G, Ballantyne, CM, Hall, AS, Braund, PS, Balmforth, AJ, Whincup, PH, Morris, R, Lawlor, DA, Lowe, GDO, Timpson, N, Ebrahim, S, Ben-Shlomo, Y, Tybjaerg-Hansen, A, Zacho, J, Brown, M, Ricketts, SL, Ashford, S, Lange, L, Reiner, A, Cushman, M, Tracy, R, Wu, C, Ge, J, Zou, Y, Sun, A, Hung, J, McQuillan, B, Thompson, P, Beilby, J, Warrington, N, Palmer, LJ, Wanner, C, Drechsler, C, Hoffmann, MM, Fowkes, FGR, Tzoulaki, I, Kumari, M, Miller, M, Marmot, M, Onland-Moret, C, van der Schouw, YT, Boer, JM, Wijmenga, C, Khaw, K-T, Vasan, RS, Schnabel, RB, Yamamoto, JF, Benjamin, EJ, Schunkert, H, Erdmann, J, Koenig, IR, Hengstenberg, C, Chiodini, B, Franzosi, MG, Pietri, S, Gori, F, Rudock, M, Liu, Y, Lohman, K, Humphries, SE, Hamsten, A, Norman, PE, Hankey, GJ, Jamrozik, K, Rimm, EB, Pai, JK, Psaty, BM, Heckbert, SR, Bis, JC, Yusuf, S, Xie, C, Collins, R, Bennett, D, Kooner, J, Chambers, J, Elliott, P, Maerz, W, Kleber, ME, Boehm, BO, Winkelmann, BR, Melander, O, Berglund, G, Koenig, W, Thorand, B, Baumert, J, Peters, A, Manson, J, Cooper, JA, Talmud, PJ, Ladenvall, P, Johansson, L, Jansson, J-H, Hallmans, G, Reilly, MP, Qu, L, Li, M, Rader, DJ, Watkins, H, Hopewell, J, Frossard, P, Sattar, N, Robertson, M, Shepherd, J, Schaefer, E, Hofman, A, Witteman, JCM, Kardys, I, Dehghan, A, de Faire, U, Bennet, A, Gigante, B, Leander, K, Peters, B, Maitland-van der Zee, AH, de Boer, A, Klungel, O, Greenland, P, Dai, J, Liu, S, Brunner, E, Kivimaki, M, O'Reilly, D, Ford, I, Packard, CJ, Dis, CRPCH, CIHDS, CC, CUPID, C, Medical Research Council (MRC), University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Pulmonology, and Coronel Institute of Occupational Health

Subjects
Male, Coronary Disease, Bioinformatics, Gene Frequency, MARKERS, Polymorphism (computer science), Risk Factors, Myocardial infarction, Prospective Studies, Prospective cohort study, General Environmental Science, Genetics, RISK, biology, General Engineering, Mendelian Randomization Analysis, General Medicine, Middle Aged, C-Reactive Protein, 1117 Public Health And Health Services, CARDIOVASCULAR-DISEASE, Meta-analysis, symbols, Female, Life Sciences & Biomedicine, Ischaemic Heart Disease, Polymorphism, Single Nucleotide, Molecular Genetics, symbols.namesake, Medicine, General & Internal, INFLAMMATION, Drugs: Cardiovascular System, General & Internal Medicine, medicine, INSTRUMENTAL VARIABLES, Humans, C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC), Allele frequency, METAANALYSIS, POLYMORPHISMS, Science & Technology, business.industry, Research, C-reactive protein, medicine.disease, GENE, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Mendelian inheritance, biology.protein, General Earth and Planetary Sciences, business
Abstract

Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P

Published
2011

37. Prospective study of insulin-like growth factor-I, insulin-like growth factor binding protein 3, genetic variants in the IGF-1 and IGFBP-3 genes and risk of coronary artery disease

Author

Ricketts, SL, Rensing, KL, Holly, JM, Chen, L, Young, EH, Luben, R, Ashford, S, Song, K, Yuan, X, Dehghan, Abbas, Wright, BJ, Waterworth, DM, Mooser, V, Waeber, G, Vollenweider, P, Epstein, SE, Burnett, MS, Devaney, JM, Hakonarson, HH, Rader, DJ, Reilly, MP, Danesh, J, Thompson, SG, Dunning, AM, Duijn, Cornelia, Samani, NJ, McPherson, P, Wareham, NJ, Khaw, K-T, Boekholdt, SM, Sandhu, MS, and Epidemiology

Published
2011

38. Geotechnical reconnaissance of the 2010 Darfield (Canterbury) earthquake

Author

Cubrinovski, M., Green, R.A., Allen, J., Ashford, S., Bradley, B., Bowman, E., Cox, B., Hutchinson, T., Kavazanjian, E., Orense, R., Pender, M., Quigley, M., and Wotherspoon, L.

Abstract

On 4 September 2010, a magnitude M\ud w\ud 7.1 earthquake struck the Canterbury region on the South Island\ud of New Zealand.\ud The epicentre of the earthquake was located in the Darfield area about 40 km west of\ud the city of Christchurch.\ud E\ud xtensive damage was inflicted to lifelines and residential houses due to\ud widespread liquefaction and lateral spreading in areas close to major s\ud treams, rivers and wetlands\ud throughout Christchurch and Kaiapoi.\ud U\ud nreinforced masonry buildings\ud also suffered extensive damage\ud throughout the region. Despite the severe damage to infrastructure and residential houses, fortunately, no\ud deaths occurred and on\ud ly two injuries were reported in this earthquake. From an engineering viewpoint,\ud one may argue that the most significant aspects of the 2010 Darfield Earthquake were\ud geotechnical in\ud nature, with liquefaction and lateral spreading being the principal cu\ud lpri\ud ts for the inflicted damage.\ud Following the earthquake, a\ud n intensive\ud geotechnical reconnaissance was conducted\ud to capture evidence\ud and perishable data from this event.\ud The surveys were performed on foot, by car and from a helicopter\ud over a period of six da\ud ys. A broad\ud -\ud brush field reconnaissance was conducted in the first two days,\ud followed by pin\ud -\ud point investigations at specific locations including detailed site inspections and field\ud testing using: Dynamic Cone Penetration Test (DCPT), Swedish Weight Soundin\ud g (SWS), and Spectral\ud An\ud alysis of Surface Waves (SASW).\ud This paper summarizes the observations and preliminary findings from this early reconnaissance work\ud .

Published
2010

42. Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

Author

Chen, L., Lim, N., Yuan, X., Surakka, I., Zhang, W., Thompson, J. R., Song, K., Elliott, P., Khaw, K.-T., Ricketts, S. L., Schlessinger, D., Jackson, A., Inouye, M., Boekholdt, S. M., Loos, R. J. F., Johnson, T., Sanna, S., Scuteri, A., Hadley, D., Ripatti, S., Struchalin, M., Braund, P. S., Luben, R., Aulchenko, Y. S., Wheeler, E., Deloukas, P., Young, E. H., Rodwell, S. A., Luan, J., Waterworth, D. M., Ashford, S., and Zhao, J. H.

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of LDL-c, HDL-c and triglycerides.

Published
2010
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43. 'The Practical Perforator Flap': the sural artery flap for lower extremity soft tissue reconstruction in wounds of war

Author

Waes, O.J.F. (Oscar) van, Halm, J.A. (Jens), Vermeulen, J. (Jefrey), Ashford, S. (Sofie), Waes, O.J.F. (Oscar) van, Halm, J.A. (Jens), Vermeulen, J. (Jefrey), and Ashford, S. (Sofie)

Abstract

Background: Sural artery perforator flaps have been described for use as both local flaps and in free tissue transfer. We present the use of this flap for compound soft tissue defects of the lower limb in civilian casualties of armed conflict in Afghanistan. Methods/results: Detailed description of the management of blast and high-velocity projectile wounds of the lower extremity with the use of local sural perforator flaps and a review of literature. Conclusions: Sural artery perforator flaps may be harvested to cover complex lower limb defects. The use of this technique is not limited t

Published
2012
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44. Terrorism

Author

Ashford, S. and Ashford, S.

Abstract

Terrorism is a concept that dates from the French Revolution. Terrorism is defined as a destructive method of political action which uses violence to cause fear for political ends. While some political goals may be achieved only through the use of terrorism, terrorists often kill or injure noncombatants or the innocent in order to maximize terror and to seek widespread publicity for their actions. Contemporary terrorism is often conceived in terms of war. While terrorism may be perpetrated by individuals against a state, states can enact policies of terrorism against their own citizens or subjects of another nation or country.

Published
2012

45. Association between C reactive protein and coronary heart disease : mendelian randomisation analysis based on individual participant data

Author

Wensley, Frances, Gao, Pei, Burgess, Stephen, Kaptoge, Stephen, Di Angelantonio, Emanuele, Shah, Tina, Engert, James C., Clarke, Robert, Davey-Smith, George, Nordestgaard, Borge G., Saleheen, Danish, Samani, Nilesh J., Sandhu, Manjinder, Anand, Sonia, Pepys, Mark B., Smeeth, Liam, Whittaker, John, Casas, Juan Pablo, Thompson, Simon G., Hingorani, Aroon D., Danesh, John, Eiriksdottir, G., Harris, T. B., Launer, L. J., Gudnason, V., Folsom, A. R., Andrews, G., Ballantyne, C. M., Samani, N. J., Hall, A. S., Braund, P. S., Balmforth, A. J., Whincup, P. H., Morris, R., Lawlor, D. A., Lowe, G. D. O., Timpson, N., Ebrahim, S., Ben-Shlomo, Y., Davey-Smith, G., Nordestgaard, B. G., Tybjaerg-Hansen, A., Zacho, J., Brown, M., Sandhu, M., Ricketts, S. L., Ashford, S., Lange, L., Reiner, A., Cushman, M., Tracy, R., Wu, C., Ge, J., Zou, Y., Sun, A., Hung, J., McQuillan, B., Thompson, P., Beilby, J., Warrington, N., Palmer, L. J., Wanner, C., Drechsler, C., Hoffmann, M. M., Fowkes, F. G. R., Tzoulaki, I., Kumari, M., Miller, M., Marmot, M., Onland-Moret, C., van der Schouw, Y. T., Boer, J. M., Wijmenga, C., Khaw, K-T, Vasan, R. S., Schnabel, R. B., Yamamoto, J. F., Benjamin, E. J., Schunkert, H., Erdmann, J., Koenig, I. R., Hengstenberg, C., Chiodini, B., Franzosi, M. G., Pietri, S., Gori, F., Rudock, M., Liu, Y., Lohman, K., Humphries, S. E., Hamsten, A., Norman, P. E., Hankey, G. J., Jamrozik, K., Rimm, E. B., Pai, J. K., Psaty, B. M., Heckbert, S. R., Bis, J. C., Yusuf, S., Anand, S., Engert, J. C., Xie, C., Collins, R., Clarke, R., Bennett, D., Kooner, J., Chambers, J., Elliott, P., Maerz, W., Kleber, M. E., Boehm, B. O., Winkelmann, B. R., Melander, O., Berglund, G., Koenig, W., Thorand, B., Baumert, J., Peters, A., Manson, J., Cooper, J. A., Talmud, P. J., Ladenvall, P., Johansson, L., Jansson, Jan-Håkan, Hallmans, Göran, Reilly, M. P., Qu, L., Li, M., Rader, D. J., Watkins, H., Hopewell, J., Saleheen, D., Danesh, J., Frossard, P., Sattar, N., Robertson, M., Shepherd, J., Schaefer, E., Hofman, A., Witteman, J. C. M., Kardys, I., Dehghan, A., de Faire, U., Bennet, A., Gigante, B., Leander, K., Peters, B., Maitland-van der Zee, A. H., de Boer, A., Klungel, O., Greenland, P., Dai, J., Liu, S., Brunner, E., Kivimaki, M., O'Reilly, D., Ford, I., Packard, C. J., Wensley, Frances, Gao, Pei, Burgess, Stephen, Kaptoge, Stephen, Di Angelantonio, Emanuele, Shah, Tina, Engert, James C., Clarke, Robert, Davey-Smith, George, Nordestgaard, Borge G., Saleheen, Danish, Samani, Nilesh J., Sandhu, Manjinder, Anand, Sonia, Pepys, Mark B., Smeeth, Liam, Whittaker, John, Casas, Juan Pablo, Thompson, Simon G., Hingorani, Aroon D., Danesh, John, Eiriksdottir, G., Harris, T. B., Launer, L. J., Gudnason, V., Folsom, A. R., Andrews, G., Ballantyne, C. M., Samani, N. J., Hall, A. S., Braund, P. S., Balmforth, A. J., Whincup, P. H., Morris, R., Lawlor, D. A., Lowe, G. D. O., Timpson, N., Ebrahim, S., Ben-Shlomo, Y., Davey-Smith, G., Nordestgaard, B. G., Tybjaerg-Hansen, A., Zacho, J., Brown, M., Sandhu, M., Ricketts, S. L., Ashford, S., Lange, L., Reiner, A., Cushman, M., Tracy, R., Wu, C., Ge, J., Zou, Y., Sun, A., Hung, J., McQuillan, B., Thompson, P., Beilby, J., Warrington, N., Palmer, L. J., Wanner, C., Drechsler, C., Hoffmann, M. M., Fowkes, F. G. R., Tzoulaki, I., Kumari, M., Miller, M., Marmot, M., Onland-Moret, C., van der Schouw, Y. T., Boer, J. M., Wijmenga, C., Khaw, K-T, Vasan, R. S., Schnabel, R. B., Yamamoto, J. F., Benjamin, E. J., Schunkert, H., Erdmann, J., Koenig, I. R., Hengstenberg, C., Chiodini, B., Franzosi, M. G., Pietri, S., Gori, F., Rudock, M., Liu, Y., Lohman, K., Humphries, S. E., Hamsten, A., Norman, P. E., Hankey, G. J., Jamrozik, K., Rimm, E. B., Pai, J. K., Psaty, B. M., Heckbert, S. R., Bis, J. C., Yusuf, S., Anand, S., Engert, J. C., Xie, C., Collins, R., Clarke, R., Bennett, D., Kooner, J., Chambers, J., Elliott, P., Maerz, W., Kleber, M. E., Boehm, B. O., Winkelmann, B. R., Melander, O., Berglund, G., Koenig, W., Thorand, B., Baumert, J., Peters, A., Manson, J., Cooper, J. A., Talmud, P. J., Ladenvall, P., Johansson, L., Jansson, Jan-Håkan, Hallmans, Göran, Reilly, M. P., Qu, L., Li, M., Rader, D. J., Watkins, H., Hopewell, J., Saleheen, D., Danesh, J., Frossard, P., Sattar, N., Robertson, M., Shepherd, J., Schaefer, E., Hofman, A., Witteman, J. C. M., Kardys, I., Dehghan, A., de Faire, U., Bennet, A., Gigante, B., Leander, K., Peters, B., Maitland-van der Zee, A. H., de Boer, A., Klungel, O., Greenland, P., Dai, J., Liu, S., Brunner, E., Kivimaki, M., O'Reilly, D., Ford, I., and Packard, C. J.

Abstract

Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10(-34)) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference). Conclusion Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.

Published
2011
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46. Genetic variants influencing circulating lipid levels and risk of coronary artery disease

Author

Waterworth, D. (Dawn), Ricketts, S.L. (Sally), Song, K. (Kijoung), Chen, L. (Leslie), Zhao, J.H. (Jing Hua), Ripatti, S. (Samuli), Aulchenko, Y.S. (Yurii), Zhang, W. (Weihua), Yuan, X. (Xin), Lim, N. (Noha), Luan, J., Ashford, S. (Sofie), Wheeler, E. (Eleanor), Young, E.H. (Elizabeth), Hadley, D. (David), Thompson, J.R. (John), Braund, P.S. (Peter), Johnson, T. (Toby), Struchalin, M.V. (Maksim), Surakka, I. (Ida), Luben, R.N. (Robert), Khaw, K-T. (Kay-Tee), Rodwell, S.A. (Sheila), Loos, R.J.F. (Ruth), Boekholdt, S.M. (Matthijs), Inouye, M. (Michael), Deloukas, P. (Panagiotis), Elliott, P. (Paul), Schlessinger, D., Sanna, S. (Serena), Scuteri, A. (Angelo), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Roberts, R. (Robert), Stewart, A. (Alison), Kesaniemi, Y.A. (Antero), Mahley, R. (Robert), Grundy, S.M. (Scott), McArdle, W.L. (Wendy), Cardon, L. (Lon), Waeber, G. (Gérard), Vollenweider, P. (Peter), Chambers, J.C. (John), Boehnke, M. (Michael), Abecasis, G.R. (Gonçalo), Salomaa, V. (Veikko), Järvelin, M.R., Ruokonen, A. (Aimo), Barroso, I.E. (Inês), Epstein, S.E. (Stephen), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), Witteman, J.C.M. (Jacqueline), Hall, A.S. (Alistair), Samani, N.J. (Nilesh), Strachan, D.P. (David), Barter, P. (Phil), Tikka-Kleemola, P. (Päivi), Kooner, J.S. (Jaspal), Peltonen, L. (Leena Johanna), Wareham, N.J. (Nick), McPherson, R. (Ruth), Mooser, V. (Vincent), Sandhu, M.S. (Manjinder), Waterworth, D. (Dawn), Ricketts, S.L. (Sally), Song, K. (Kijoung), Chen, L. (Leslie), Zhao, J.H. (Jing Hua), Ripatti, S. (Samuli), Aulchenko, Y.S. (Yurii), Zhang, W. (Weihua), Yuan, X. (Xin), Lim, N. (Noha), Luan, J., Ashford, S. (Sofie), Wheeler, E. (Eleanor), Young, E.H. (Elizabeth), Hadley, D. (David), Thompson, J.R. (John), Braund, P.S. (Peter), Johnson, T. (Toby), Struchalin, M.V. (Maksim), Surakka, I. (Ida), Luben, R.N. (Robert), Khaw, K-T. (Kay-Tee), Rodwell, S.A. (Sheila), Loos, R.J.F. (Ruth), Boekholdt, S.M. (Matthijs), Inouye, M. (Michael), Deloukas, P. (Panagiotis), Elliott, P. (Paul), Schlessinger, D., Sanna, S. (Serena), Scuteri, A. (Angelo), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Roberts, R. (Robert), Stewart, A. (Alison), Kesaniemi, Y.A. (Antero), Mahley, R. (Robert), Grundy, S.M. (Scott), McArdle, W.L. (Wendy), Cardon, L. (Lon), Waeber, G. (Gérard), Vollenweider, P. (Peter), Chambers, J.C. (John), Boehnke, M. (Michael), Abecasis, G.R. (Gonçalo), Salomaa, V. (Veikko), Järvelin, M.R., Ruokonen, A. (Aimo), Barroso, I.E. (Inês), Epstein, S.E. (Stephen), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), Witteman, J.C.M. (Jacqueline), Hall, A.S. (Alistair), Samani, N.J. (Nilesh), Strachan, D.P. (David), Barter, P. (Phil), Tikka-Kleemola, P. (Päivi), Kooner, J.S. (Jaspal), Peltonen, L. (Leena Johanna), Wareham, N.J. (Nick), McPherson, R. (Ruth), Mooser, V. (Vincent), and Sandhu, M.S. (Manjinder)

Abstract

OBJECTIVE-: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS

Published
2010
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