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1. The involvement of non-B DNA forming sequences in mediating missense mutations, micro-deletions and micro-insertions in human inherited disease

Author

Kamat, M. A.

Subjects
572.8
Abstract

The involvement of the local DNA sequence features (repetitive elements capable of adopting non-B structures, hotspot motifs, mononucleotide runs and tandem repeats) and epigenetic marks in mediating germline missense and nonsense mutations, micro-deletions and micro-insertions causing human inherited disease and obtained from Human Gene Mutation Database (HGMD; http://www.hgmd.org) was studied in silico. A novel algorithm with a linear running time has been designed to detect the non-B DNA forming repeats in DNA sequences. The distributions of these repeats in the vicinity of mutations were analysed. We found that ~15% of missense mutations, ~12% of nonsense mutations, ~28% of micro-deletions and ~21% of micro-insertions occurred within direct repeats and is explicable by the formation/resolution/correction of non-B slipped structures. Several novel mutational mechanisms such as slipped strand mispairing/non-B slipped structure formation/DNA repair, non-B triplex formation/DNA repair and hairpin loop formation/DNA repair mechanisms have been proposed to explain single basepair substitutions leading to the formation of respectively exact direct, mirror and inverted repeats from inexact repeats. The role of CpG dinucleotides, CpHpG trinucleotides in mediating single base-pair substitutions and 83 known hotspot motifs together with other repetitive elements was studied in the context of micro-deletions and micro-insertions. We found that the number of single basepair missense and nonsense mutations (C>T and G>A) in CpG or CpHpG oligonucleotides was significantly (Fisher’s Exact test; p<2.37×10-120 higher than would have occurred by chance. Three DNA hotspot motifs, Chinese hamster scaffold attachment region motif WWWAAHAWWA, DNA polymerase α frameshift hotspot motif TCCCCC and its mirror image motif, were found to be overrepresented in both ± 20bp and ±2bp vicinity of micro-deletions and micro-insertions. Enrichment in the post-translational histone modification marks and binding sites (H3k4me3, H3k36me3, CTCF binding sites, DHSs) was found in the vicinity of all types of mutations analysed whereas histone modification mark H3k27me3 was overrepresented in the vicinity of missense and micro-lesion mutations. Thus, this study is a first systematic ascertainment of the involvement of non-B DNA forming sequences and epigenetic marks in mediating subtle mutations causing or associated with human inherited disease. The results shed light on the plausible underlying mutational mechanisms that involve non-B DNA forming repeats.

Published
2014

2. Phage predation and antibiotic exposure are inversely associated with disease severity and shape pathogen genetic diversity in cholera patients

Author

Madi, N., Cato, E. T., Sayeed, Md. Abu, Islam, K., Khabir, Md. I.UI., Bhuiyan, Md. T. R., Begum, Y., Rashid, M.M., Creasy-Marrazzo, A., Brinkley, L., Kamat, M., Cuénod, A., Bailey, L. S., Basso, K. B., Qadri, F., Khan, A. I., Shapiro, B. J., and Nelson, E. J.

Subjects
Article
Abstract

Nearly a century has passed since d’Hérelle and colleagues discovered phages that infect Vibrio cholerae and influence the clinical and epidemiologic trajectories of cholera outbreaks. Despite an increasingly detailed picture of the molecular mechanisms of resistance and counter-resistance that shape phage and bacterial interactions, we lack an understanding of how these interactions play out during natural infection, how they are affected by antibiotic exposure, and how they relate to clinical outcomes. To fill these gaps, we conducted a nation-wide study of diarrheal disease patients in the cholera-endemic setting of Bangladesh. A total of 2574 stool samples were collected from enrolled patients at hospital admission and screened for V. cholerae and virulent phages (ICP1, 2, or 3). All 282 culture positive samples, and an additional 107 culture negative but PCR positive samples, were analyzed by shotgun metagenomic sequencing. From these metagenomes, we estimated the relative abundances of V. cholerae , phages, and members of the gut microbiome, while accounting for antibiotic exposure determined by quantitative mass spectrometry. Consistent with d’Hérelle’s thesis, we observed higher phage to V. cholerae ratios in patients with mild dehydration, demonstrating in the modern era that phages are indicative of disease severity. Antibiotics were associated with less V. cholerae and with mild disease;; ciprofloxacin in particular was associated with several known antibiotic resistance genes. Phage resistance genes in the V. cholerae integrative conjugative element (ICE) were associated with lower phage to V. cholerae ratios. In the absence of detectable ICEs, phages shaped genetic diversity, selecting for nonsynonymous point mutations in the V. cholerae genome. Together, our results point to both antibiotics and phages as inverse correlates of disease severity, while also selecting for resistance genes or mutations within cholera patients.

Published
2023

4. Publisher Correction:Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author

Surendran, P, Feofanova, EV, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, AV, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Velez Edwards, DR, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, De Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, I, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, YV, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, AI, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Davey Smith, G, Boer, RAD, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, MI, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, JI, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, Van der Harst, P, Van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, DI, Levy, D, Newton-Cheh, C, Munroe, PB, Howson, JMM, and United Kingdom Research and Innovation

Subjects
Genetics & Heredity, Understanding Society Scientific Group, Science & Technology, business.industry, Published Erratum, Million Veteran Program, MEDLINE, Computational biology, 06 Biological Sciences, Biology, Blood pressure, Text mining, Meta-analysis, EPIC-InterAct, Genetics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business, Life Sciences & Biomedicine, EPIC-CVD, 11 Medical and Health Sciences, LifeLines Cohort Study, Developmental Biology
Abstract

In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article.

Published
2021

5. Genome-wide association studies reveal distinct genetic correlates and increased heritability of antimicrobial resistance in Vibrio cholerae under anaerobic conditions

Author

Creasy-Marrazzo, A., primary, Saber, M.M., additional, Kamat, M., additional, Bailey, L. S., additional, Brinkley, L., additional, Cato, E. T., additional, Begum, Y., additional, Rashid, M.M., additional, Khan, A. I., additional, Qadri, F., additional, Basso, K. B., additional, Shapiro, B. J., additional, and Nelson, E. J., additional

Published
2021
Full Text
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6. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author

Surendran, P., Feofanova, E. V., Lahrouchi, N., Ntalla, I., Karthikeyan, S., Cook, J., Chen, L., Mifsud, B., Yao, C., Kraja, A. T., Cartwright, J. H., Hellwege, J. N., Giri, A., Tragante, V., Thorleifsson, G., Liu, D. J., Prins, B. P., Stewart, I. D., Cabrera, C. P., Eales, J. M., Akbarov, A., Auer, P. L., Bielak, L. F., Bis, J. C., Braithwaite, V. S., Brody, J. A., Daw, E. W., Warren, H. R., Drenos, F., Nielsen, S. F., Faul, J. D., Fauman, E. B., Fava, C., Ferreira, T., Foley, C. N., Franceschini, N., Gao, H., Giannakopoulou, O., Giulianini, F., Gudbjartsson, D. F., Guo, X., Harris, S. E., Havulinna, A. S., Helgadottir, A., Huffman, J. E., Hwang, S. -J., Kanoni, S., Kontto, J., Larson, M. G., Li-Gao, R., Lindstrom, J., Lotta, L. A., Lu, Y., Luan, J., Mahajan, A., Malerba, G., Masca, N. G. D., Mei, H., Menni, C., Mook-Kanamori, D. O., Mosen-Ansorena, D., Muller-Nurasyid, M., Pare, G., Paul, D. S., Perola, M., Poveda, A., Rauramaa, R., Richard, M., Richardson, T. G., Sepulveda, N., Sim, X., Smith, A. V., Smith, J. A., Staley, J. R., Stanakova, A., Sulem, P., Theriault, S., Thorsteinsdottir, U., Trompet, S., Varga, T. V., Velez Edwards, D. R., Veronesi, G., Weiss, S., Willems, S. M., Yao, J., Young, R., Yu, B., Zhang, W., Zhao, J. -H., Zhao, W., Evangelou, E., Aeschbacher, S., Asllanaj, E., Blankenberg, S., Bonnycastle, L. L., Bork-Jensen, J., Brandslund, I., Braund, P. S., Burgess, S., Cho, K., Christensen, C., Connell, J., Mutsert, R., Dominiczak, A. F., Dorr, M., Eiriksdottir, G., Farmaki, A. -E., Gaziano, J. M., Grarup, N., Grove, M. L., Hallmans, G., Hansen, T., Have, C. T., Heiss, G., Jorgensen, M. E., Jousilahti, P., Kajantie, E., Kamat, M., Karajamaki, A. M., Karpe, F., Koistinen, H. A., Kovesdy, C. P., Kuulasmaa, K., Laatikainen, T., Lannfelt, L., Lee, I. -T., Lee, W. -J., de Boer, R. A., van der Harst, P., van der Meer, P., Verweij, N., Linneberg, A., Martin, L. W., Moitry, M., Nadkarni, G., Neville, M. J., Palmer, C. N. A., Papanicolaou, G. J., Pedersen, O., Peters, J., Poulter, N., Rasheed, A., Rasmussen, K. L., Rayner, N. W., Magi, R., Renstrom, F., Rettig, R., Rossouw, J., Schreiner, P. J., Sever, P. S., Sigurdsson, E. L., Skaaby, T., Sun, Y. V., Sundstrom, J., Thorgeirsson, G., Esko, T., Trabetti, E., Tsao, P. S., Tuomi, T., Turner, S. T., Tzoulaki, I., Vaartjes, I., Vergnaud, A. -C., Willer, C. J., Wilson, P. W. F., Witte, D. R., Yonova-Doing, E., Zhang, H., Aliya, N., Almgren, P., Amouyel, P., Asselbergs, F. W., Barnes, M. R., Blakemore, A. I., Boehnke, M., Bots, M. L., Bottinger, E. P., Buring, J. E., Chambers, J. C., Chen, Y. -D. I., Chowdhury, R., Conen, D., Correa, A., Davey Smith, G., Boer, R. A., Deary, I. J., Dedoussis, G., Deloukas, P., Di Angelantonio, E., Elliott, P., Butterworth, A. S., Danesh, J., Langenberg, C., Mccarthy, M. I., Franks, P. W., Rolandsson, O., Wareham, N. J., Felix, S. B., Ferrieres, J., Ford, I., Fornage, M., Franks, S., Frossard, P., Gambaro, G., Gaunt, T. R., Groop, L., Gudnason, V., Harris, T. B., Hayward, C., Hennig, B. J., Herzig, K. -H., Ingelsson, E., Tuomilehto, J., Jarvelin, M. -R., Jukema, J. W., Kardia, S. L. R., Kee, F., Kooner, J. S., Kooperberg, C., Launer, L. J., Lind, L., Loos, R. J. F., Majumder, A. S., Laakso, M., Melander, O., Mohlke, K. L., Murray, A. D., Nordestgaard, B. G., Orho-Melander, M., Packard, C. J., Padmanabhan, S., Palmas, W., Polasek, O., Porteous, D. J., Prentice, A. M., Province, M. A., Relton, C. L., Rice, K., Ridker, P. M., Rosendaal, F. R., Rotter, J. I., Rudan, I., Salomaa, V., Samani, N. J., Sattar, N., Sheu, W. H. -H., Smith, B. H., Soranzo, N., Spector, T. D., Starr, J. M., Sebert, S., Taylor, K. D., Lakka, T. A., Timpson, N. J., Tobin, M. D., Zeggini, E., Ramachandran, V. S., Virtamo, J., Volker, U., Weir, D. R., Charchar, F. J., Edwards, D. R. V., Edwards, T. L., Hung, A. M., O'Donnell, C. J., Tomaszewski, M., Caulfield, M. J., Holm, H., Lindgren, C. M., Liu, C., Manning, A. K., Morris, A. P., Morrison, A. C., Psaty, B. M., Saleheen, D., Stefansson, K., Boerwinkle, E., Chasman, D. I., Levy, D., Newton-Cheh, C., Munroe, P. B., Howson, J. M. M., Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), UNIVERSITY OF OULU, Epidemiology, Complex Disease Genetics, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, HUS Children and Adolescents, Lastentautien yksikkö, Clinicum, Children's Hospital, Helsinki University Hospital Area, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Endokrinologian yksikkö, Department of Public Health, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Feofanova, Elena V [0000-0003-1428-7199], Chasman, Daniel I [0000-0003-3357-0862], Munroe, Patricia B [0000-0002-4176-2947], Howson, Joanna MM [0000-0001-7618-0050], Apollo - University of Cambridge Repository, Cardiology, and ACS - Heart failure & arrhythmias

Subjects
Candidate gene, Blood Pressure, GATA5 Transcription Factor, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Hypertension, Mutation, Phospholipase C beta, Polymorphism, Single Nucleotide, LOCI, Genome-wide association study, 0302 clinical medicine, Polymorphism (computer science), genetics, GENOME-WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, COMMON VARIANTS, IDENTIFIES COMMON, RISK, FREQUENCY, TRAITS, HYPERTENSION, GENETICS, EPIC-CVD, 11 Medical and Health Sciences, health care economics and organizations, Genetics & Heredity, Genetics, 0303 health sciences, Million Veteran Program, 1184 Genetics, developmental biology, physiology, Single Nucleotide, humanities, 3. Good health, genetic association study, EPIC-InterAct, epidemiology, Life Sciences & Biomedicine, Understanding Society Scientific Group, hypertension, education, Biology, Article, 03 medical and health sciences, Mendelian randomization, Polymorphism, Allele frequency, Gene, 030304 developmental biology, Science & Technology, 06 Biological Sciences, meta-analysis, Minor allele frequency, genome-wide association studies, 3111 Biomedicine, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology
Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P

Published
2020

7. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author

Surendran, P, Feofanova, E, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, A, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Edwards, DRV, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, de Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, T, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, Y, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, A, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Smith, GD, de Boer, RA, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, M, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, J, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, van der Harst, P, van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, D, Levy, D, Newton-Cheh, C, Munroe, PB, Howson, JMM, Surendran, P, Feofanova, E, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, A, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Edwards, DRV, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, de Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, T, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, Y, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, A, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Smith, GD, de Boer, RA, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, M, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, J, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, van der Harst, P, van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, D, Levy, D, Newton-Cheh, C, Munroe, PB, and Howson, JMM

Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Published
2020

8. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author

Surendran, P. (Praveen), Feofanova, E. V. (Elena, V), Lahrouchi, N. (Najim), Ntalla, I. (Ioanna), Karthikeyan, S. (Savita), Cook, J. (James), Chen, L. (Lingyan), Mifsud, B. (Borbala), Yao, C. (Chen), Kraja, A. T. (Aldi T.), Cartwright, J. H. (James H.), Hellwege, J. N. (Jacklyn N.), Giri, A. (Ayush), Tragante, V. (Vinicius), Thorleifsson, G. (Gudmar), Liu, D. J. (Dajiang J.), Prins, B. P. (Bram P.), Stewart, I. D. (Isobel D.), Cabrera, C. P. (Claudia P.), Eales, J. M. (James M.), Akbarov, A. (Artur), Auer, P. L. (Paul L.), Bielak, L. F. (Lawrence F.), Bis, J. C. (Joshua C.), Braithwaite, V. S. (Vickie S.), Brody, J. A. (Jennifer A.), Daw, E. W. (E. Warwick), Warren, H. R. (Helen R.), Drenos, F. (Fotios), Nielsen, S. F. (Sune Fallgaard), Faul, J. D. (Jessica D.), Fauman, E. B. (Eric B.), Fava, C. (Cristiano), Ferreira, T. (Teresa), Foley, C. N. (Christopher N.), Franceschini, N. (Nora), Gao, H. (He), Giannakopoulou, O. (Olga), Giulianini, F. (Franco), Gudbjartsson, D. F. (Daniel F.), Guo, X. (Xiuqing), Harris, S. E. (Sarah E.), Havulinna, A. S. (Aki S.), Helgadottir, A. (Anna), Huffman, J. E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Kanoni, S. (Stavroula), Kontto, J. (Jukka), Larson, M. G. (Martin G.), Li-Gao, R. (Ruifang), Lindstrom, J. (Jaana), Lotta, L. A. (Luca A.), Lu, Y. (Yingchang), Luan, J. (Jian'an), Mahajan, A. (Anubha), Malerba, G. (Giovanni), Masca, N. G. (Nicholas G. D.), Mei, H. (Hao), Menni, C. (Cristina), Mook-Kanamori, D. O. (Dennis O.), Mosen-Ansorena, D. (David), Muller-Nurasyid, M. (Martina), Pare, G. (Guillaume), Paul, D. S. (Dirk S.), Perola, M. (Markus), Poveda, A. (Alaitz), Rauramaa, R. (Rainer), Richard, M. (Melissa), Richardson, T. G. (Tom G.), Sepulveda, N. (Nuno), Sim, X. (Xueling), Smith, A. V. (Albert, V), Smith, J. A. (Jennifer A.), Staley, J. R. (James R.), Stanakova, A. (Alena), Sulem, P. (Patrick), Theriault, S. (Sebastien), Thorsteinsdottir, U. (Unnur), Trompet, S. (Stella), Varga, T. V. (Tibor V.), Edwards, D. R. (Digna R. Velez), Veronesi, G. (Giovanni), Weiss, S. (Stefan), Willems, S. M. (Sara M.), Yao, J. (Jie), Young, R. (Robin), Yu, B. (Bing), Zhang, W. (Weihua), Zhao, J.-H. (Jing-Hua), Zhao, W. (Wei), Evangelou, E. (Evangelos), Aeschbacher, S. (Stefanie), Asllanaj, E. (Eralda), Blankenberg, S. (Stefan), Bonnycastle, L. L. (Lori L.), Bork-Jensen, J. (Jette), Brandslund, I. (Ivan), Braund, P. S. (Peter S.), Burgess, S. (Stephen), Cho, K. (Kelly), Christensen, C. (Cramer), Connell, J. (John), de Mutsert, R. (Renee), Dominiczak, A. F. (Anna F.), Dorr, M. (Marcus), Eiriksdottir, G. (Gudny), Farmaki, A.-E. (Aliki-Eleni), Gaziano, J. M. (J. Michael), Grarup, N. (Niels), Grove, M. L. (Megan L.), Hallmans, G. (Goran), Hansen, T. (Torben), Have, C. T. (Christian T.), Heiss, G. (Gerardo), Jorgensen, M. E. (Marit E.), Jousilahti, P. (Pekka), Kajantie, E. (Eero), Kamat, M. (Mihir), Karajamaki, A. (AnneMari), Karpe, F. (Fredrik), Koistinen, H. A. (Heikki A.), Kovesdy, C. P. (Csaba P.), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Lannfelt, L. (Lars), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Linneberg, A. (Allan), Martin, L. W. (Lisa W.), Moitry, M. (Marie), Nadkarni, G. (Girish), Neville, M. J. (Matt J.), Palmer, C. N. (Colin N. A.), Papanicolaou, G. J. (George J.), Pedersen, O. (Oluf), Peters, J. (James), Poulter, N. (Neil), Rasheed, A. (Asif), Rasmussen, K. L. (Katrine L.), Rayner, N. W. (N. William), Magi, R. (Reedik), Renstrom, F. (Frida), Rettig, R. (Rainer), Rossouw, J. (Jacques), Schreiner, P. J. (Pamela J.), Sever, P. S. (Peter S.), Sigurdsson, E. L. (Emil L.), Skaaby, T. (Tea), Sun, Y. V. (Yan, V), Sundstrom, J. (Johan), Thorgeirsson, G. (Gudmundur), Esko, T. (Tonu), Trabetti, E. (Elisabetta), Tsao, P. S. (Philip S.), Tuomi, T. (Tiinamaija), Turner, S. T. (Stephen T.), Tzoulaki, I. (Ioanna), Vaartjes, I. (Ilonca), Vergnaud, A.-C. (Anne-Claire), Willer, C. J. (Cristen J.), Wilson, P. W. (Peter W. F.), Witte, D. R. (Daniel R.), Yonova-Doing, E. (Ekaterina), Zhang, H. (He), Aliya, N. (Naheed), Almgren, P. (Peter), Amouyel, P. (Philippe), Asselbergs, F. W. (Folkert W.), Barnes, M. R. (Michael R.), Blakemore, A. I. (Alexandra, I), Boehnke, M. (Michael), Bots, M. L. (Michiel L.), Bottinger, E. P. (Erwin P.), Buring, J. E. (Julie E.), Chambers, J. C. (John C.), Chen, Y. I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Conen, D. (David), Correa, A. (Adolfo), Smith, G. D. (George Davey), de Boer, R. A. (Rudolf A.), Deary, I. J. (Ian J.), Dedoussis, G. (George), Deloukas, P. (Panos), Di Angelantonio, E. (Emanuele), Elliott, P. (Paul), Felix, S. B. (Stephan B.), Ferrieres, J. (Jean), Ford, I. (Ian), Fornage, M. (Myriam), Franks, P. W. (Paul W.), Franks, S. (Stephen), Frossard, P. (Philippe), Gambaro, G. (Giovanni), Gaunt, T. R. (Tom R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Harris, T. B. (Tamara B.), Hayward, C. (Caroline), Hennig, B. J. (Branwen J.), Herzig, K.-H. (Karl-Heinz), Ingelsson, E. (Erik), Tuomilehto, J. (Jaakko), Järvelin, M.-R. (Marjo-Riitta), Jukema, J. W. (J. Wouter), Kardia, S. L. (Sharon L. R.), Kee, F. (Frank), Kooner, J. S. (Jaspal S.), Kooperberg, C. (Charles), Launer, L. J. (Lenore J.), Lind, L. (Lars), Loos, R. J. (Ruth J. F.), Majumder, A. A. (Abdulla Al Shafi), Laakso, M. (Markku), McCarthy, M. I. (Mark, I), Melander, O. (Olle), Mohlke, K. L. (Karen L.), Murray, A. D. (Alison D.), Nordestgaard, B. G. (Borge Gronne), Orho-Melander, M. (Marju), Packard, C. J. (Chris J.), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Polasek, O. (Ozren), Porteous, D. J. (David J.), Prentice, A. M. (Andrew M.), Province, M. A. (Michael A.), Relton, C. L. (Caroline L.), Rice, K. (Kenneth), Ridker, P. M. (Paul M.), Rolandsson, O. (Olov), Rosendaal, F. R. (Frits R.), Rotter, J. I. (Jerome, I), Rudan, I. (Igor), Salomaa, V. (Veikko), Samani, N. J. (Nilesh J.), Sattar, N. (Naveed), Sheu, W. H. (Wayne H-H), Smith, B. H. (Blair H.), Soranzo, N. (Nicole), Spector, T. D. (Timothy D.), Starr, J. M. (John M.), Sebert, S. (Sylvain), Taylor, K. D. (Kent D.), Lakka, T. A. (Timo A.), Timpson, N. J. (Nicholas J.), Tobin, M. D. (Martin D.), van der Harst, P. (Pim), van der Meer, P. (Peter), Ramachandran, V. S. (Vasan S.), Verweij, N. (Niek), Virtamo, J. (Jarmo), Volker, U. (Uwe), Weir, D. R. (David R.), Zeggini, E. (Eleftheria), Charchar, F. J. (Fadi J.), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Tomaszewski, M. (Maciej), Butterworth, A. S. (Adam S.), Caulfield, M. J. (Mark J.), Danesh, J. (John), Edwards, T. L. (Todd L.), Holm, H. (Hilma), Hung, A. M. (Adriana M.), Lindgren, C. M. (Cecilia M.), Liu, C. (Chunyu), Manning, A. K. (Alisa K.), Morris, A. P. (Andrew P.), Morrison, A. C. (Alanna C.), O'Donnell, C. J. (Christopher J.), Psaty, B. M. (Bruce M.), Saleheen, D. (Danish), Stefansson, K. (Kari), Boerwinkle, E. (Eric), Chasman, D. I. (Daniel, I), Levy, D. (Daniel), Newton-Cheh, C. (Christopher), Munroe, P. B. (Patricia B.), Howson, J. M. (Joanna M. M.), Surendran, P. (Praveen), Feofanova, E. V. (Elena, V), Lahrouchi, N. (Najim), Ntalla, I. (Ioanna), Karthikeyan, S. (Savita), Cook, J. (James), Chen, L. (Lingyan), Mifsud, B. (Borbala), Yao, C. (Chen), Kraja, A. T. (Aldi T.), Cartwright, J. H. (James H.), Hellwege, J. N. (Jacklyn N.), Giri, A. (Ayush), Tragante, V. (Vinicius), Thorleifsson, G. (Gudmar), Liu, D. J. (Dajiang J.), Prins, B. P. (Bram P.), Stewart, I. D. (Isobel D.), Cabrera, C. P. (Claudia P.), Eales, J. M. (James M.), Akbarov, A. (Artur), Auer, P. L. (Paul L.), Bielak, L. F. (Lawrence F.), Bis, J. C. (Joshua C.), Braithwaite, V. S. (Vickie S.), Brody, J. A. (Jennifer A.), Daw, E. W. (E. Warwick), Warren, H. R. (Helen R.), Drenos, F. (Fotios), Nielsen, S. F. (Sune Fallgaard), Faul, J. D. (Jessica D.), Fauman, E. B. (Eric B.), Fava, C. (Cristiano), Ferreira, T. (Teresa), Foley, C. N. (Christopher N.), Franceschini, N. (Nora), Gao, H. (He), Giannakopoulou, O. (Olga), Giulianini, F. (Franco), Gudbjartsson, D. F. (Daniel F.), Guo, X. (Xiuqing), Harris, S. E. (Sarah E.), Havulinna, A. S. (Aki S.), Helgadottir, A. (Anna), Huffman, J. E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Kanoni, S. (Stavroula), Kontto, J. (Jukka), Larson, M. G. (Martin G.), Li-Gao, R. (Ruifang), Lindstrom, J. (Jaana), Lotta, L. A. (Luca A.), Lu, Y. (Yingchang), Luan, J. (Jian'an), Mahajan, A. (Anubha), Malerba, G. (Giovanni), Masca, N. G. (Nicholas G. D.), Mei, H. (Hao), Menni, C. (Cristina), Mook-Kanamori, D. O. (Dennis O.), Mosen-Ansorena, D. (David), Muller-Nurasyid, M. (Martina), Pare, G. (Guillaume), Paul, D. S. (Dirk S.), Perola, M. (Markus), Poveda, A. (Alaitz), Rauramaa, R. (Rainer), Richard, M. (Melissa), Richardson, T. G. (Tom G.), Sepulveda, N. (Nuno), Sim, X. (Xueling), Smith, A. V. (Albert, V), Smith, J. A. (Jennifer A.), Staley, J. R. (James R.), Stanakova, A. (Alena), Sulem, P. (Patrick), Theriault, S. (Sebastien), Thorsteinsdottir, U. (Unnur), Trompet, S. (Stella), Varga, T. V. (Tibor V.), Edwards, D. R. (Digna R. Velez), Veronesi, G. (Giovanni), Weiss, S. (Stefan), Willems, S. M. (Sara M.), Yao, J. (Jie), Young, R. (Robin), Yu, B. (Bing), Zhang, W. (Weihua), Zhao, J.-H. (Jing-Hua), Zhao, W. (Wei), Evangelou, E. (Evangelos), Aeschbacher, S. (Stefanie), Asllanaj, E. (Eralda), Blankenberg, S. (Stefan), Bonnycastle, L. L. (Lori L.), Bork-Jensen, J. (Jette), Brandslund, I. (Ivan), Braund, P. S. (Peter S.), Burgess, S. (Stephen), Cho, K. (Kelly), Christensen, C. (Cramer), Connell, J. (John), de Mutsert, R. (Renee), Dominiczak, A. F. (Anna F.), Dorr, M. (Marcus), Eiriksdottir, G. (Gudny), Farmaki, A.-E. (Aliki-Eleni), Gaziano, J. M. (J. Michael), Grarup, N. (Niels), Grove, M. L. (Megan L.), Hallmans, G. (Goran), Hansen, T. (Torben), Have, C. T. (Christian T.), Heiss, G. (Gerardo), Jorgensen, M. E. (Marit E.), Jousilahti, P. (Pekka), Kajantie, E. (Eero), Kamat, M. (Mihir), Karajamaki, A. (AnneMari), Karpe, F. (Fredrik), Koistinen, H. A. (Heikki A.), Kovesdy, C. P. (Csaba P.), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Lannfelt, L. (Lars), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Linneberg, A. (Allan), Martin, L. W. (Lisa W.), Moitry, M. (Marie), Nadkarni, G. (Girish), Neville, M. J. (Matt J.), Palmer, C. N. (Colin N. A.), Papanicolaou, G. J. (George J.), Pedersen, O. (Oluf), Peters, J. (James), Poulter, N. (Neil), Rasheed, A. (Asif), Rasmussen, K. L. (Katrine L.), Rayner, N. W. (N. William), Magi, R. (Reedik), Renstrom, F. (Frida), Rettig, R. (Rainer), Rossouw, J. (Jacques), Schreiner, P. J. (Pamela J.), Sever, P. S. (Peter S.), Sigurdsson, E. L. (Emil L.), Skaaby, T. (Tea), Sun, Y. V. (Yan, V), Sundstrom, J. (Johan), Thorgeirsson, G. (Gudmundur), Esko, T. (Tonu), Trabetti, E. (Elisabetta), Tsao, P. S. (Philip S.), Tuomi, T. (Tiinamaija), Turner, S. T. (Stephen T.), Tzoulaki, I. (Ioanna), Vaartjes, I. (Ilonca), Vergnaud, A.-C. (Anne-Claire), Willer, C. J. (Cristen J.), Wilson, P. W. (Peter W. F.), Witte, D. R. (Daniel R.), Yonova-Doing, E. (Ekaterina), Zhang, H. (He), Aliya, N. (Naheed), Almgren, P. (Peter), Amouyel, P. (Philippe), Asselbergs, F. W. (Folkert W.), Barnes, M. R. (Michael R.), Blakemore, A. I. (Alexandra, I), Boehnke, M. (Michael), Bots, M. L. (Michiel L.), Bottinger, E. P. (Erwin P.), Buring, J. E. (Julie E.), Chambers, J. C. (John C.), Chen, Y. I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Conen, D. (David), Correa, A. (Adolfo), Smith, G. D. (George Davey), de Boer, R. A. (Rudolf A.), Deary, I. J. (Ian J.), Dedoussis, G. (George), Deloukas, P. (Panos), Di Angelantonio, E. (Emanuele), Elliott, P. (Paul), Felix, S. B. (Stephan B.), Ferrieres, J. (Jean), Ford, I. (Ian), Fornage, M. (Myriam), Franks, P. W. (Paul W.), Franks, S. (Stephen), Frossard, P. (Philippe), Gambaro, G. (Giovanni), Gaunt, T. R. (Tom R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Harris, T. B. (Tamara B.), Hayward, C. (Caroline), Hennig, B. J. (Branwen J.), Herzig, K.-H. (Karl-Heinz), Ingelsson, E. (Erik), Tuomilehto, J. (Jaakko), Järvelin, M.-R. (Marjo-Riitta), Jukema, J. W. (J. Wouter), Kardia, S. L. (Sharon L. R.), Kee, F. (Frank), Kooner, J. S. (Jaspal S.), Kooperberg, C. (Charles), Launer, L. J. (Lenore J.), Lind, L. (Lars), Loos, R. J. (Ruth J. F.), Majumder, A. A. (Abdulla Al Shafi), Laakso, M. (Markku), McCarthy, M. I. (Mark, I), Melander, O. (Olle), Mohlke, K. L. (Karen L.), Murray, A. D. (Alison D.), Nordestgaard, B. G. (Borge Gronne), Orho-Melander, M. (Marju), Packard, C. J. (Chris J.), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Polasek, O. (Ozren), Porteous, D. J. (David J.), Prentice, A. M. (Andrew M.), Province, M. A. (Michael A.), Relton, C. L. (Caroline L.), Rice, K. (Kenneth), Ridker, P. M. (Paul M.), Rolandsson, O. (Olov), Rosendaal, F. R. (Frits R.), Rotter, J. I. (Jerome, I), Rudan, I. (Igor), Salomaa, V. (Veikko), Samani, N. J. (Nilesh J.), Sattar, N. (Naveed), Sheu, W. H. (Wayne H-H), Smith, B. H. (Blair H.), Soranzo, N. (Nicole), Spector, T. D. (Timothy D.), Starr, J. M. (John M.), Sebert, S. (Sylvain), Taylor, K. D. (Kent D.), Lakka, T. A. (Timo A.), Timpson, N. J. (Nicholas J.), Tobin, M. D. (Martin D.), van der Harst, P. (Pim), van der Meer, P. (Peter), Ramachandran, V. S. (Vasan S.), Verweij, N. (Niek), Virtamo, J. (Jarmo), Volker, U. (Uwe), Weir, D. R. (David R.), Zeggini, E. (Eleftheria), Charchar, F. J. (Fadi J.), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Tomaszewski, M. (Maciej), Butterworth, A. S. (Adam S.), Caulfield, M. J. (Mark J.), Danesh, J. (John), Edwards, T. L. (Todd L.), Holm, H. (Hilma), Hung, A. M. (Adriana M.), Lindgren, C. M. (Cecilia M.), Liu, C. (Chunyu), Manning, A. K. (Alisa K.), Morris, A. P. (Andrew P.), Morrison, A. C. (Alanna C.), O'Donnell, C. J. (Christopher J.), Psaty, B. M. (Bruce M.), Saleheen, D. (Danish), Stefansson, K. (Kari), Boerwinkle, E. (Eric), Chasman, D. I. (Daniel, I), Levy, D. (Daniel), Newton-Cheh, C. (Christopher), Munroe, P. B. (Patricia B.), and Howson, J. M. (Joanna M. M.)

Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 x 10(⁻⁸)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets., Correction A Publisher Correction to this article was published on 16 March 2021.

Published
2020

21. Unexpected findings from a large Asian HCV real life study

Author

Lim, S.G., primary, Phyo, W.W., additional, Shah, S., additional, Win, K.M., additional, Hamid, S.S., additional, Piratvisuth, T., additional, Tan, S.S., additional, Dan, Y.Y., additional, Lee, Y.M., additional, Ahmed, T., additional, Yang, W.L., additional, Chen, K.P., additional, Kamat, M., additional, Wadhawan, M., additional, Madan, K., additional, Mehta, R., additional, Shukla, A., additional, Dhore, P., additional, Eapen, C.E., additional, Abraham, P., additional, Tyagi, S., additional, Koshy, A., additional, Aung, H.B., additional, Jafri, W., additional, Abid, S., additional, Arisar, F.A.Q., additional, Tanwandee, T., additional, Yin, T.P., additional, Tee, H.P., additional, Said, R.B.H.M., additional, Goh, K.L., additional, Ho, S.H., additional, Mohamed, R., additional, and Bakar, N.A., additional

Published
2018
Full Text
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22. On a concurrent element-by-element preconditioned conjugate gradient algorithm for multiple load cases

Author

Watson, Brian and Kamat, M. P

Subjects
Computer Programming And Software
Abstract

Element-by-element preconditioned conjugate gradient (EBE-PCG) algorithms have been advocated for use in parallel/vector processing environments as being superior to the conventional LDL(exp T) decomposition algorithm for single load cases. Although there may be some advantages in using such algorithms for a single load case, when it comes to situations involving multiple load cases, the LDL(exp T) decomposition algorithm would appear to be decidedly more cost-effective. The authors have outlined an EBE-PCG algorithm suitable for multiple load cases and compared its effectiveness to the highly efficient LDL(exp T) decomposition scheme. The proposed algorithm offers almost no advantages over the LDL(exp T) algorithm for the linear problems investigated on the Alliant FX/8. However, there may be some merit in the algorithm in solving nonlinear problems with load incrementation, but that remains to be investigated.

Published
1990

33. The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Author

Astle, W.J., Elding, H., Jiang, T., Allen, D., Ruklisa, D., Mann, A.L., Mead, D., Bouman, H., Riveros-Mckay, F., Kostadima, M.A., Lambourne, J.J., Sivapalaratnam, S., Downes, K., Kundu, K., Bomba, L., Berentsen, K., Bradley, J.R., Daugherty, L.C., Delaneau, O., Freson, K., Garner, S.F., Grassi, L., Guerrero, J., Haimel, M., Janssen-Megens, E.M., Kaan, A., Kamat, M., Kim, B., Mandoli, A., Marchini, J., Martens, J.H.A., Meacham, S., Megy, K., O'Connell, J., Petersen, R., Sharifi, N., Sheard, S.M., Staley, J.R., Tuna, S., Ent, M. van der, Walter, K., Wang, S., Wheeler, E., Wilder, S.P., Iotchkova, V., Moore, C., Sambrook, J., Stunnenberg, H.G., Di Angelantonio, E., Kaptoge, S., Kuijpers, T.W., Carrillo-de-Santa-Pau, E., Juan, D., Rico, D., Valencia, A., Chen, L, Ge, B., Vasquez, L., Kwan, T., Garrido-Martin, D., Watt, S., Yang, Y., Guigo, R., Beck, S., Paul, D.S., Pastinen, T., Bujold, D., Bourque, G., Frontini, M., Danesh, J., Roberts, D.J., Ouwehand, W.H., Butterworth, A.S., Soranzo, N., Astle, W.J., Elding, H., Jiang, T., Allen, D., Ruklisa, D., Mann, A.L., Mead, D., Bouman, H., Riveros-Mckay, F., Kostadima, M.A., Lambourne, J.J., Sivapalaratnam, S., Downes, K., Kundu, K., Bomba, L., Berentsen, K., Bradley, J.R., Daugherty, L.C., Delaneau, O., Freson, K., Garner, S.F., Grassi, L., Guerrero, J., Haimel, M., Janssen-Megens, E.M., Kaan, A., Kamat, M., Kim, B., Mandoli, A., Marchini, J., Martens, J.H.A., Meacham, S., Megy, K., O'Connell, J., Petersen, R., Sharifi, N., Sheard, S.M., Staley, J.R., Tuna, S., Ent, M. van der, Walter, K., Wang, S., Wheeler, E., Wilder, S.P., Iotchkova, V., Moore, C., Sambrook, J., Stunnenberg, H.G., Di Angelantonio, E., Kaptoge, S., Kuijpers, T.W., Carrillo-de-Santa-Pau, E., Juan, D., Rico, D., Valencia, A., Chen, L, Ge, B., Vasquez, L., Kwan, T., Garrido-Martin, D., Watt, S., Yang, Y., Guigo, R., Beck, S., Paul, D.S., Pastinen, T., Bujold, D., Bourque, G., Frontini, M., Danesh, J., Roberts, D.J., Ouwehand, W.H., Butterworth, A.S., and Soranzo, N.

Abstract

Contains fulltext : 163344.pdf (Publisher’s version ) (Open Access)

Published
2016

37. THU-334 - Unexpected findings from a large Asian HCV real life study

Author

Lim, S.G., Phyo, W.W., Shah, S., Win, K.M., Hamid, S.S., Piratvisuth, T., Tan, S.S., Dan, Y.Y., Lee, Y.M., Ahmed, T., Yang, W.L., Chen, K.P., Kamat, M., Wadhawan, M., Madan, K., Mehta, R., Shukla, A., Dhore, P., Eapen, C.E., Abraham, P., Tyagi, S., Koshy, A., Aung, H.B., Jafri, W., Abid, S., Arisar, F.A.Q., Tanwandee, T., Yin, T.P., Tee, H.P., Said, R.B.H.M., Goh, K.L., Ho, S.H., Mohamed, R., and Bakar, N.A.

Published
2018
Full Text
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44. The impact of cisplat based chemotherapy on advanced ovarian cancer

Author

Prasad G, Dalal A, Tongaonkar H, Chatterjee S, and Kamat M

Subjects
Ovarian Neoplasms, administration & dosage, lcsh:R, lcsh:Medicine, drug therapy, surgery, Survival Rate, Methotrexate, Treatment Outcome, Doxorubicin, Antineoplastic Combined Chemotherapy Protocols, Comparative Study, Female, pathology, Fluorouracil, Cisplatin, Cyclophosphamide, Human
Abstract

Cisplatinum based chemotherapy has become the standard treatment for ovarian cancers due to its proved superiority over non-cisplat based regimes. However, the therapeutic impact of cisplat based regimes compared to cheaper non-cisplatinum based regimes is questionable when multiple variables such as residual disease, histologic type, grade are introduced. This report is a study of 110 Stage III ovarian cancer patients from 1985-89, with cisplat (n = 69) and non cisplat (n = 41) based chemotherapy. The results of both regimes with reference to the multiple variable factors are presented. We conclude that cisplat based regimes appear to be superior to non-cisplat based regimes except probably in poorly differentiated ovarian tumors where the results were similar with either regimen.

Published
1995

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