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1. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

Author

Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, van der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Generation Scotland, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, and Wright, AF

Subjects
Generation Scotland, Humans, Genetic Predisposition to Disease, HMGN1 Protein, Cohort Studies, Cognition, Cognition Disorders, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Scotland, Female, Male, Atherosclerosis, Genome-Wide Association Study, and over, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Published
2015

2. Sorghum

Author

Boxall, R. A., primary, Gebre-Tsadik, M., additional, Jayaraj, K., additional, Ramam, C. P., additional, Patternaik, B. B., additional, and Hodges, R. J., additional

Published
2007
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4. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Author

Shrine, N. (Nick), Guyatt, A. L. (Anna L.), Erzurumluoglu, A. M. (A. Mesut), Jackson, V. E. (Victoria E.), Hobbs, B. D. (Brian D.), Melbourne, C. A. (Carl A.), Batini, C. (Chiara), Fawcett, K. A. (Katherine A.), Song, K. (Kijoung), Sakornsakolpat, P. (Phuwanat), Li, X. (Xingnan), Boxall, R. (Ruth), Reeve, N. F. (Nicola F.), Obeidat, M. (Ma'en), Zhao, J. H. (Jing Hua), Wielscher, M. (Matthias), Weiss, S. (Stefan), Kentistou, K. A. (Katherine A.), Cook, J. P. (James P.), Sun, B. B. (Benjamin B.), Zhou, J. (Jian), Hui, J. (Jennie), Karrasch, S. (Stefan), Imboden, M. (Medea), Harris, S. E. (Sarah E.), Marten, J. (Jonathan), Enroth, S. (Stefan), Kerr, S. M. (Shona M.), Surakka, I. (Ida), Vitart, V. (Veronique), Lehtimäki, T. (Terho), Allen, R. J. (Richard J.), Bakke, P. S. (Per S.), Beaty, T. H. (Terri H.), Bleecker, E. R. (Eugene R.), Bosse, Y. (Yohan), Brandsma, C.-A. (Corry-Anke), Chen, Z. (Zhengming), Crapo, J. D. (James D.), Danesh, J. (John), DeMeo, D. L. (Dawn L.), Dudbridge, F. (Frank), Ewert, R. (Ralf), Gieger, C. (Christian), Gulsvik, A. (Amund), Hansell, A. L. (Anna L.), Hao, K. (Ke), Hoffman, J. D. (Joshua D.), Hokanson, J. E. (John E.), Homuth, G. (Georg), Joshi, P. K. (Peter K.), Joubert, P. (Philippe), Langenberg, C. (Claudia), Li, X. (Xuan), Li, L. (Liming), Lin, K. (Kuang), Lind, L. (Lars), Locantore, N. (Nicholas), Luan, J. (Jian'an), Mahajan, A. (Anubha), Maranville, J. C. (Joseph C.), Murray, A. (Alison), Nickle, D. C. (David C.), Packer, R. (Richard), Parker, M. M. (Margaret M.), Paynton, M. L. (Megan L.), Porteous, D. J. (David J.), Prokopenko, D. (Dmitry), Qiao, D. (Dandi), Rawal, R. (Rajesh), Runz, H. (Heiko), Sayers, I. (Ian), Sin, D. D. (Don D.), Smith, B. H. (Blair H.), Artigas, M. S. (Maria Soler), Sparrow, D. (David), Tal-Singer, R. (Ruth), Timmers, P. R. (Paul R. H. J.), Van den Berge, M. (Maarten), Whittaker, J. C. (John C.), Woodruff, P. G. (Prescott G.), Verges-Armstrong, L. M. (Laura M.), Troyanskaya, O. G. (Olga G.), Raitakari, O. T. (Olli T.), Kähönen, M. (Mika), Polasek, O. (Ozren), Gyllensten, U. (Ulf), Rudan, I. (Igor), Deary, I. J. (Ian J.), Probst-Hensch, N. M. (Nicole M.), Schulz, H. (Holger), James, A. L. (Alan L.), Wilson, J. F. (James F.), Stubbe, B. (Beate), Zeggini, E. (Eleftheria), Järvelin, M.-R. (Marjo-Riitta), Wareham, N. (Nick), Silverman, E. K. (Edwin K.), Hayward, C. (Caroline), Morris, A. P. (Andrew P.), Butterworth, A. S. (Adam S.), Scott, R. A. (Robert A.), Walters, R. G. (Robin G.), Meyers, D. A. (Deborah A.), Cho, M. H. (Michael H.), Strachan, D. P. (David P.), Hall, I. P. (Ian P.), Tobin, M. D. (Martin D.), Wain, L. V. (Louise, V), Shrine, N. (Nick), Guyatt, A. L. (Anna L.), Erzurumluoglu, A. M. (A. Mesut), Jackson, V. E. (Victoria E.), Hobbs, B. D. (Brian D.), Melbourne, C. A. (Carl A.), Batini, C. (Chiara), Fawcett, K. A. (Katherine A.), Song, K. (Kijoung), Sakornsakolpat, P. (Phuwanat), Li, X. (Xingnan), Boxall, R. (Ruth), Reeve, N. F. (Nicola F.), Obeidat, M. (Ma'en), Zhao, J. H. (Jing Hua), Wielscher, M. (Matthias), Weiss, S. (Stefan), Kentistou, K. A. (Katherine A.), Cook, J. P. (James P.), Sun, B. B. (Benjamin B.), Zhou, J. (Jian), Hui, J. (Jennie), Karrasch, S. (Stefan), Imboden, M. (Medea), Harris, S. E. (Sarah E.), Marten, J. (Jonathan), Enroth, S. (Stefan), Kerr, S. M. (Shona M.), Surakka, I. (Ida), Vitart, V. (Veronique), Lehtimäki, T. (Terho), Allen, R. J. (Richard J.), Bakke, P. S. (Per S.), Beaty, T. H. (Terri H.), Bleecker, E. R. (Eugene R.), Bosse, Y. (Yohan), Brandsma, C.-A. (Corry-Anke), Chen, Z. (Zhengming), Crapo, J. D. (James D.), Danesh, J. (John), DeMeo, D. L. (Dawn L.), Dudbridge, F. (Frank), Ewert, R. (Ralf), Gieger, C. (Christian), Gulsvik, A. (Amund), Hansell, A. L. (Anna L.), Hao, K. (Ke), Hoffman, J. D. (Joshua D.), Hokanson, J. E. (John E.), Homuth, G. (Georg), Joshi, P. K. (Peter K.), Joubert, P. (Philippe), Langenberg, C. (Claudia), Li, X. (Xuan), Li, L. (Liming), Lin, K. (Kuang), Lind, L. (Lars), Locantore, N. (Nicholas), Luan, J. (Jian'an), Mahajan, A. (Anubha), Maranville, J. C. (Joseph C.), Murray, A. (Alison), Nickle, D. C. (David C.), Packer, R. (Richard), Parker, M. M. (Margaret M.), Paynton, M. L. (Megan L.), Porteous, D. J. (David J.), Prokopenko, D. (Dmitry), Qiao, D. (Dandi), Rawal, R. (Rajesh), Runz, H. (Heiko), Sayers, I. (Ian), Sin, D. D. (Don D.), Smith, B. H. (Blair H.), Artigas, M. S. (Maria Soler), Sparrow, D. (David), Tal-Singer, R. (Ruth), Timmers, P. R. (Paul R. H. J.), Van den Berge, M. (Maarten), Whittaker, J. C. (John C.), Woodruff, P. G. (Prescott G.), Verges-Armstrong, L. M. (Laura M.), Troyanskaya, O. G. (Olga G.), Raitakari, O. T. (Olli T.), Kähönen, M. (Mika), Polasek, O. (Ozren), Gyllensten, U. (Ulf), Rudan, I. (Igor), Deary, I. J. (Ian J.), Probst-Hensch, N. M. (Nicole M.), Schulz, H. (Holger), James, A. L. (Alan L.), Wilson, J. F. (James F.), Stubbe, B. (Beate), Zeggini, E. (Eleftheria), Järvelin, M.-R. (Marjo-Riitta), Wareham, N. (Nick), Silverman, E. K. (Edwin K.), Hayward, C. (Caroline), Morris, A. P. (Andrew P.), Butterworth, A. S. (Adam S.), Scott, R. A. (Robert A.), Walters, R. G. (Robin G.), Meyers, D. A. (Deborah A.), Cho, M. H. (Michael H.), Strachan, D. P. (David P.), Hall, I. P. (Ian P.), Tobin, M. D. (Martin D.), and Wain, L. V. (Louise, V)

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function–associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Published
2019

6. Lipids, lipoproteins, and metabolites and risk of myocardial infarction and stroke

Author

Holmes, M. V. (Michael V.), Millwood, I. Y. (Iona Y.), Kartsonaki, C. (Christiana), Hill, M. R. (Michael R.), Bennett, D. A. (Derrick A.), Boxall, R. (Ruth), Guo, Y. (Yu), Xu, X. (Xin), Bian, Z. (Zheng), Hu, R. (Ruying), Walters, R. G. (Robin G.), Chen, J. (Junshi), Ala-Korpela, M. (Mika), Parish, S. (Sarah), Clarke, R. J. (Robert J.), Peto, R. (Richard), Collins, R. (Rory), Li, L. (Liming), and Chen, Z. (Zhengming)

Subjects
myocardial infarction, etiology, ischemic stroke, lipids (amino acids, peptides, and proteins), epidemiology, intracerebral hemorrhage, metabolomics
Abstract

Background: Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes. Objectives: This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH). Methods: In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker. Results: Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH. Conclusions: Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non–lipid-related metabolites associated with all 3 diseases.

Published
2018

7. Lipids, lipoproteins and metabolites and risk of incident myocardial infarction and stroke subtypes

Author

Holmes, MV, Millwood, IY, Kartsonaki, C, Hill, MR, Bennett, DA, Boxall, R, Guo, Y, Xu, X, Bian, Z, Hu, R, Walters, RG, Chen, J, Ala-Korpela, M, Parish, SE, Clarke, RJ, Peto, R, Collins, RE, Li, L, and Chen, Z

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

Background Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles and circulating metabolites for MI and stroke subtypes. Objectives To investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS) and intracerebral hemorrhage (ICH). Methods In a nested case-control study (912 MI, 1146 IS, 1138 ICH cases and 1466 common controls) aged 30-79 years in China Kadoorie Biobank, NMR spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a one standard deviation higher metabolic marker. Results Very-low-, intermediate- and low-density lipoprotein particles were positively associated with MI and IS. HDL particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (ORs 0.79 and 0.88), whereas cholesterol in small HDL was not (ORs 0.99 and 1.06). Triglycerides within all lipoproteins, including most HDL particles, positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose and docosahexaenoic acid associated with all three diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH. Conclusions Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas TG concentrations were positively associations with MI. Glycoprotein acetyls and several non-lipid related metabolites associated with all three diseases.

Published
2017

8. Association of CETP gene variants with risk for vascular and nonvascular diseases among Chinese adults

Author

Millwood, I, Bennett, D, Holmes, M, Boxall, R, Guo, Y, Bian, Z, Yang, L, Sansome, S, Chen, Y, Du, H, Yu, C, Hacker, A, Reilly, D, Tan, Y, Hill, M, Chen, J, Peto, R, Shen, H, Collins, R, Clarke, R, Li, L, Walters, R, Chen, Z, and Group, on behalf of the China Kadoorie Biobank Collaborative

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

Importance: Raising HDL-cholesterol through pharmacological inhibition of cholesteryl ester transfer protein is a potentially important strategy for prevention and treatment of cardiovascular diseases. Objective: To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower cholesteryl ester transfer protein activity on cardiovascular diseases and other outcomes.Design: A prospective biobank study, with 9-year follow-up through linkage to health insurance records and death and disease registries.Setting: Five urban and five rural areas of China. Participants: 151,217 individuals aged 30-79 years at baseline with genotype data, 17,854 of whom also had lipid measurements and 4,657 had lipoprotein particle measurements.Exposures: Five CETP variants including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to effects on HDL-cholesterol.Main outcomes and measures: Baseline lipids and lipoprotein particles, cardiovascular risk factors, and incidence of carotid plaque and pre-defined major vascular and non-vascular diseases and a phenome-wide range of diseases.Results: Overall the mean LDL-cholesterol was 91 and HDL-cholesterol was 48 mg/dL. CETP variants were strongly associated with higher concentrations of HDL-cholesterol (e.g. 6.1 mg/dL per rs2303790 allele; P=9.4x10-4766 ), but were not associated with lower LDL-cholesterol. Within HDL particles, cholesterol esters were increased and triglycerides reduced, while within VLDL particles, cholesterol esters were reduced and triglycerides increased. Scaled to 10mg/dL higher HDL-cholesterol, the CETP genetic score was not associated with occlusive cardiovascular disease (18,550 events; OR=0.98 [95%CI 0.91-1.06]), major coronary events (5,767 events; 1.08 [0.95- 1.22]), myocardial infarction (3,118 events; 1.14 [0.97-1.34]) ischemic stroke (13,759 events; 0.94 [0.83-1.06]), intracerebral haemorrhage (6,532 events; 0.94 [0.86-1.02]) or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. There were no associations with non-vascular diseases other than an increased risk of eye diseases with rs2303790 (4,090 events; 1.43 [1.13-1.80], P=0.0028).Conclusions and relevance: CETP variants were associated with altered HDL metabolism but did not lower LDL-cholesterol and had no significant effects on cardiovascular disease risk. These results suggest that in the absence of reduced LDL-cholesterol, increasing HDL-cholesterol by inhibition of cholesteryl ester transfer protein may not confer significant benefits for cardiovascular diseases.

Published
2017

9. CETP gene variants and risk of vascular and non-vascular diseases in ~150,000 Chinese adults

Author

Millwood, IY, Bennett, D, Holmes, MV, Boxall, R, Guo, Y, Bian, Z, Yang, L, Sansome, GS, Chen, Y, Huaidong, D, Yu, C, Hacker, A, Reilly, D, Tan, Y, Hill, MR, Chen, J, Peto, R, Shen, H, Collins, RE, Clarke, RJ, Li, L, Walters, R, and Chen, Z

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

Importance Raising HDL-cholesterol through pharmacological inhibition of cholesteryl ester transfer protein is a potentially important strategy for prevention and treatment of cardiovascular diseases. Objective To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower cholesteryl ester transfer protein activity on cardiovascular diseases and other outcomes. Design A prospective biobank study, with 9-year follow-up through linkage to health insurance records and death and disease registries. Setting Five urban and five rural areas of China. Participants 151,217 individuals aged 30-79 years at baseline with genotype data, 17,854 of whom also had lipid measurements and 4,657 had lipoprotein particle measurements. Exposures Five CETP variants including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to effects on HDL-cholesterol. Main outcomes and measure Baseline lipids and lipoprotein particles, cardiovascular risk factors, and incidence of carotid plaque and pre-defined major vascular and non-vascular diseases and a phenome-wide range of diseases. Results Overall the mean LDL-cholesterol was 91 and HDL-cholesterol was 48 mg/dL. CETP variants were strongly associated with higher concentrations of HDL-cholesterol (e.g. 6.1 mg/dL per rs2303790 allele; P=9.4x10-4766 ), but were not associated with lower LDL-cholesterol. Within HDL particles, cholesterol esters were increased and triglycerides reduced, while within VLDL particles, cholesterol esters were reduced and triglycerides increased. Scaled to 10mg/dL higher HDL-cholesterol, the CETP genetic score was not associated with occlusive cardiovascular disease (18,550 events; OR=0.98 [95%CI 0.91-1.06]), major coronary events (5,767 events; 1.08 [0.95-1.22]), myocardial infarction (3,118 events; 1.14 [0.97-1.34]) ischemic stroke (13,759 events; 0.94 [0.83-1.06]), intracerebral haemorrhage (6,532 events; 0.94 [0.86-1.02]) or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. There were no associations with non-vascular diseases other than an increased risk of eye diseases with rs2303790 (4,090 events; 1.43 [1.13-1.80], P=0.0028). Conclusions and relevance CETP variants were associated with altered HDL metabolism but did not lower LDL-cholesterol and had no significant effects on cardiovascular disease risk. These results suggest that in the absence of reduced LDL-cholesterol, increasing HDL-cholesterol by inhibition of cholesteryl ester transfer protein may not confer significant benefits for cardiovascular diseases.

Published
2017

10. A Review of Programs for Low Achievers in Grade 9 and 10 Mathematics. Resources Review, October 1975.

Author

Queensland Dept. of Education, Brisbane (Australia)., Murray, S., and Boxall, R.

Abstract

This brief review concentrates on ten commercially produced programs for general mathematics courses in grades 9 and 10. The review is designed to assist teachers in assessing programs for low-achieving mathematics students. Nine Australian schools participated in a test project of these programs during the last term of 1974. For each program, the full title of the program is listed, its publisher, a description of the materials used, cost, and teacher comments about the program. Some programs provide for individual instruction and short term goals; others present mathematics in a concrete manner through various games and other novel approaches; environmental and practical problems form the basis of still other programs outlined. A table presents an overview of the programs tested, rating the programs in terms of emphasis upon such aspects as environmental and mathematical topics, low reading age, improving problem solving techniques, increasing computational skills, using a carefully sequenced mathematics program, and involvement of students with concrete materials. (JW)

Published
1975

11. Resources Review: S.M.P. in Queensland High Schools.

Author

Queensland Dept. of Education, Brisbane (Australia)., Murray, S., and Boxall, R.

Abstract

This resource review aims mainly at providing the conceptual basis of the School Mathematics Project (S.M.P.) so that teachers can make informed decisions regarding its use. The review is divided into three main parts: (1) a brief introduction to S.M.P. materials and philosophy; (2) reports from six Queensland (Australia) state high schools using S.M.P.; and (3) an in-depth look at the S.M.P. A through H series. (MN)

Published
1977

12. International Congress Of Gynæcology And Obstetrics

Author

Playfair, W. S., Black, J. Watt, Routh, Amand, Eden, T. W., Galabin, A. L., Horrocks, P., Targett, J. H., Hayes, T. C., Phillips, J., Herman, G. E., Lewers, A. H. N., Duncan, W., Boxall, R., Champneys, F. H., Griffith, W. S. A., Dakin, W. R., Stabb, A. F., Handfield-Jones, M., Gow, W. J., Cullingworth, C. J., Tate, W. W. H., Williams, J., Spencer, H. R., Blacker, G. F., Potter, J. B., Pollock, W. R., and Scharlieb, Mary

Published
1900

13. Genetic contributions to variation in general cognitive function:a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

Author

Davies, G., Armstrong, N., Bis, J. C., Bressler, J., Chouraki, V., Giddaluru, S., Hofer, E., Ibrahim-Verbaas, C. A., Kirin, M., Lahti, J., van der Lee, S. J., Le Hellard, S., Liu, T., Marioni, R. E., Oldmeadow, C., Postmus, I., Smith, A. V., Smith, J. A., Thalamuthu, A., Thomson, R., Vitart, V., Wang, J., Yu, L., Zgaga, L., Zhao, W., Boxall, R., Harris, S. E., Hill, W. D., Liewald, D. C., Luciano, M., Adams, H., Ames, D., Amin, N., Amouyel, P., Assareh, A. A., Au, R., Becker, J. T., Beiser, A., Berr, C., Bertram, L., Boerwinkle, E., Buckley, B. M., Campbell, H., Corley, J., De Jager, P. L., Dufouil, C., Eriksson, J. G., Espeseth, T., Faul, J. D., Ford, I., Gottesman, R. F., Griswold, M. E., Gudnason, V., Harris, T. B., Heiss, G., Hofman, A., Holliday, E. G., Huffman, J., Kardia, S. L. R., Kochan, N., Knopman, D. S., Kwok, J. B., Lambert, J-C, Lee, T., Li, G., Li, S-C, Loitfelder, M., Lopez, O. L., Lundervold, A. J., Lundquist, Anders, Mather, K. A., Mirza, S. S., Nyberg, Lars, Oostra, B. A., Palotie, A., Papenberg, G., Pattie, A., Petrovic, K., Polasek, O., Psaty, B. M., Redmond, P., Reppermund, S., Rotter, J. I., Schmidt, H., Schuur, M., Schofield, P. W., Scott, R. J., Steen, V. M., Stott, D. J., Van Swieten, J. C., Taylor, K. D., Trollor, J., Trompet, S., Uitterlinden, A. G., Weinstein, G., Widen, E., Windham, B. G., Jukema, J. W., Wright, A. F., Wright, M. J., Yang, Q., Amieva, H., Attia, J. R., Bennett, D. A., Brodaty, H., de Craen, A. J. M., Hayward, C., Ikram, M. A., Lindenberger, U., Nilsson, Lars-Göran, Porteous, D. J., Raikkonen, K., Reinvang, I., Rudan, I., Sachdev, P. S., Schmidt, R., Schofield, P. R., Srikanth, V., Starr, J. M., Turner, S. T., Weir, D. R., Wilson, J. F., Van Duijn, C., Launer, L., Fitzpatrick, A. L., Seshadri, S., Jr, T. H. Mosley, Deary, I. J., Epidemiology, Neurology, Radiology & Nuclear Medicine, Clinical Genetics, and Internal Medicine

Subjects
Male, Neurologi, SUSCEPTIBILITY LOCI, Neuropsychological Tests, Polymorphism, Single Nucleotide, IDENTIFIES VARIANTS, APOLIPOPROTEIN-E, Cohort Studies, Cognition, OLD-AGE, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, HUMAN INTELLIGENCE, Aged, TYPE-4 ALLELE, Aged, 80 and over, TEST BATTERIES, Middle Aged, Atherosclerosis, CPG-BINDING PROTEIN-2, ALZHEIMERS-DISEASE, Phenotype, Scotland, Neurology, Female, Cognition Disorders, Immediate Communication, HUMAN HEIGHT, HMGN1 Protein, Genome-Wide Association Study
Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.

Published
2015

14. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

Author

Davies, G., Armstrong, N., Bis, J.C., Bressler, J., Chouraki, V., Giddaluru, S., Hofer, E., Ibrahim-Verbaas, C.A., Kirin, M., Lahti, J., Lee, S.J. van der, Hellard, S. le, Liu, T., Marioni, R.E., Oldmeadow, C., Postmus, I., Smith, A.V., Smith, J.A., Thalamuthu, A., Thomson, R., Vitart, V., Wang, J., Yu, L., Zgaga, L., Zhao, W., Boxall, R., Harris, S.E., Hill, W.D., Liewald, D.C., Luciano, M., Adams, H., Ames, D., Amin, N., Amouyel, P., Assareh, A.A., Au, R., Becker, J.T., Beiser, A., Berr, C., Bertram, L., Boerwinkle, E., Buckley, B.M., Campbell, H., Corley, J., Jager, P.L. de, Dufouil, C., Eriksson, J.G., Espeseth, T., Faul, J.D., Ford, I., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Heiss, G., Hofman, A., Holliday, E.G., Huffman, J., Kardia, S.L.R., Kochan, N., Knopman, D.S., Kwok, J.B., Lambert, J.C., Lee, T., Li, G., Li, S.C., Loitfelder, M., Lopez, O.L., Lundervold, A.J., Lundqvist, A., Mather, K.A., Mirza, S.S., Nyberg, L., Oostra, B.A., Palotie, A., Papenberg, G., Pattie, A., Petrovic, K., Polasek, O., Psaty, B.M., Redmond, P., Reppermund, S., Rotter, J.I., Schmidt, H., Schuur, M., Schofield, P.W., Scott, R.J., Steen, V.M., Stott, D.J., Swieten, J.C. van, Taylor, K.D., Trollor, J., Trompet, S., Uitterlinden, A.G., Weinstein, G., Widen, E., Windham, B.G., Jukema, J.W., Wright, A.F., Wright, M.J., Yang, Q., Amieva, H., Attia, J.R., Bennett, D.A., Brodaty, H., Craen, A.J.M. de, Hayward, C., Ikram, M.A., Lindenberger, U., Nilsson, L.G., Porteous, D.J., Raikkonen, K., Reinvang, I., Rudan, I., Sachdev, P.S., Schmidt, R., Schofield, P.R., Srikanth, V., Starr, J.M., Turner, S.T., Weir, D.R., Wilson, J.F., Duijn, C. van, Launer, L., Fitzpatrick, A.L., Seshadri, S., Jr, T.H.M., Deary, I.J., and Generation Scotland

Subjects
Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], Social sciences: 200::Psychology: 260::Cognitive psychology: 267 [VDP], Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 [VDP], Samfunnsvitenskap: 200::Psykologi: 260::Kognitiv psykologi: 267 [VDP]
Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C. publishedVersion

Published
2015

15. Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

Author

Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, Van Der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Scotland, G, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, JC, Lee, T, Li, G, Li, SC, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, Van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, Wright, AF, Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, Van Der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Scotland, G, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, JC, Lee, T, Li, G, Li, SC, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, Van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, and Wright, AF

Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10-9, MIR2113; rs17522122, P=2.55 × 10-8, AKAP6; rs10119, P=5.67 × 10-9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10-6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ∼1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10-17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Published
2015

16. Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium

Author

Davies, G. (Gail), Armstrong, N.J. (Nicola), Bis, J.C. (Joshua), Bressler, J. (Jan), Chouraki, V. (Vincent), Giddaluru, S. (Sudheer), Hofer, E., Ibrahim-Verbaas, C.A. (Carla), Kirin, M. (Mirna), Lahti, J., Lee, S.J. (Sven) van der, Le Hellard, S. (Stephanie), Liu, T., Marioni, R.E. (Riccardo), Oldmeadow, C. (Christopher), Postmus, D. (Douwe), Smith, A.V. (Davey), Smith, J.A. (Jennifer A), Thalamuthu, A. (Anbupalam), Thomson, R. (Russell), Vitart, V. (Veronique), Wang, J., Yu, L., Zgaga, L. (Lina), Zhao, W. (Wei), Boxall, R. (Ruth), Harris, S.E. (Sarah), Hill, W.D. (W. David), Liewald, D.C. (David C.), Luciano, M. (Michelle), Adams, H.H.H. (Hieab), Ames, D. (David), Amin, N. (Najaf), Amouyel, P. (Philippe), Assareh, A.A., Au, R., Becker, J.T. (James), Beiser, A., Berr, C. (Claudine), Bertram, L. (Lars), Boerwinkle, E.A. (Eric), Buckley, B.M. (Brendan M.), Campbell, H. (Harry), Corley, J. (Janie), De Jager, P.L., Dufouil, C. (Carole), Eriksson, J.G. (Johan G.), Espeseth, T. (Thomas), Faul, J.D., Ford, I., Scotland, G. (Generation), Gottesman, R.F. (Rebecca), Griswold, M.D. (Michael), Gudnason, V. (Vilmundur), Harris, T.B., Heiss, G. (Gerardo), Hofman, A. (Albert), Holliday, E.G. (Elizabeth), Huffman, J.E. (Jennifer), Kardia, S.L.R. (Sharon), Kochan, N.A. (Nicole A.), Knopman, D.S. (David), Kwok, J.B., Lambert, J.-C., Lee, T., Li, G., Li, S.-C., Loitfelder, M. (Marisa), Lopez, O.L. (Oscar), Lundervold, A.J., Lundqvist, A., Mather, R., Mirza, S.S. (Saira), Nyberg, L., Oostra, B.A. (Ben), Palotie, A. (Aarno), Papenberg, G., Pattie, A. (Alison), Petrovic, K. (Katja), Polasek, O. (Ozren), Psaty, B.M. (Bruce), Redmond, P. (Paul), Reppermund, S., Rotter, J.I., Schmidt, R. (Reinhold), Schuur, M. (Maaike), Schofield, P.W., Scott, R.J., Steen, V.M. (Vidar), Stott, D.J. (David J.), Swieten, J.C. (John) van, Taylor, K.D. (Kent), Trollor, J., Trompet, S. (Stella), Uitterlinden, A.G. (André), Weinstein, G., Widen, E. (Elisabeth), Windham, B.G. (Gwen), Jukema, J.W. (Jan Wouter), Wright, A. (Alan), Wright, M.J. (Margaret), Yang, Q. (Qiong Fang), Amieva, H. (Hélène), Attia, J. (John), Bennett, D.A. (David), Brodaty, H. (Henry), Craen, A.J. (Anton) de, Hayward, C., Ikram, M.A. (Arfan), Lindenberger, U., Nilsson, L.-G., Porteous, D.J. (David J.), Räikkönen, K. (Katri), Reinvang, I. (Ivar), Rudan, I. (Igor), Sachdev, P.S. (Perminder), Schmidt, R., Schofield, P. (Peter), Srikanth, V., Starr, J.M. (John), Turner, S.T. (Stephen), Weir, D.R. (David R.), Wilson, J.F. (James F), Duijn, C.M. (Cornelia) van, Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), Mosley, T.H. (Thomas H.), Deary, I.J. (Ian), Davies, G. (Gail), Armstrong, N.J. (Nicola), Bis, J.C. (Joshua), Bressler, J. (Jan), Chouraki, V. (Vincent), Giddaluru, S. (Sudheer), Hofer, E., Ibrahim-Verbaas, C.A. (Carla), Kirin, M. (Mirna), Lahti, J., Lee, S.J. (Sven) van der, Le Hellard, S. (Stephanie), Liu, T., Marioni, R.E. (Riccardo), Oldmeadow, C. (Christopher), Postmus, D. (Douwe), Smith, A.V. (Davey), Smith, J.A. (Jennifer A), Thalamuthu, A. (Anbupalam), Thomson, R. (Russell), Vitart, V. (Veronique), Wang, J., Yu, L., Zgaga, L. (Lina), Zhao, W. (Wei), Boxall, R. (Ruth), Harris, S.E. (Sarah), Hill, W.D. (W. David), Liewald, D.C. (David C.), Luciano, M. (Michelle), Adams, H.H.H. (Hieab), Ames, D. (David), Amin, N. (Najaf), Amouyel, P. (Philippe), Assareh, A.A., Au, R., Becker, J.T. (James), Beiser, A., Berr, C. (Claudine), Bertram, L. (Lars), Boerwinkle, E.A. (Eric), Buckley, B.M. (Brendan M.), Campbell, H. (Harry), Corley, J. (Janie), De Jager, P.L., Dufouil, C. (Carole), Eriksson, J.G. (Johan G.), Espeseth, T. (Thomas), Faul, J.D., Ford, I., Scotland, G. (Generation), Gottesman, R.F. (Rebecca), Griswold, M.D. (Michael), Gudnason, V. (Vilmundur), Harris, T.B., Heiss, G. (Gerardo), Hofman, A. (Albert), Holliday, E.G. (Elizabeth), Huffman, J.E. (Jennifer), Kardia, S.L.R. (Sharon), Kochan, N.A. (Nicole A.), Knopman, D.S. (David), Kwok, J.B., Lambert, J.-C., Lee, T., Li, G., Li, S.-C., Loitfelder, M. (Marisa), Lopez, O.L. (Oscar), Lundervold, A.J., Lundqvist, A., Mather, R., Mirza, S.S. (Saira), Nyberg, L., Oostra, B.A. (Ben), Palotie, A. (Aarno), Papenberg, G., Pattie, A. (Alison), Petrovic, K. (Katja), Polasek, O. (Ozren), Psaty, B.M. (Bruce), Redmond, P. (Paul), Reppermund, S., Rotter, J.I., Schmidt, R. (Reinhold), Schuur, M. (Maaike), Schofield, P.W., Scott, R.J., Steen, V.M. (Vidar), Stott, D.J. (David J.), Swieten, J.C. (John) van, Taylor, K.D. (Kent), Trollor, J., Trompet, S. (Stella), Uitterlinden, A.G. (André), Weinstein, G., Widen, E. (Elisabeth), Windham, B.G. (Gwen), Jukema, J.W. (Jan Wouter), Wright, A. (Alan), Wright, M.J. (Margaret), Yang, Q. (Qiong Fang), Amieva, H. (Hélène), Attia, J. (John), Bennett, D.A. (David), Brodaty, H. (Henry), Craen, A.J. (Anton) de, Hayward, C., Ikram, M.A. (Arfan), Lindenberger, U., Nilsson, L.-G., Porteous, D.J. (David J.), Räikkönen, K. (Katri), Reinvang, I. (Ivar), Rudan, I. (Igor), Sachdev, P.S. (Perminder), Schmidt, R., Schofield, P. (Peter), Srikanth, V., Starr, J.M. (John), Turner, S.T. (Stephen), Weir, D.R. (David R.), Wilson, J.F. (James F), Duijn, C.M. (Cornelia) van, Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), Mosley, T.H. (Thomas H.), and Deary, I.J. (Ian)

Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10-9, MIR2113; rs17522122, P=2.55 × 10-8, AKAP6; rs10119, P=5.67 × 10-9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10-6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ∼1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10-17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Published
2015
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17. Genome-wide studies of verbal declarative memory in nondemented older people: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Author

Debette, S. (Stéphanie), Ibrahim-Verbaas, C.A. (Carla), Bressler, J. (Jan), Schuur, M. (Maaike), Smith, A.V. (Davey), Bis, J.C. (Joshua), Davies, G. (Gail), Wolf, C. (Christiane), Gudnason, V. (Vilmundur), Chibnik, L.B. (Lori), Yang, Q. (Qiong Fang), DeStefano, A.L. (Anita), De Quervain, D.J.F. (Dominique J.F.), Srikanth, V. (Velandai), Lahti, J. (Jari), Grabe, H.J. (Hans Jörgen), Smith, J.A. (Jennifer A), Priebe, L., Yu, L. (Lei), Karbalai, N. (Nazanin), Hayward, C. (Caroline), Wilson, J.F. (James F), Campbell, H. (Harry), Petrovic, K. (Katja), Fornage, M. (Myriam), Chauhan, G. (Ganesh), Yeo, R. (Robin), Boxall, R. (Ruth), Becker, J.T. (James), Stegle, O. (Oliver), Mather, R., Chouraki, V. (Vincent), Sun, Q. (Qi), Rose, L.M. (Lynda), Resnick, S.M. (Susan), Oldmeadow, C. (Christopher), Kirin, M. (Mirna), Wright, A. (Alan), Jonsdottir, M.K. (Maria K.), Au, R. (Rhoda), Becker, A. (Albert), Amin, N. (Najaf), Nalls, M.A. (Michael), Turner, S.T. (Stephen), Kardia, S.L.R. (Sharon), Oostra, B.A. (Ben), Windham, G. (Gwen), Coker, L.H. (Laura), Zhao, W. (Wei), Knopman, D.S. (David), Heiss, G. (Gerardo), Griswold, M.D. (Michael), Gottesman, R.F. (Rebecca), Vitart, V. (Veronique), Hastie, N. (Nick), Zgaga, L. (Lina), Rudan, I. (Igor), Polasek, O. (Ozren), Holliday, E.G. (Elizabeth), Schofield, P. (Peter), Choi, S.-H. (Seung-Hoan), Tanaka, T. (Toshiko), An, Y. (Yang), Perry, R.T. (Rodney T.), Kennedy, R.E. (Richard E.), Sale, M.M. (Michèle M.), Wang, J. (Jing), Wadley, V.G. (Virginia G.), Liewald, D.C. (David C.), Ridker, P.M. (Paul), Gow, A.J. (Alan J.), Pattie, A. (Alison), Starr, J.M. (John), Porteous, D.J. (David J.), Liu, X. (Xuan), Thomson, R. (Russell), Armstrong, N.J. (Nicola), Eiriksdottir, G. (Gudny), Assareh, A.A. (Arezoo), Kochan, N.A. (Nicole A.), Widen, E. (Elisabeth), Palotie, A. (Aarno), Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Vogler, C. (Christian), Swieten, J.C. (John) van, Shulman, L. (Lee), Beiser, A. (Alexa), Rotter, J.I. (Jerome I.), Schmidt, C.O. (Carsten O.), Hoffmann, W. (Wolfgang), Nöthen, M.M. (Markus M.), Ferrucci, L. (Luigi), Attia, J. (John), Uitterlinden, A.G. (André), Amouyel, P. (Philippe), Dartigues, J.-F. (Jean-François), Amieva, H. (Hélène), Räikkönen, K. (Katri), Garcia, M. (Melissa), Wolf, P.A. (Philip), Hofman, A. (Albert), Longstreth Jr, W.T., Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), DeJager, P.L. (Philip L.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Breteler, M.M.B. (Monique), Teumer, A. (Alexander), Lopez, O.L. (Oscar), Cichon, S. (Sven), Chasman, D.I. (Daniel), Grodstein, F. (Francine), Müller-Myhsok, B. (B.), Tzourio, C. (Christophe), Papassotiropoulos, A. (Andreas), Bennett, D.A. (David), Ikram, M.A. (Arfan), Deary, I.J. (Ian), Duijn, C.M. (Cornelia) van, Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), Mosley, T.H. (Thomas H.), Debette, S. (Stéphanie), Ibrahim-Verbaas, C.A. (Carla), Bressler, J. (Jan), Schuur, M. (Maaike), Smith, A.V. (Davey), Bis, J.C. (Joshua), Davies, G. (Gail), Wolf, C. (Christiane), Gudnason, V. (Vilmundur), Chibnik, L.B. (Lori), Yang, Q. (Qiong Fang), DeStefano, A.L. (Anita), De Quervain, D.J.F. (Dominique J.F.), Srikanth, V. (Velandai), Lahti, J. (Jari), Grabe, H.J. (Hans Jörgen), Smith, J.A. (Jennifer A), Priebe, L., Yu, L. (Lei), Karbalai, N. (Nazanin), Hayward, C. (Caroline), Wilson, J.F. (James F), Campbell, H. (Harry), Petrovic, K. (Katja), Fornage, M. (Myriam), Chauhan, G. (Ganesh), Yeo, R. (Robin), Boxall, R. (Ruth), Becker, J.T. (James), Stegle, O. (Oliver), Mather, R., Chouraki, V. (Vincent), Sun, Q. (Qi), Rose, L.M. (Lynda), Resnick, S.M. (Susan), Oldmeadow, C. (Christopher), Kirin, M. (Mirna), Wright, A. (Alan), Jonsdottir, M.K. (Maria K.), Au, R. (Rhoda), Becker, A. (Albert), Amin, N. (Najaf), Nalls, M.A. (Michael), Turner, S.T. (Stephen), Kardia, S.L.R. (Sharon), Oostra, B.A. (Ben), Windham, G. (Gwen), Coker, L.H. (Laura), Zhao, W. (Wei), Knopman, D.S. (David), Heiss, G. (Gerardo), Griswold, M.D. (Michael), Gottesman, R.F. (Rebecca), Vitart, V. (Veronique), Hastie, N. (Nick), Zgaga, L. (Lina), Rudan, I. (Igor), Polasek, O. (Ozren), Holliday, E.G. (Elizabeth), Schofield, P. (Peter), Choi, S.-H. (Seung-Hoan), Tanaka, T. (Toshiko), An, Y. (Yang), Perry, R.T. (Rodney T.), Kennedy, R.E. (Richard E.), Sale, M.M. (Michèle M.), Wang, J. (Jing), Wadley, V.G. (Virginia G.), Liewald, D.C. (David C.), Ridker, P.M. (Paul), Gow, A.J. (Alan J.), Pattie, A. (Alison), Starr, J.M. (John), Porteous, D.J. (David J.), Liu, X. (Xuan), Thomson, R. (Russell), Armstrong, N.J. (Nicola), Eiriksdottir, G. (Gudny), Assareh, A.A. (Arezoo), Kochan, N.A. (Nicole A.), Widen, E. (Elisabeth), Palotie, A. (Aarno), Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Vogler, C. (Christian), Swieten, J.C. (John) van, Shulman, L. (Lee), Beiser, A. (Alexa), Rotter, J.I. (Jerome I.), Schmidt, C.O. (Carsten O.), Hoffmann, W. (Wolfgang), Nöthen, M.M. (Markus M.), Ferrucci, L. (Luigi), Attia, J. (John), Uitterlinden, A.G. (André), Amouyel, P. (Philippe), Dartigues, J.-F. (Jean-François), Amieva, H. (Hélène), Räikkönen, K. (Katri), Garcia, M. (Melissa), Wolf, P.A. (Philip), Hofman, A. (Albert), Longstreth Jr, W.T., Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), DeJager, P.L. (Philip L.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Breteler, M.M.B. (Monique), Teumer, A. (Alexander), Lopez, O.L. (Oscar), Cichon, S. (Sven), Chasman, D.I. (Daniel), Grodstein, F. (Francine), Müller-Myhsok, B. (B.), Tzourio, C. (Christophe), Papassotiropoulos, A. (Andreas), Bennett, D.A. (David), Ikram, M.A. (Arfan), Deary, I.J. (Ian), Duijn, C.M. (Cornelia) van, Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), and Mosley, T.H. (Thomas H.)

Abstract

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. MET

Published
2015
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18. Genome-wide studies of verbal declarative memory in nondemented older people: The cohorts for heart and aging research in genomic epidemiology consortium

Author

Debette, S., Ibrahim Verbaas, C.A., Bressler, J., Schuur, M., Smith, A., Bis, J.C., Davies, G., Wolf, C., Gudnason, V., Chibnik, L.B., Yang, Q., DeStefano, A.L., de Quervain, D.J.F., Srikanth, V., Lahti, J., Grabe, H.J., Smith, J.A., Priebe, L., Yu, L., Karbalai, N., Hayward, C., Wilson, J.F., Campbell, H., Petrovic, K., Fornage, M., Chauhan, G., Yeo, R., Boxall, R., Becker, J., Stegle, O., Mather, K.A., Chouraki, V., Sun, Q., Rose, L.M., Resnick, S., Oldmeadow, C., Kirin, M., Wright, A.F., Jonsdottir, M.K., Au, R., Becker, A., Amin, N., Nalls, M.A., Turner, S.T., Kardia, S.L.R., Oostra, B., Windham, G., Coker, L.H., Zhao, W., Knopman, D.S., Heiss, G., Griswold, M.E., Gottesman, R.F., Vitart, V., Hastie, N.D., Zgaga, L., Rudan, I., Polasek, O., Holliday, E.G., Schofield, P., Choi, S.H., Tanaka, T., An, Y., Perry, R.T., Kennedy, R.E., Sale, M.M., Wang, J., Wadley, V.G., Liewald, D.C., Ridker, P.M., Gow, A.J., Pattie, A., Starr, J.M., Porteous, D., Liu, X., Thomson, R., Armstrong, N.J., Eiriksdottir, G., Assareh, A.A., Kochan, N.A., Widen, E., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Vogler, C., van Swieten, J.C., Shulman, J.M., Beiser, A., Rotter, J., Schmidt, C.O., Hoffmann, W., Nöthen, M.M., Ferrucci, L., Attia, J., Uitterlinden, A.G., Amouyel, P., Dartigues, J-F, Amieva, H., Räikkönen, K., Garcia, M., Wolf, P.A., Hofman, A., Longstreth, W.T., Psaty, B.M., Boerwinkle, E., DeJager, P.L., Sachdev, P.S., Schmidt, R., Breteler, M.M.B., Teumer, A., Lopez, O.L., Cichon, S., Chasman, D.I., Grodstein, F., Müller-Myhsok, B., Tzourio, C., Papassotiropoulos, A., Bennett, D.A., Ikram, M.A., Deary, I.J., van Duijn, C.M., Launer, L., Fitzpatrick, A.L., Seshadri, S., Mosley, T.H., Debette, S., Ibrahim Verbaas, C.A., Bressler, J., Schuur, M., Smith, A., Bis, J.C., Davies, G., Wolf, C., Gudnason, V., Chibnik, L.B., Yang, Q., DeStefano, A.L., de Quervain, D.J.F., Srikanth, V., Lahti, J., Grabe, H.J., Smith, J.A., Priebe, L., Yu, L., Karbalai, N., Hayward, C., Wilson, J.F., Campbell, H., Petrovic, K., Fornage, M., Chauhan, G., Yeo, R., Boxall, R., Becker, J., Stegle, O., Mather, K.A., Chouraki, V., Sun, Q., Rose, L.M., Resnick, S., Oldmeadow, C., Kirin, M., Wright, A.F., Jonsdottir, M.K., Au, R., Becker, A., Amin, N., Nalls, M.A., Turner, S.T., Kardia, S.L.R., Oostra, B., Windham, G., Coker, L.H., Zhao, W., Knopman, D.S., Heiss, G., Griswold, M.E., Gottesman, R.F., Vitart, V., Hastie, N.D., Zgaga, L., Rudan, I., Polasek, O., Holliday, E.G., Schofield, P., Choi, S.H., Tanaka, T., An, Y., Perry, R.T., Kennedy, R.E., Sale, M.M., Wang, J., Wadley, V.G., Liewald, D.C., Ridker, P.M., Gow, A.J., Pattie, A., Starr, J.M., Porteous, D., Liu, X., Thomson, R., Armstrong, N.J., Eiriksdottir, G., Assareh, A.A., Kochan, N.A., Widen, E., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Vogler, C., van Swieten, J.C., Shulman, J.M., Beiser, A., Rotter, J., Schmidt, C.O., Hoffmann, W., Nöthen, M.M., Ferrucci, L., Attia, J., Uitterlinden, A.G., Amouyel, P., Dartigues, J-F, Amieva, H., Räikkönen, K., Garcia, M., Wolf, P.A., Hofman, A., Longstreth, W.T., Psaty, B.M., Boerwinkle, E., DeJager, P.L., Sachdev, P.S., Schmidt, R., Breteler, M.M.B., Teumer, A., Lopez, O.L., Cichon, S., Chasman, D.I., Grodstein, F., Müller-Myhsok, B., Tzourio, C., Papassotiropoulos, A., Bennett, D.A., Ikram, M.A., Deary, I.J., van Duijn, C.M., Launer, L., Fitzpatrick, A.L., Seshadri, S., and Mosley, T.H.

Abstract

Background Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. Methods We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. Results rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. Conclusions This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Published
2015

37. PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations.

Author

Holmes MV, Kartsonaki C, Boxall R, Lin K, Reeve N, Yu C, Lv J, Bennett DA, Hill MR, Yang L, Chen Y, Du H, Turnbull I, Collins R, Clarke RJ, Tobin MD, Li L, Millwood IY, Chen Z, and Walters RG

Subjects
Humans, China epidemiology, Male, Female, Middle Aged, Aged, United Kingdom epidemiology, Risk Assessment, Prospective Studies, Risk Factors, Cholesterol, LDL blood, Cardiovascular Diseases genetics, Cardiovascular Diseases epidemiology, Biomarkers blood, Phenotype, East Asian People, Proprotein Convertase 9 genetics, Genetic Predisposition to Disease
Abstract

Aims: Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition., Methods and Results: In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 0.45-0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67-0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66-0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD: n = 6836; 1.38 (1.08-1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 × 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 × 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI., Conclusion: The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections., Lay Summary: Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease.PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD).These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication., Competing Interests: Conflict of interest: The Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford (CTSU) is co-ordinating a PCSK9 phase III cardiovascular outcome trial (ORION 4). M.V.H. has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of CTSU did not accept any personal payment. M.V.H. was at the University of Oxford when this work was conducted and is presently employed by 23andMe and holds stock in 23andMe., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2024
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38. Author Correction: New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Author

Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, Batini C, Fawcett KA, Song K, Sakornsakolpat P, Li X, Boxall R, Reeve NF, Obeidat M, Zhao JH, Wielscher M, Weiss S, Kentistou KA, Cook JP, Sun BB, Zhou J, Hui J, Karrasch S, Imboden M, Harris SE, Marten J, Enroth S, Kerr SM, Surakka I, Vitart V, Lehtimäki T, Allen RJ, Bakke PS, Beaty TH, Bleecker ER, Bossé Y, Brandsma CA, Chen Z, Crapo JD, Danesh J, DeMeo DL, Dudbridge F, Ewert R, Gieger C, Gulsvik A, Hansell AL, Hao K, Hoffman JD, Hokanson JE, Homuth G, Joshi PK, Joubert P, Langenberg C, Li X, Li L, Lin K, Lind L, Locantore N, Luan J, Mahajan A, Maranville JC, Murray A, Nickle DC, Packer R, Parker MM, Paynton ML, Porteous DJ, Prokopenko D, Qiao D, Rawal R, Runz H, Sayers I, Sin DD, Smith BH, Artigas MS, Sparrow D, Tal-Singer R, Timmers PRHJ, Van den Berge M, Whittaker JC, Woodruff PG, Yerges-Armstrong LM, Troyanskaya OG, Raitakari OT, Kähönen M, Polašek O, Gyllensten U, Rudan I, Deary IJ, Probst-Hensch NM, Schulz H, James AL, Wilson JF, Stubbe B, Zeggini E, Jarvelin MR, Wareham N, Silverman EK, Hayward C, Morris AP, Butterworth AS, Scott RA, Walters RG, Meyers DA, Cho MH, Strachan DP, Hall IP, Tobin MD, and Wain LV

Published
2024
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39. bubbleHeatmap: an R package for visualization of nightingale health metabolomics datasets.

Author

Boxall R, Holmes MV, and Walters RG

Abstract

Summary: We present bubbleHeatmap, an R plotting package which combines elements of a bubble plot and heatmap to conveniently display two numerical variables for each data point across a categorical two dimensional grid. This has particular advantages for visualizing the 251 metabolomic measures produced by the automated, high-throughput, 1 H-NMR-based platform provided by Nightingale Health, which includes 12 measures repeated across each of 14 lipoprotein subclasses. As these metabolomic profiles are currently available for large biobanks, we provide a figure template to aid the use of bubbleHeatmap in displaying results from analyses using these data., Availability and Implementation: https://cran.r-project.org/web/packages/bubbleHeatmap., Competing Interests: M.V.H. was at the University of Oxford when this work was conducted and is now an employee of 23andMe and holds stock in 23andMe., (© The Author(s) 2023. Published by Oxford University Press.)

Published
2023
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40. Response to comment on "Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics".

Author

Bovijn J, Krebs K, Chen CY, Boxall R, Censin JC, Ferreira T, Pulit SL, Glastonbury CA, Laber S, Millwood IY, Lin K, Li L, Chen Z, Milani L, Smith GD, Walters RG, Mägi R, Neale BM, Lindgren CM, and Holmes MV

Subjects
Human Genetics, Humans, Cardiovascular Diseases genetics
Abstract

Triangulation of evidence from clinical trials and human genetics suggests a potential excess risk of cardiovascular disease events arising from therapeutic inhibition of sclerostin.

Published
2021
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41. Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.

Author

Bovijn J, Krebs K, Chen CY, Boxall R, Censin JC, Ferreira T, Pulit SL, Glastonbury CA, Laber S, Millwood IY, Lin K, Li L, Chen Z, Milani L, Smith GD, Walters RG, Mägi R, Neale BM, Lindgren CM, and Holmes MV

Subjects
Bone Density, Human Genetics, Humans, Bone Density Conservation Agents, Fractures, Bone, Osteoporosis drug therapy, Osteoporosis genetics
Abstract

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2020
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42. Author Correction: New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Author

Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, Batini C, Fawcett KA, Song K, Sakornsakolpat P, Li X, Boxall R, Reeve NF, Obeidat M, Zhao JH, Wielscher M, Weiss S, Kentistou KA, Cook JP, Sun BB, Zhou J, Hui J, Karrasch S, Imboden M, Harris SE, Marten J, Enroth S, Kerr SM, Surakka I, Vitart V, Lehtimäki T, Allen RJ, Bakke PS, Beaty TH, Bleecker ER, Bossé Y, Brandsma CA, Chen Z, Crapo JD, Danesh J, DeMeo DL, Dudbridge F, Ewert R, Gieger C, Gulsvik A, Hansell AL, Hao K, Hoffman JD, Hokanson JE, Homuth G, Joshi PK, Joubert P, Langenberg C, Li X, Li L, Lin K, Lind L, Locantore N, Luan J, Mahajan A, Maranville JC, Murray A, Nickle DC, Packer R, Parker MM, Paynton ML, Porteous DJ, Prokopenko D, Qiao D, Rawal R, Runz H, Sayers I, Sin DD, Smith BH, Artigas MS, Sparrow D, Tal-Singer R, Timmers PRHJ, Van den Berge M, Whittaker JC, Woodruff PG, Yerges-Armstrong LM, Troyanskaya OG, Raitakari OT, Kähönen M, Polašek O, Gyllensten U, Rudan I, Deary IJ, Probst-Hensch NM, Schulz H, James AL, Wilson JF, Stubbe B, Zeggini E, Jarvelin MR, Wareham N, Silverman EK, Hayward C, Morris AP, Butterworth AS, Scott RA, Walters RG, Meyers DA, Cho MH, Strachan DP, Hall IP, Tobin MD, and Wain LV

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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43. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Author

Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, Batini C, Fawcett KA, Song K, Sakornsakolpat P, Li X, Boxall R, Reeve NF, Obeidat M, Zhao JH, Wielscher M, Weiss S, Kentistou KA, Cook JP, Sun BB, Zhou J, Hui J, Karrasch S, Imboden M, Harris SE, Marten J, Enroth S, Kerr SM, Surakka I, Vitart V, Lehtimäki T, Allen RJ, Bakke PS, Beaty TH, Bleecker ER, Bossé Y, Brandsma CA, Chen Z, Crapo JD, Danesh J, DeMeo DL, Dudbridge F, Ewert R, Gieger C, Gulsvik A, Hansell AL, Hao K, Hoffman JD, Hokanson JE, Homuth G, Joshi PK, Joubert P, Langenberg C, Li X, Li L, Lin K, Lind L, Locantore N, Luan J, Mahajan A, Maranville JC, Murray A, Nickle DC, Packer R, Parker MM, Paynton ML, Porteous DJ, Prokopenko D, Qiao D, Rawal R, Runz H, Sayers I, Sin DD, Smith BH, Soler Artigas M, Sparrow D, Tal-Singer R, Timmers PRHJ, Van den Berge M, Whittaker JC, Woodruff PG, Yerges-Armstrong LM, Troyanskaya OG, Raitakari OT, Kähönen M, Polašek O, Gyllensten U, Rudan I, Deary IJ, Probst-Hensch NM, Schulz H, James AL, Wilson JF, Stubbe B, Zeggini E, Jarvelin MR, Wareham N, Silverman EK, Hayward C, Morris AP, Butterworth AS, Scott RA, Walters RG, Meyers DA, Cho MH, Strachan DP, Hall IP, Tobin MD, and Wain LV

Subjects
Aged, Aged, 80 and over, Case-Control Studies, Female, Genome-Wide Association Study methods, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Risk Factors, Smoking genetics, Genetic Predisposition to Disease genetics, Lung physiopathology, Pulmonary Disease, Chronic Obstructive genetics
Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Published
2019
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44. Lipids, Lipoproteins, and Metabolites and Risk of Myocardial Infarction and Stroke.

Author

Holmes MV, Millwood IY, Kartsonaki C, Hill MR, Bennett DA, Boxall R, Guo Y, Xu X, Bian Z, Hu R, Walters RG, Chen J, Ala-Korpela M, Parish S, Clarke RJ, Peto R, Collins R, Li L, and Chen Z

Subjects
Adult, Aged, Biomarkers blood, Case-Control Studies, Cohort Studies, Female, Humans, Male, Middle Aged, Myocardial Infarction diagnosis, Prospective Studies, Risk Factors, Stroke diagnosis, Lipid Metabolism physiology, Lipids blood, Lipoproteins blood, Metabolomics methods, Myocardial Infarction blood, Stroke blood
Abstract

Background: Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes., Objectives: This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH)., Methods: In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker., Results: Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH., Conclusions: Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non-lipid-related metabolites associated with all 3 diseases., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2018
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45. Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults.

Author

Millwood IY, Bennett DA, Holmes MV, Boxall R, Guo Y, Bian Z, Yang L, Sansome S, Chen Y, Du H, Yu C, Hacker A, Reilly DF, Tan Y, Hill MR, Chen J, Peto R, Shen H, Collins R, Clarke R, Li L, Walters RG, and Chen Z

Subjects
Adult, Aged, Asian People ethnology, Asian People genetics, Cardiovascular Diseases ethnology, Cholesterol, HDL genetics, Cholesterol, HDL metabolism, Cholesterol, LDL genetics, Cholesterol, LDL metabolism, Female, Gene Frequency genetics, Genotype, Humans, Loss of Function Mutation genetics, Male, Middle Aged, Myocardial Infarction ethnology, Myocardial Infarction genetics, Prospective Studies, Rural Health, Stroke ethnology, Stroke genetics, Urban Health, Cardiovascular Diseases genetics, Cholesterol Ester Transfer Proteins genetics
Abstract

Importance: Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD)., Objective: To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes., Design, Setting, and Participants: This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries., Exposures: Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels., Main Outcomes and Measures: Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases., Results: Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003)., Conclusions and Relevance: CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.

Published
2018
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46. Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

Author

Debette S, Ibrahim Verbaas CA, Bressler J, Schuur M, Smith A, Bis JC, Davies G, Wolf C, Gudnason V, Chibnik LB, Yang Q, deStefano AL, de Quervain DJ, Srikanth V, Lahti J, Grabe HJ, Smith JA, Priebe L, Yu L, Karbalai N, Hayward C, Wilson JF, Campbell H, Petrovic K, Fornage M, Chauhan G, Yeo R, Boxall R, Becker J, Stegle O, Mather KA, Chouraki V, Sun Q, Rose LM, Resnick S, Oldmeadow C, Kirin M, Wright AF, Jonsdottir MK, Au R, Becker A, Amin N, Nalls MA, Turner ST, Kardia SL, Oostra B, Windham G, Coker LH, Zhao W, Knopman DS, Heiss G, Griswold ME, Gottesman RF, Vitart V, Hastie ND, Zgaga L, Rudan I, Polasek O, Holliday EG, Schofield P, Choi SH, Tanaka T, An Y, Perry RT, Kennedy RE, Sale MM, Wang J, Wadley VG, Liewald DC, Ridker PM, Gow AJ, Pattie A, Starr JM, Porteous D, Liu X, Thomson R, Armstrong NJ, Eiriksdottir G, Assareh AA, Kochan NA, Widen E, Palotie A, Hsieh YC, Eriksson JG, Vogler C, van Swieten JC, Shulman JM, Beiser A, Rotter J, Schmidt CO, Hoffmann W, Nöthen MM, Ferrucci L, Attia J, Uitterlinden AG, Amouyel P, Dartigues JF, Amieva H, Räikkönen K, Garcia M, Wolf PA, Hofman A, Longstreth WT Jr, Psaty BM, Boerwinkle E, DeJager PL, Sachdev PS, Schmidt R, Breteler MM, Teumer A, Lopez OL, Cichon S, Chasman DI, Grodstein F, Müller-Myhsok B, Tzourio C, Papassotiropoulos A, Bennett DA, Ikram MA, Deary IJ, van Duijn CM, Launer L, Fitzpatrick AL, Seshadri S, and Mosley TH Jr

Subjects
Aged, Aged, 80 and over, Apolipoproteins E genetics, Claudin-5 genetics, Cohort Studies, Female, Genome-Wide Association Study, Genotype, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, Proteins genetics, Proteoglycans genetics, Regression Analysis, Sulfotransferases genetics, Aging genetics, Memory Disorders genetics, Polymorphism, Single Nucleotide genetics, Verbal Learning physiology
Abstract

Background: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting., Methods: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults., Results: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism., Conclusions: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Published
2015
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47. Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder.

Author

Walker RM, Rybka J, Anderson SM, Torrance HS, Boxall R, Sussmann JE, Porteous DJ, McIntosh AM, and Evans KL

Subjects
Adolescent, Adult, Female, Humans, Male, MicroRNAs genetics, Young Adult, Bipolar Disorder genetics, Family Health, Gene Expression Regulation physiology, MicroRNAs metabolism
Abstract

Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment. We sought to establish whether altered miRNA expression might play a causative role in the development of BD by studying young, unmedicated relatives of individuals with BD, who are at a higher genetic risk of developing BD themselves (high-risk individuals). The expression of 20 miRNAs previously implicated in either BD or schizophrenia was measured by qRT-PCR in whole-blood samples from 34 high-risk and 46 control individuals. Three miRNAs, miR-15b, miR-132 and miR-652 were up-regulated in the high-risk individuals, consistent with previous reports of increased expression of these miRNAs in patients with schizophrenia. Our findings suggest that the altered expression of these miRNAs might represent a mechanism of genetic susceptibility for BD. Moreover, our observation of altered miRNA expression in the blood prior to the onset of illness provides hope that one day blood-based tests may aid in the risk-stratification and treatment of BD., (Copyright © 2015. Published by Elsevier Ltd.)

Published
2015
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48. DISC1 and Huntington's disease--overlapping pathways of vulnerability to neurological disorder?

Author

Boxall R, Porteous DJ, and Thomson PA

Subjects
Disease Susceptibility, Humans, Huntingtin Protein, Huntington Disease etiology, Nervous System Diseases etiology, Nuclear Proteins metabolism, Protein Binding, Huntington Disease metabolism, Nerve Tissue Proteins metabolism, Nervous System Diseases metabolism
Abstract

We re-annotated the interacting partners of the neuronal scaffold protein DISC1 using a knowledge-based approach that incorporated recent protein interaction data and published literature to. This revealed two highly connected networks. These networks feature cellular function and maintenance, and cell signaling. Of potentially greatest interest was the novel finding of a high degree of connectivity between the DISC1 scaffold protein, linked to psychiatric illness, and huntingtin, the protein which is mutated in Huntington's disease. The potential link between DISC1, huntingtin and their interacting partners may open new areas of research into the effects of pathway dysregulation in severe neurological disorders.

Published
2011
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50. Short term bioassay of cigarettes containing Cytrel tobacco supplement.

Author

Boxall RR, Gilpin GR, Bensilum S, and Lindsay DW

Subjects
Animals, Cellulose toxicity, Cilia drug effects, Epidermis drug effects, Hemolysis drug effects, Macrophages ultrastructure, Organ Culture Techniques, Pulmonary Alveoli pathology, Rats, Sulfhydryl Compounds metabolism, Cellulose analogs & derivatives, Smoking pathology, Trachea pathology
Abstract

The toxicity of smoke from cigarettes containing tobacco, Cytrel tobacco supplement, or mixtures of the 2 materials, was investigated using 6 short term test methods. The tests used were rat trachea organ culture and mouse skin thickening tests, which may provide information on carcinogenicity, a ciliatoxicity test, an alveolar macrophage viability test, a haemolysis assay and a thiol inactivation test to provide measures of irritant and cytotoxic effects. In each case a response to the smoke from cigarettes containing tobacco alone was detected, while the magnitude of this response declined as the proportion of tobacco supplement in the blend increased. The least response was found with smoke from cigarettes containing Cytrel tobacco supplement alone.

Published
1979

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