Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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23891470
TITLE
Meta-analysis of gene-level associations for rare variants based on single-variant statistics.
ABSTRACT
Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.
Copyright 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2013 Aug 8
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2013/04/30
revised 2013/06/05
accepted 2013/06/12
aheadofprint 2013/07/25
entrez 2013/07/30 06:00
pubmed 2013/07/31 06:00
medline 2013/12/18 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Hu YJ Hu Yi-Juan YJ Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, USA.
Berndt SI Berndt Sonja I SI
Gustafsson S Gustafsson Stefan S
Ganna A Ganna Andrea A
Genetic Investigation of ANthropometric Traits (GIANT) Consortium
Hirschhorn J Hirschhorn Joel J
North KE North Kari E KE
Ingelsson E Ingelsson Erik E
Lin DY Lin Dan-Yu DY
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Berndt Sonja I SI
Gustafsson Stefan S
Mägi Reedik R
Ganna Andrea A
Wheeler Eleanor E
Feitosa Mary F MF
Justice Anne E AE
Monda Keri L KL
Croteau-Chonka Damien C DC
Day Felix R FR
Esko Tõnu T
Fall Tove T
Ferreira Teresa T
Gentilini Davide D
Jackson Anne U AU
Luan Jian'an J
Randall Joshua C JC
Vedantam Sailaja S
Willer Cristen J CJ
Winkler Thomas W TW
Wood Andrew R AR
Workalemahu Tsegaselassie T
Hu Yi-Juan YJ
Lee Sang Hong SH
Liang Liming L
Lin Dan-Yu DY
Min Josine L JL
Neale Benjamin M BM
Thorleifsson Gudmar G
Yang Jian J
Albrecht Eva E
Amin Najaf N
Bragg-Gresham Jennifer L JL
Cadby Gemma G
den Heijer Martin M
Eklund Niina N
Fischer Krista K
Goel Anuj A
Hottenga Jouke-Jan JJ
Huffman Jennifer E JE
Jarick Ivonne I
Johansson Åsa
Johnson Toby T
Kanoni Stavroula S
Kleber Marcus E ME
König Inke R IR
Kristiansson Kati K
Kutalik Zoltán Z
Lamina Claudia C
Lecoeur Cecile C
Li Guo G
Mangino Massimo M
McArdle Wendy L WL
Medina-Gomez Carolina C
Müller-Nurasyid Martina M
Ngwa Julius S JS
Nolte Ilja M IM
Paternoster Lavinia L
Pechlivanis Sonali S
Perola Markus M
Peters Marjolein J MJ
Preuss Michael M
Rose Lynda M LM
Shi Jianxin J
Shungin Dmitry D
Smith Albert Vernon AV
Strawbridge Rona J RJ
Surakka Ida I
Teumer Alexander A
Trip Mieke D MD
Tyrer Jonathan J
Van Vliet-Ostaptchouk Jana V JV
Vandenput Liesbeth L
Waite Lindsay L LL
Zhao Jing Hua JH
Absher Devin D
Asselbergs Folkert W FW
Atalay Mustafa M
Attwood Antony P AP
Balmforth Anthony J AJ
Basart Hanneke H
Beilby John J
Bonnycastle Lori L LL
Brambilla Paolo P
Bruinenberg Marcel M
Campbell Harry H
Chasman Daniel I DI
Chines Peter S PS
Collins Francis S FS
Connell John M JM
Cookson William W
de Faire Ulf U
de Vegt Femmie F
Dei Mariano M
Dimitriou Maria M
Edkins Sarah S
Estrada Karol K
Evans David M DM
Farrall Martin M
Ferrario Marco M MM
Ferrières Jean J
Franke Lude L
Frau Francesca F
Gejman Pablo V PV
Grallert Harald H
Grönberg Henrik H
Gudnason Vilmundur V
Hall Alistair S AS
Hall Per P
Hartikainen Anna-Liisa AL
Hayward Caroline C
Heard-Costa Nancy L NL
Heath Andrew C AC
Hebebrand Johannes J
Homuth Georg G
Hu Frank B FB
Hunt Sarah E SE
Hyppönen Elina E
Iribarren Carlos C
Jacobs Kevin B KB
Jansson John-Olov JO
Jula Antti A
Kähönen Mika M
Kathiresan Sekar S
Kee Frank F
Khaw Kay-Tee KT
Kivimaki Mika M
Koenig Wolfgang W
Kraja Aldi T AT
Kumari Meena M
Kuulasmaa Kari K
Kuusisto Johanna J
Laitinen Jaana H JH
Lakka Timo A TA
Langenberg Claudia C
Launer Lenore J LJ
Lind Lars L
Lindström Jaana J
Liu Jianjun J
Liuzzi Antonio A
Lokki Marja-Liisa ML
Lorentzon Mattias M
Madden Pamela A PA
Magnusson Patrik K PK
Manunta Paolo P
Marek Diana D
März Winfried W
Mateo Leach Irene I
McKnight Barbara B
Medland Sarah E SE
Mihailov Evelin E
Milani Lili L
Montgomery Grant W GW
Mooser Vincent V
Mühleisen Thomas W TW
Munroe Patricia B PB
Musk Arthur W AW
Narisu Narisu N
Navis Gerjan G
Nicholson George G
Nohr Ellen A EA
Ong Ken K KK
Oostra Ben A BA
Palmer Colin N A CN
Palotie Aarno A
Peden John F JF
Pedersen Nancy N
Peters Annette A
Polasek Ozren O
Pouta Anneli A
Pramstaller Peter P PP
Prokopenko Inga I
Pütter Carolin C
Radhakrishnan Aparna A
Raitakari Olli O
Rendon Augusto A
Rivadeneira Fernando F
Rudan Igor I
Saaristo Timo E TE
Sambrook Jennifer G JG
Sanders Alan R AR
Sanna Serena S
Saramies Jouko J
Schipf Sabine S
Schreiber Stefan S
Schunkert Heribert H
Shin So-Youn SY
Signorini Stefano S
Sinisalo Juha J
Skrobek Boris B
Soranzo Nicole N
Stančáková Alena A
Stark Klaus K
Stephens Jonathan C JC
Stirrups Kathleen K
Stolk Ronald P RP
Stumvoll Michael M
Swift Amy J AJ
Theodoraki Eirini V EV
Thorand Barbara B
Tregouet David-Alexandre DA
Tremoli Elena E
Van der Klauw Melanie M MM
van Meurs Joyce B J JB
Vermeulen Sita H SH
Viikari Jorma J
Virtamo Jarmo J
Vitart Veronique V
Waeber Gérard G
Wang Zhaoming Z
Widén Elisabeth E
Wild Sarah H SH
Willemsen Gonneke G
Winkelmann Bernhard R BR
Witteman Jacqueline C M JC
Wolffenbuttel Bruce H R BH
Wong Andrew A
Wright Alan F AF
Zillikens M Carola MC
Amouyel Philippe P
Boehm Bernhard O BO
Boerwinkle Eric E
Boomsma Dorret I DI
Caulfield Mark J MJ
Chanock Stephen J SJ
Cupples L Adrienne LA
Cusi Daniele D
Dedoussis George V GV
Erdmann Jeanette J
Eriksson Johan G JG
Franks Paul W PW
Froguel Philippe P
Gieger Christian C
Gyllensten Ulf U
Hamsten Anders A
Harris Tamara B TB
Hengstenberg Christian C
Hicks Andrew A AA
Hingorani Aroon A
Hinney Anke A
Hofman Albert A
Hovingh Kees G KG
Hveem Kristian K
Illig Thomas T
Jarvelin Marjo-Riitta MR
Jöckel Karl-Heinz KH
Keinanen-Kiukaanniemi Sirkka M SM
Kiemeney Lambertus A LA
Kuh Diana D
Laakso Markku M
Lehtimäki Terho T
Levinson Douglas F DF
Martin Nicholas G NG
Metspalu Andres A
Morris Andrew D AD
Nieminen Markku S MS
Njølstad Inger I
Ohlsson Claes C
Oldehinkel Albertine J AJ
Ouwehand Willem H WH
Palmer Lyle J LJ
Penninx Brenda B
Power Chris C
Province Michael A MA
Psaty Bruce M BM
Qi Lu L
Rauramaa Rainer R
Ridker Paul M PM
Ripatti Samuli S
Salomaa Veikko V
Samani Nilesh J NJ
Snieder Harold H
Sørensen Thorkild I A TI
Spector Timothy D TD
Stefansson Kari K
Tönjes Anke A
Tuomilehto Jaakko J
Uitterlinden André G AG
Uusitupa Matti M
van der Harst Pim P
Vollenweider Peter P
Wallaschofski Henri H
Wareham Nicholas J NJ
Watkins Hugh H
Wichmann H-Erich HE
Wilson James F JF
Abecasis Goncalo R GR
Assimes Themistocles L TL
Barroso Inês I
Boehnke Michael M
Borecki Ingrid B IB
Deloukas Panos P
Fox Caroline S CS
Frayling Timothy T
Groop Leif C LC
Haritunian Talin T
Heid Iris M IM
Hunter David D
Kaplan Robert C RC
Karpe Fredrik F
Moffatt Miriam M
Mohlke Karen L KL
O'Connell Jeffrey R JR
Pawitan Yudi Y
Schadt Eric E EE
Schlessinger David D
Steinthorsdottir Valgerdur V
Strachan David P DP
Thorsteinsdottir Unnur U
van Duijn Cornelia M CM
Visscher Peter M PM
Di Blasio Anna Maria AM
Hirschhorn Joel N JN
Lindgren Cecilia M CM
Morris Andrew P AP
Meyre David D
Scherag André A
McCarthy Mark I MI
Speliotes Elizabeth K EK
North Kari E KE
Loos Ruth J F RJ
Ingelsson Erik E
JOURNAL
VOLUME: 93
ISSUE: 2
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 2013
MONTH: Aug
DAY: 8
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1537-6605
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
090532 Wellcome Trust United Kingdom
097117 Wellcome Trust United Kingdom
14136 Cancer Research UK United Kingdom
G1000143 Medical Research Council United Kingdom
HHSN26800625226C PHS HHS United States
HHSN268200625226C PHS HHS United States
HHSN268201100010C PHS HHS United States
HHSN268201100011C PHS HHS United States
HHSN268201100012C PHS HHS United States
HHSN26820110005C PHS HHS United States
HHSN26820110006C PHS HHS United States
HHSN26820110007C PHS HHS United States
HHSN26820110008C PHS HHS United States
HHSN26820110009C PHS HHS United States
K05 AA017688 NIAAA NIH HHS United States
MC_PC_U127561128 Medical Research Council United Kingdom
MR/K013351/1 Medical Research Council United Kingdom
P01 CA142538 NCI NIH HHS United States
P01CA142538 NCI NIH HHS United States
R01 CA082659 NCI NIH HHS United States
R01 DK075787 NIDDK NIH HHS United States
R01CA082659 NCI NIH HHS United States
R01HL086694 NHLBI NIH HHS United States
R01HL087641 NHLBI NIH HHS United States
R01HL59367 NHLBI NIH HHS United States
U01HG004402 NHGRI NIH HHS United States
U01HG004803 NHGRI NIH HHS United States
UL1RR025005 NCRR NIH HHS United States
Intramural NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Computer Simulation
Gene Frequency
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Models, Genetic
Phenotype
Polymorphism, Single Nucleotide
Receptors, LDL genetics
Receptors, Odorant genetics
Software genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 LDLR protein, human
0 Receptors, LDL
0 Receptors, Odorant
OTHER ID's
OTHERID SOURCE
PMC3738834 NLM