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Nat Genet. 2015 Nov;47(11):1282-93. doi: 10.1038/ng.3405. Epub 2015 Sep 21.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

Kato N1, Loh M2,3,4, Takeuchi F1, Verweij N5, Wang X6, Zhang W3,7, Kelly TN8, Saleheen D9,10,11, Lehne B3, Mateo Leach I5, Drong AW12, Abbott J13, Wahl S14,15,16, Tan ST7,17, Scott WR3,17, Campanella G3, Chadeau-Hyam M3, Afzal U3,7, Ahluwalia TS18,19,20, Bonder MJ21, Chen P6, Dehghan A22, Edwards TL23, Esko T24,25,26,27, Go MJ28, Harris SE29,30, Hartiala J31,32, Kasela S24, Kasturiratne A33, Khor CC6,34,35,36, Kleber ME37, Li H38, Mok ZY39, Nakatochi M40, Sapari NS39, Saxena R41, Stewart AF42,43, Stolk L44, Tabara Y45, Teh AL46, Wu Y47, Wu JY48,49, Zhang Y50,51, Aits I52, Da Silva Couto Alves A53, Das S53, Dorajoo R34, Hopewell JC54, Kim YK28, Koivula RW55, Luan J56, Lyytikäinen LP57,58, Nguyen QN59, Pereira MA60, Postmus I61,62, Raitakari OT63,64, Scannell Bryan M65, Scott RA56, Sorice R66, Tragante V67, Traglia M68,69, White J70, Yamamoto K71, Zhang Y72, Adair LS73, Ahmed A74, Akiyama K1, Asif R9, Aung T75, Barroso I76,77,78, Bjonnes A41, Braun TR79, Cai H80,81, Chang LC48, Chen CH48,49, Cheng CY6,35,75,82, Chong YS46,83, Collins R54, Courtney R80,81, Davies G30,84, Delgado G37, Do LD59, Doevendans PA67, Gansevoort RT85, Gao YT86, Grammer TB37, Grarup N18, Grewal J3,7, Gu D87, Wander GS88, Hartikainen AL89,90,91, Hazen SL92,93, He J94, Heng CK95, Hixson JE96, Hofman A22, Hsu C97, Huang W98, Husemoen LL99, Hwang JY28, Ichihara S100, Igase M101, Isono M1, Justesen JM18, Katsuya T102,103, Kibriya MG65, Kim YJ28, Kishimoto M104, Koh WP6,105, Kohara K101, Kumari M106, Kwek K107, Lee NR108,109, Lee J6, Liao J35,75, Lieb W52, Liewald DC30,84, Matsubara T110, Matsushita Y104, Meitinger T111,112, Mihailov E24, Milani L24, Mills R7, Mononen N57,58, Müller-Nurasyid M113,114,115, Nabika T116, Nakashima E117,118, Ng HK39, Nikus K119, Nutile T66, Ohkubo T120, Ohnaka K121, Parish S54, Paternoster L122, Peng H72, Peters A15,115, Pham ST59, Pinidiyapathirage MJ33, Rahman M74,123, Rakugi H103, Rolandsson O124, Rozario MA39, Ruggiero D66, Sala CF68, Sarju R88, Shimokawa K1, Snieder H125, Sparsø T18, Spiering W126, Starr JM30,127, Stott DJ128, Stram DO97, Sugiyama T129, Szymczak S130, Tang WH92,131, Tong L65, Trompet S132, Turjanmaa V133,134, Ueshima H135,136, Uitterlinden AG22,44, Umemura S137, Vaarasmaki M89,90,91, van Dam RM6, van Gilst WH5, van Veldhuisen DJ5, Viikari JS138,139, Waldenberger M14,15, Wang Y38, Wang A72, Wilson R14,15, Wong TY35,75, Xiang YB86, Yamaguchi S140, Ye X38, Young RD10, Young TL141,142, Yuan JM143, Zhou X144,145, Asselbergs FW67,146,147, Ciullo M66, Clarke R54, Deloukas P148,149, Franke A130, Franks PW55,124,150, Franks S151, Friedlander Y152, Gross MD153, Guo Z72, Hansen T18, Jarvelin MR2,53,91,154,155, Jørgensen T99, Jukema JW132,146,156, Kähönen M133,134, Kajio H104, Kivimaki M106, Lee JY157,158, Lehtimäki T57,58, Linneberg A99,159,160, Miki T101, Pedersen O18, Samani NJ161,162, Sørensen TI18,122,163, Takayanagi R164, Toniolo D68,165; BIOS-consortium; CARDIo GRAMplusCD; LifeLines Cohort Study; InterAct Consortium, Ahsan H65, Allayee H31,32, Chen YT48, Danesh J10,166, Deary IJ30,84, Franco OH22, Franke L21, Heijman BT167, Holbrook JD46, Isaacs A22, Kim BJ28, Lin X38, Liu J6,34, März W37,168,169, Metspalu A24, Mohlke KL47, Sanghera DK79, Shu XO80,81, van Meurs JB44, Vithana E35,75,141, Wickremasinghe AR33, Wijmenga C21, Wolffenbuttel BH170, Yokota M171, Zheng W80,81, Zhu D50,51, Vineis P3, Kyrtopoulos SA172, Kleinjans JC173, McCarthy MI12,174, Soong R39,175, Gieger C14,15, Scott J17, Teo YY6,34,75,176,177,178, He J8, Elliott P3, Tai ES6,102,179, van der Harst P5,21,146, Kooner JS7,17,180, Chambers JC3,7,180.

Author information

1
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
2
Institute of Health Sciences, University of Oulu, Oulu, Finland.
3
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
4
Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore.
5
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
6
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
7
Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.
8
Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
9
Center for Non-Communicable Diseases, Karachi, Pakistan.
10
Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
11
Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
12
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
13
Bioinformatics Support Service, Imperial College London, London, UK.
14
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
15
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
16
German Center for Diabetes Research (DZD), Neuherberg, Germany.
17
National Heart and Lung Institute, Imperial College London, London, UK.
18
Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
19
Copenhagen Prospective Studies on Asthma in Childhood (COSPAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
20
Steno Diabetes Center, Gentofte, Denmark.
21
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
22
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
23
Vanderbilt Epidemiology Center, Center for Human Genetics Research, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
24
Estonian Genome Center, University of Tartu, Tartu, Estonia.
25
Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA.
26
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
27
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
28
Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Republic of Korea.
29
Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and Medical Research Council (MRC) Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
30
Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
31
Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
32
Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
33
Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
34
Genome Institute of Singapore, A*STAR, Singapore.
35
Department of Ophthalmology, National University of Singapore, Singapore.
36
Department of Paediatrics, National University of Singapore, Singapore.
37
Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
38
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
39
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
40
Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
41
Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
42
University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ottawa, Ontario, Canada.
43
Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada.
44
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
45
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
46
Singapore Institute for Clinical Sciences (SICS), A*STAR, Singapore.
47
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
48
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
49
School of Chinese Medicine, China Medical University, Taichung, Taiwan.
50
State Key Laboratory of Medical Genetics, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
51
Shanghai Institute of Hypertension, Shanghai, China.
52
Institute of Epidemiology and Biobank popgen, Christian Albrechts University of Kiel, Kiel, Germany.
53
Department of Epidemiology and Biostatistics, MRC Health Protection Agency (PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
54
Clinical Trials Support Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
55
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.
56
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
57
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
58
Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
59
Vietnam National Heart Institute, Bach Mai Hospital, Hanoi, Vietnam.
60
School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
61
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
62
Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands.
63
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
64
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
65
Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
66
Institute of Genetics and Biophysics A Buzzati-Traverso, CNR, Naples, Italy.
67
Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
68
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
69
Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Burlo Garofolo', Trieste, Italy.
70
University College London Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK.
71
Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
72
Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China.
73
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
74
UChicago Research Bangladesh, Uttara, Dhaka, Bangladesh.
75
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
76
Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, UK.
77
National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
78
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
79
Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
80
Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.
81
Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
82
Centre for Quantitative Medicine, Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical School, Singapore.
83
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
84
Department of Psychology, University of Edinburgh, Edinburgh, UK.
85
Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
86
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
87
Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
88
Dayanand Medical College and Hospital Unit, Hero DMC Heart Institute, Ludhiana, India.
89
Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.
90
Medical Research Center, University of Oulu, Oulu, Finland.
91
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
92
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.
93
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
94
Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
95
Department of Paediatrics, Yong Loo Lin School of Medicine, Singapore.
96
Human Genetics Center, University of Texas School of Public Health at Houston, Houston, Texas, USA.
97
University of Southern California Keck School of Medicine, Los Angeles, California, USA.
98
Department of Genetics, Chinese National Human Genomic Center, Shanghai, China.
99
Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.
100
Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.
101
Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
102
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.
103
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.
104
National Center for Global Health and Medicine, Toyama, Japan.
105
Duke-National University of Singapore Graduate Medical School, Singapore.
106
Department of Epidemiology and Public Health, University College London, London, UK.
107
K.K. Women's and Children's Hospital, Singapore.
108
University of San Carlos Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines.
109
Department of Anthropology, Sociology and History, University of San Carlos, Cebu City, Philippines.
110
Department of Internal Medicine, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.
111
Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
112
Institute of Human Genetics, Technische Universität München, Munich, Germany.
113
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
114
Department of Medicine I, Ludwig Maximilians University Munich, Munich, Germany.
115
German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
116
Department of Functional Pathology, Shimane University Faculty of Medicine, Izumo, Japan.
117
Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
118
Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan.
119
Heart Centre, Department of Cardiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.
120
Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan.
121
Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
122
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
123
Research and Evaluation Division, Bangladesh Rehabilitation Assistance Committee (BRAC), Dhaka, Bangladesh.
124
Department of Public Health and Clinical Medicine, Section for Family Medicine, Umeå Universitet, Umeå, Sweden.
125
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
126
Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
127
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
128
Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
129
Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
130
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
131
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
132
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
133
Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
134
Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland.
135
Department of Health Science, Shiga University of Medical Science, Otsu, Japan.
136
Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.
137
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
138
Division of Medicine, Turku University Hospital, Turku, Finland.
139
Department of Medicine, University of Turku, Turku, Finland.
140
Third Department of Internal Medicine, Shimane University Faculty of Medicine, Izumo, Japan.
141
Neuroscience and Behavioural Disorders (NBD) Program, Duke-National University of Singapore Graduate Medical School, Singapore.
142
Duke Eye Center, Duke University Medical Center, Durham, North Carolina, USA.
143
Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
144
Bioinformatics Division, Tsinghua National Laboratory for Informatics Science and Technology (TNLIST), Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.
145
Department of Psychiatry, University of Hong Kong, Hong Kong.
146
Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of the Netherlands (ICIN)-Netherlands Heart Institute, Utrecht, the Netherlands.
147
Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
148
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
149
King Abdulaziz University, Jeddah, Saudi Arabia.
150
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
151
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, UK.
152
Hebrew University, School of Public Health, Jerusalem, Israel.
153
School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
154
Biocenter Oulu, University of Oulu, Oulu, Finland.
155
Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland.
156
ICIN, Utrecht, the Netherlands.
157
Ministry of Health and Welfare, Seoul, Republic of Korea.
158
THERAGEN ETEX Bio Institute, Suwon, Republic of Korea.
159
Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.
160
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
161
Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.
162
NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
163
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
164
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan.
165
Institute of Molecular Genetics, National Research Council (CNR), Pavia, Italy.
166
Wellcome Trust Sanger Institute, Hinxton, UK.
167
Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
168
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
169
Synlab Academy, Synlab Services, Mannheim, Germany.
170
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
171
Department of Genome Science, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.
172
National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
173
Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands.
174
Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
175
Department of Pathology, National University of Singapore, Singapore.
176
National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.
177
Life Sciences Institute, National University of Singapore, Singapore.
178
Department of Statistics and Applied Probability, National University of Singapore, Singapore.
179
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
180
Imperial College Healthcare NHS Trust, London, UK.

Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

PMID:
26390057
PMCID:
PMC4719169
DOI:
10.1038/ng.3405
[Indexed for MEDLINE]
Free PMC Article

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