近日一个大型国际研究小组利用整合分析(meta-analysis)方法发现了几十个从前已确定和未确定的与人类身高相关的位点，研究论文发表在12月31日的《美国人类遗传学杂志》（American Journal of Human Genetics）上。
研究人员从大约50个研究中收集了超过10万人的所谓“基因中心”基因型信息和身高数据，发现了64个与人类身高相关的DNA位点，其中包括了几个过去在全基因组分析中未发现的罕见变异。
“大样本量及密集的遗传覆盖率包括低频率SNPs提高了鉴别微小效应变异的能力，使得我们能够鉴定以前未报道的基因与身高之间的联系，”共同作者、费城儿童医院的遗传学研究人员Brendan Keating说道。
过去的研究表明个体的身高受到其所在环境以及日照等多因素影响，但大多数的性状变异似乎都有其遗传基础，许多基因都对个体的身高产生细微的影响。之前已有超过180个位点被证实与人类的身高相关，但是还有许多性状的遗传机制尚不明确。
为了找到基因组编码区内新的身高相关变异，Keating和同事们利用Illumina 公司的IBC芯片（ITMAT-BroadCare array）对47个研究中6个不同种族的114,223位个体进行了基因分型分析。尽管主要设计用于检测心血管、代谢和炎症相关过程中的遗传变异，但是IBC芯片携带的2000个基因编码位点的49320个SNPs信息，使得研究人员确信可利用它来寻找基因中常见和罕见的遗传变异。
研究人员从25个研究中获得了个体身高及其他数据，从另外22个研究中获得了总体水平的数据。首先研究小组集中研究了具有欧洲血统的53394人的个体水平数据，然后对另外37052个获得总体水平数据的欧洲个体进行了研究结果的重复验证，最后对来自5个非欧洲群体的个体进行了扩展分析。
研究人员总共从中发现了64个与身高相关的位点，其中33个已在过去对欧洲个体的整合分析中得到确定。检测发现的显著相关的SNPs，其中8个基因中的22个变异是相当罕见的，仅存在于不到5%的人群中。
尽管研究人员在欧洲家系群体的IL11和SMAD3基因上发现了与身高相关的罕见SNPs，但是在非裔美国人、南亚人、东亚人、美国原住民以及西班牙个体中研究人员并未找到具有阵列范围显著性的位点。虽然如此，对6个种群的整合分析表明在欧洲群体中大部分与身高相关的位点在其他群体中也能找到相似的定位。
虽然有一些检测到的变异与身高没有明显的关联，但是研究人员强调有许多其他的变异影响了一些潜在相关的信号包括能量代谢、胶原形成和生长激素信号通路中的基因。
此外，研究人员还认为可将身高遗传学作为其他复杂人类性状的模型，相似的策略同样适用于了解其他的人类基因表型。“我们的研究证实密集携带罕见SNPs基因覆盖度结合大规模的整合分析的策略适用于鉴别与常见复杂性状相关的其他变异，”研究人员说。（生物谷Bioon.com）
生物谷推荐原文出处：
American Journal of Human Genetics doi:10.1016/j.ajhg.2010.11.007
Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height
Matthew B. Lanktree1, 115, Yiran Guo2, 3, 115, Muhammed Murtaza4, 66, Joseph T. Glessner2, Swneke D. Bailey6, N. Charlotte Onland-Moret21, Guillaume Lettre5, Halit Ongen8, Ramakrishnan Rajagopalan10, Toby Johnson9, Haiqing Shen11, Christopher P. Nelson15, 86, Norman Klopp12, Jens Baumert12, Sandosh Padmanabhan54, Nathan Pankratz24, 83, James S. Pankow83, Sonia Shah87, Kira Taylor13, John Barnard14, Bas J. Peters108, Cliona M. Maloney30, Maximilian T. Lobmeyer16, Alice Stanton58, M. Hadi Zafarmand18, 109, Simon P.R. Romaine23, Amar Mehta25, Erik P.A. van Iperen22, 82, Yan Gong16, Tom S. Price20, Erin N. Smith31, Cecilia E. Kim2, Yun R. Li2, Folkert W. Asselbergs18, 21, 109, Larry D. Atwood35, Kristian M. Bailey23, Deepak Bhatt99, Florianne Bauer21, Elijah R. Behr45, Tushar Bhangale43, Jolanda M.A. Boer28, Bernhard O. Boehm92, Jonathan P. Bradfield2, Morris Brown95, Peter S. Braund15, 86, Paul R. Burton32, Cara Carty19, Hareesh R. Chandrupatla29, Wei Chen105, John Connell38, Chrysoula Dalgeorgou46, Anthonius de Boer108, Fotios Drenos27, Clara C. Elbers21, James C. Fang51, Caroline S. Fox35, Edward C. Frackelton2, Barry Fuchs36, Clement E. Furlong10, Quince Gibson11, Christian Gieger12, Anuj Goel8, 72, Diederik E. Grobbee104, Claire Hastie54, Philip J. Howard9, Guan-Hua Huang52, W. Craig Johnson34, Qing Li111, Marcus E. Kleber88, Barbara E.K. Klein17, Ronald Klein17, Charles Kooperberg19, Bonnie Ky50, Andrea LaCroix19, Paul Lanken36, Mark Lathrop96, Mingyao Li29, Vanessa Marshall94, Olle Melander55, Frank D. Mentch2, Nuala J. Meyer36, Keri L. Monda40, Alexandre Montpetit42, Gurunathan Murugesan33, Karen Nakayama10, Dave Nondahl17, Abiodun Onipinla9, Suzanne Rafelt15, 86, Stephen J. Newhouse9, F. George Otieno2, Sanjey R. Patel41, Mary E. Putt102, Santiago Rodriguez53, Radwan N. Safa49, Douglas B. Sawyer48, Pamela J. Schreiner39, Claire Simpson111, Suthesh Sivapalaratnam26, Sathanur R. Srinivasan105, Christine Suver30, Gary Swergold112, Nancy K. Sweitzer47, Kelly A. Thomas2, Barbara Thorand12, Nicholas J. Timpson53, Sam Tischfield44, Martin Tobin32, Maciej Tomaszweski15, 86, W.M. Monique Verschuren28, Chris Wallace97, Bernhard Winkelmann93, Haitao Zhang2, Dongling Zheng46, Li Zhang14, Joseph M. Zmuda37, Robert Clarke107, Anthony J. Balmforth23, John Danesh65, Ian N. Day53, Nicholas J. Schork31, Paul I.W. de Bakker62, 44, 21, Christian Delles54, David Duggan59, Aroon D. Hingorani7, 71, Joel N. Hirschhorn44, 77, 78, Marten H. Hofker63, Steve E. Humphries27, Mika Kivimaki7, Debbie A. Lawlor53, Kandice Kottke-Marchant100, Jessica L. Mega60, Braxton D. Mitchell11, David A. Morrow60, Jutta Palmen27, Susan Redline41, Denis C. Shields57, Alan R. Shuldiner11, 80, Patrick M. Sleiman2, George Davey Smith53, Martin Farrall8, 72, Yalda Jamshidi46, David C. Christiani25, 81, Juan P. Casas110, Alistair S. Hall23, Pieter A. Doevendans18, Jason D. Christie36, Gerald S. Berenson105, Sarah S. Murray31, Thomas Illig12, Gerald W. Dorn85, Thomas P. Cappola50, Eric Boerwinkle68, Peter Sever101, Daniel J. Rader29, 74, Muredach P. Reilly29, 74, Mark Caulfield9, Philippa J. Talmud27, Eric Topol98, James C. Engert67, Kai Wang2, Anna Dominiczak56, Anders Hamsten106, Sean P. Curtis113, Roy L. Silverstein61, Leslie A. Lange40, Marc S. Sabatine60, Mieke Trip26, Danish Saleheen65, 66, John F. Peden8, 72, Karen J. Cruickshanks17, 79, Winfried M?rz89, 90, 91, Jeffrey R. O'Connell11, Olaf H. Klungel108, Cisca Wijmenga69, Anke Hilse Maitland-van der Zee108, Eric E. Schadt84, Julie A. Johnson64, Gail P. Jarvik10, George J. Papanicolaou70, Hugh Watkins on behalf of PROCARDIS72, Struan F.A. Grant2, 75, Patricia B. Munroe9, Kari E. North13, 76, Nilesh J. Samani15, 86, Wolfgang Koenig103, Tom R. Gaunt53, Sonia S. Anand73, Yvonne T. van der Schouw104, Meena Kumari on behalf of the Whitehall II Study the WHII 50K Group7, Nicole Soranzo4, Garret A. FitzGerald74, Alex Reiner19, Robert A. Hegele1, Hakon Hakonarson2, 75,and Brendan J. Keating29, 74, 114,
1 Department of Medicine and Biochemistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada
2 Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
3 Beijing Genomics Institute at Shenzhen, Shenzhen, China
4 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
5 Montréal Heart Institute, Université de Montréal, Montréal, Québec, H1T 1C8, Canada
6 Department of Human Genetics, McGill University, Montréal, Québec, H3A 1B1, Canada
7 Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK
8 The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
9 Clinical Pharmacology and Barts and the London Genome,Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK
10 Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, 98195, USA
11 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
12 Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
13 Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
14 Department of Quantitative Health Sciences, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
15 Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK
16 Center for Pharmacogenomics, College of Pharmacy, University of Florida, FL 32610 USA
17 Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705 USA
18 Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
19 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
20 MRC SGDP Centre, Institute of Psychiatry, London SE5 8AF, UK
21 Complex Genetics Section, Department of Medical Genetics (DBG) University Medical Center Utrecht, Utrecht STR 6, The Netherlands
22 Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
23 Leeds Institute of Genetics Health & Therapeutics, University of Leeds, Leeds LS2 9JT, UK
24 Department of Medical and Molecular Genetics, Indiana University, School of Medicine, 410 West 10th Street, HS4000, Indianapolis, IN 46202, USA
25 Department of Environmental Health, Environmental and Occupational Medicine and Epidemiology Program, Harvard School of Public Health, Boston, MA 02115 USA
26 Department of Cardiology and Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam
27 Centre for Cardiovascular Genetics, Department of Medicine, University College London, 5 University Street, London WC1E 6JF, UK
28 National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
29 Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
30 Department of Genetics, Rosetta Inpharmatics, Seattle, WA 98109-5234, USA
31 Scripps Genomic Medicine and Scripps Translational Science Institute, 3344 N. Torrey Pines Ct. Ste 300, La Jolla, CA 92037, USA
32 Department of Health Sciences, University of Leicester, Adrian Building, University Rd., Leicester LE1 7RH, UK
33 Department of Clinical Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44106, USA
34 Department of Biostatistics, University of Washington, Seattle, WA 98195 USA
35 Framingham Heart Study, Boston University School of Medicine, Boston, MA 02118-2526, USA
36 University of Pennsylvania Medical Center, Pulmonary, Allergy & Critical Care Division, Philadelphia, PA 19104-6160, USA
37 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St., Pittsburgh, PA 15261, USA
38 University of Dundee, Medical School, Ninewells Hospital and Medical School, DD1 9SY Dundee, UK
39 Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN 55454, USA
40 Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC 27514, USA
41 Harvard Medical School, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
42 McGill University and Genome Québec Innovation Centre, Montréal, Québec H3A 1A4 Canada
43 Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco
44 Broad Institute of MIT and Harvard, Cambridge, MA 02115, USA
45 Division of Cardiovascular Sciences, St George's University of London, London SW17 0RE, UK
46 Division of Clinical Developmental Sciences, St George's University of London SW17 0RE, London, UK
47 Cardiovascular Medicine, University of Wisconsin, Madison, WI 53792, USA
48 Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN 37232, USA
49 Department of Molecular Medicine, Boston University, Boston, MA 02118, USA
50 Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
51 Cardiovascular Medicine, Case Western Reserve University, Cleveland, OH 44106,USA
52 Institute of Statistics, National Chiao Tung University, Hsinchu 30010, Taiwan
53 MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
54 BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow G12 8TA, UK
55 Clinical Research Center (CRC), Malm? University Hospital, SE-205 02 Malm?, Sweden
56 Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, University Place, Glasgow G12 8QQ, UK
57 Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland
58 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
59 Translational Genomics Research Institute, Phoenix, AZ 85004, USA
60 TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA
61 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, 9500 Euclid Ave./NC10, Cleveland, OH 44195, USA
62 Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
63 Molecular Genetics, University Medical Center Groningen, Groningen University, Groningen 9700 RB, the Netherlands
64 Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, FL 32610, USA
65 Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
66 Center for Non-Communicable Diseases, Karachi, Pakistan
67 Departments of Medicine and Human Genetics, McGill University, Montréal, Québec H3A 1B1, Canada
68 Human Genetics Center and Div. of Epidemiology, 1200 Herman Pressler, Suite E-447, Houston, TX 77030, USA
69 Department of Genetics, University Medical Center Groningen and Groningen University, 9700 RB Groningen, The Netherlands
70 National Heart, Lung, and Blood Institute (NHLBI), Division of Cardiovascular Sciences, Bethesda, MD 20892, USA
71 Centre for Clinical Pharmacology, Department of Medicine, University College London, London WC1E 6JF, UK
72 Department of Cardiovascular Medicine, University of Oxford, Level 6 West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
73 Department of Medicine and Clinical Epidemiology and Biostatistics, Population Genomics Program, McMaster University, Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario L8L 2X2, Canada
74 The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
75 Department of Pediatrics, University of Pennsylvania, Philadelphia PA 19104, USA
76 Carolina Center for Genome Sciences, School of Public Health, University of North Carolina, Chapel Hill, NC 27514, USA
77 Divisions and Endocrinology and Genetics and Program in Genomics, Children's Hospital, Boston, MA 02115, USA
78 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
79 Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
80 Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD 21201, USA
81 Pulmonary and Critical Care Unit, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
82 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
83 Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN 55454, USA
84 Sage Bionetworks, Seattle, WA 98109, USA
85 Washington University Center for Pharmacogenetics, 660 S. Euclid Ave., Campus Box 8220, St. Louis, MO 63110-1093, USA
86 Leicester National Institute of Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK
87 UCL Genetic Institute, University College London, London WC1E 6BT, UK
88 LURIC Nonprofit LLC, Freiburg, Germany
89 Synlab Center of Laboratory Diagnostics Heidelberg, Heidelberg D-58509, Germany
90 Institute of Public Health, Social Medicine and Epidemiology Medical Faculty, University of Heidelberg, D-68167 Mannheim, Germany
91 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, A-8036 Graz, Austria
92 Division of Endocrinology, Diabetes and Metabolism, Centre of Excellence Baden-Wuerttemberg, Metabolic Diseases, Ulm University, D - 89081 Ulm, Germany
93 Cardiology Group Frankfurt-Sachsenhausen, Frankfurt, Germany
94 Drug Safety Research Unit, Southampton SO31 1AA, UK
95 Clinical Pharmacology and the Cambridge Institute of Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0SP, UK
96 Centre National de Genotypage, CP 5721, 91 057 Evry Cedex, France
97 JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK
98 Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, US
99 Harvard Medical School, Cambridge, MA 02115, USA
100 Pathology and Laboratory Medicine Institute, Cleveland Clinic Cleveland, OH 44195
101 International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College London, London W2 1NY, UK
102 Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA
103 Department of Internal Medicine II Cardiology, University of Ulm Medical Center, Ulm Konto Nr. 5050, Germany
104 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
105 Department of Epidemiology, 1440 Canal Street, Suite 1829, Tulane University, New Orleans, LA 70112-2750, USA
106 Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet SE-171 77 Stockholm, Sweden
107 Clinical Trial Service Unit, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX37LF, UK
108 Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TC Utrecht, The Netherlands
109 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
110 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, WC1E 7HT, UK
111 National Human Genome Research Institute, National Institutes of Health, 333 Cassell Drive, Suite 1200, Baltimore, MD 21224, USA
112 Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
113 Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
114 Current address: The Children's Hospital of Philadelphia Research Institute, 3516 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA
115 These authors contributed equally to this work.
Abstract
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 106), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 108). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 1011). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
