Genetic Epidemiology, Psychiatric Genetics, Asthma 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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PMID
24204319
TITLE
Mining the human phenome using allelic scores that index biological intermediates.
ABSTRACT
It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.
DATE PUBLISHED
2013 Oct
HISTORY
PUBSTATUS PUBSTATUSDATE
ecollection 2013/10
received 2013/03/30
accepted 2013/09/12
epublish 2013/10/31
entrez 2013/11/09 06:00
pubmed 2013/11/10 06:00
medline 2015/02/20 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Evans DM Evans David M DM MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom ; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom ; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
Brion MJ Brion Marie Jo A MJ
Paternoster L Paternoster Lavinia L
Kemp JP Kemp John P JP
McMahon G McMahon George G
Munafò M Munafò Marcus M
Whitfield JB Whitfield John B JB
Medland SE Medland Sarah E SE
Montgomery GW Montgomery Grant W GW
GIANT Consortium
CRP Consortium
TAG Consortium
Timpson NJ Timpson Nicholas J NJ
St Pourcain B St Pourcain Beate B
Lawlor DA Lawlor Debbie A DA
Martin NG Martin Nicholas G NG
Dehghan A Dehghan Abbas A
Hirschhorn J Hirschhorn Joel J
Smith GD Smith George Davey GD
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Speliotes Elizabeth K EK
Willer Cristen J CJ
Berndt Sonja I SI
Monda Keri L KL
Thorleifsson Gudmar G
Jackson Anne U AU
Allen Hana Lango HL
Lindgren Cecilia M CM
Luan Jian'an J
Mägi Reedik R
Randall Joshua C JC
Vedantam Sailaja S
Winkler Thomas W TW
Qi Lu L
Workalemahu Tsegaselassie T
Heid Iris M IM
Steinthorsdottir Valgerdur V
Stringham Heather M HM
Weedon Michael N MN
Wheeler Eleanor E
Wood Andrew R AR
Ferreira Teresa T
Weyant Robert J RJ
Segré Ayellet V AV
Estrada Karol K
Liang Liming L
Nemesh James J
Park Ju-Hyun JH
Gustafsson Stefan S
Kilpeläinen Tuomas O TO
Yang Jian J
Bouatia-Naji Nabila N
Esko Tõnu T
Feitosa Mary F MF
Kutalik Zoltán Z
Mangino Massimo M
Raychaudhuri Soumya S
Scherag Andre A
Smith Albert Vernon AV
Welch Ryan R
Zhao Jing Hua JH
Aben Katja K KK
Absher Devin M DM
Amin Najaf N
Dixon Anna L AL
Fisher Eva E
Glazer Nicole L NL
Goddard Michael E ME
Heard-Costa Nancy L NL
Hoesel Volker V
Hottenga Jouke-Jan JJ
Johansson Åsa
Johnson Toby T
Ketkar Shamika S
Lamina Claudia C
Li Shengxu S
Moffatt Miriam F MF
Myers Richard H RH
Narisu Narisu N
Perry John R B JR
Peters Marjolein J MJ
Preuss Michael M
Ripatti Samuli S
Rivadeneira Fernando F
Sandholt Camilla C
Scott Laura J LJ
Timpson Nicholas J NJ
Tyrer Jonathan P JP
van Wingerden Sophie S
Watanabe Richard M RM
White Charles C CC
Wiklund Fredrik F
Barlassina Christina C
Chasman Daniel I DI
Cooper Matthew N MN
Jansson John-Olov JO
Lawrence Robert W RW
Pellikka Niina N
Prokopenko Inga I
Shi Jianxin J
Thiering Elisabeth E
Alavere Helene H
Alibrandi Maria T S MT
Almgren Peter P
Arnold Alice M AM
Aspelund Thor T
Atwood Larry D LD
Balkau Beverley B
Balmforth Anthony J AJ
Bennett Amanda J AJ
Ben-Shlomo Yoav Y
Bergman Richard N RN
Bergmann Sven S
Biebermann Heike H
Blakemore Alexandra I F AI
Boes Tanja T
Bonnycastle Lori L LL
Bornstein Stefan R SR
Brown Morris J MJ
Buchanan Thomas A TA
Busonero Fabio F
Campbell Harry H
Cappuccio Francesco P FP
Cavalcanti-Proença Christine C
Chen Yii-Der Ida YD
Chen Chih-Mei CM
Chines Peter S PS
Clarke Robert R
Coin Lachlan L
Connell John J
Day Ian N M IN
den Heijer Martin M
Duan Jubao J
Ebrahim Shah S
Elliott Paul P
Elosua Roberto R
Eiriksdottir Gudny G
Erdos Michael R MR
Eriksson Johan G JG
Facheris Maurizio F MF
Felix Stephan B SB
Fischer-Posovszky Pamela P
Folsom Aaron R AR
Friedrich Nele N
Freimer Nelson B NB
Fu Mao M
Gaget Stefan S
Gejman Pablo V PV
Geus Eco J C EJ
Gieger Christian C
Gjesing Anette P AP
Goel Anuj A
Goyette Philippe P
Grallert Harald H
Gräßler Jürgen J
Greenawalt Danielle M DM
Groves Christopher J CJ
Gudnason Vilmundur V
Guiducci Candace C
Hartikainen Anna-Liisa AL
Hassanali Neelam N
Hall Alistair S AS
Havulinna Aki S AS
Hayward Caroline C
Heath Andrew C AC
Hengstenberg Christian C
Hicks Andrew A AA
Hinney Anke A
Hofman Albert A
Homuth Georg G
Hui Jennie J
Igl Wilmar W
Iribarren Carlos C
Isomaa Bo B
Jacobs Kevin B KB
Jarick Ivonne I
Jewell Elizabeth E
John Ulrich U
Jørgensen Torben T
Jousilahti Pekka P
Jula Antti A
Kaakinen Marika M
Kajantie Eero E
Kaplan Lee M LM
Kathiresan Sekar S
Kettunen Johannes J
Kinnunen Leena L
Knowles Joshua W JW
Kolcic Ivana I
König Inke R IR
Koskinen Seppo S
Kovacs Peter P
Kuusisto Johanna J
Kraft Peter P
Kvaløy Kirsti K
Laitinen Jaana J
Lantieri Olivier O
Lanzani Chiara C
Launer Lenore J LJ
Lecoeur Cecile C
Lehtimäki Terho T
Lettre Guillaume G
Liu Jianjun J
Lokki Marja-Liisa ML
Lorentzon Mattias M
Luben Robert N RN
Ludwig Barbara B
Manunta Paolo P
Marek Diana D
Marre Michel M
Martin Nicholas G NG
McArdle Wendy L WL
McCarthy Anne A
McKnight Barbara B
Meitinger Thomas T
Melander Olle O
Meyre David D
Midthjell Kristian K
Montgomery Grant W GW
Morken Mario A MA
Morris Andrew P AP
Mulic Rosanda R
Ngwa Julius S JS
Nelis Mari M
Neville Matt J MJ
Nyholt Dale R DR
O'Donnell Christopher J CJ
O'Rahilly Stephen S
Ong Ken K KK
Oostra Ben B
Paré Guillaume G
Parker Alex N AN
Perola Markus M
Pichler Irene I
Pietiläinen Kirsi H KH
Platou Carl G P CG
Polasek Ozren O
Pouta Anneli A
Rafelt Suzanne S
Raitakari Olli O
Rayner Nigel W NW
Ridderstråle Martin M
Rief Winfried W
Ruokonen Aimo A
Robertson Neil R NR
Rzehak Peter P
Salomaa Veikko V
Sanders Alan R AR
Sandhu Manjinder S MS
Sanna Serena S
Saramies Jouko J
Savolainen Markku J MJ
Scherag Susann S
Schipf Sabine S
Schreiber Stefan S
Schunkert Heribert H
Silander Kaisa K
Sinisalo Juha J
Siscovick David S DS
Smit Jan H JH
Soranzo Nicole N
Sovio Ulla U
Stephens Jonathan J
Surakka Ida I
Swift Amy J AJ
Tammesoo Mari-Liis ML
Tardif Jean-Claude JC
Teder-Laving Maris M
Teslovich Tanya M TM
Thompson John R JR
Thomson Brian B
Tönjes Anke A
Tuomi Tiinamaija T
van Meurs Joyce B J JB
van Ommen Gert-Jan GJ
Vatin Vincent V
Viikari Jorma J
Visvikis-Siest Sophie S
Vitart Veronique V
Vogel Carla I G CI
Voight Benjamin F BF
Waite Lindsay L LL
Wallaschofski Henri H
Walters G Bragi G
Widen Elisabeth E
Wiegand Susanna S
Wild Sarah H SH
Willemsen Gonneke G
Witte Daniel R DR
Witteman Jacqueline C JC
Xu Jianfeng J
Zhang Qunyuan Q
Zgaga Lina L
Ziegler Andreas A
Zitting Paavo P
Beilby John P JP
Farooqi I Sadaf I
Hebebrand Johannes J
Huikuri Heikki V HV
James Alan L AL
Kähönen Mika M
Levinson Douglas F DF
Macciardi Fabio F
Nieminen Markku S MS
Ohlsson Claes C
Palmer Lyle J LJ
Ridker Paul M PM
Stumvoll Michael M
Beckmann Jacques S JS
Boeing Heiner H
Boerwinkle Eric E
Boomsma Dorret I DI
Caulfield Mark J MJ
Chanock Stephen J SJ
Collins Francis S FS
Cupples L Adrienne L
Smith George Davey GD
Erdmann Jeanette J
Froguel Philippe P
Grönberg Henrik H
Gyllensten Ulf U
Hall Per P
Hansen Torben T
Harris Tamara B TB
Hattersley Andrew T AT
Hayes Richard B RB
Heinrich Joachim J
Hu Frank B FB
Hveem Kristian K
Illig Thomas T
Jarvelin Marjo-Riitta MR
Kaprio Jaakko J
Karpe Fredrik F
Khaw Kay-Tee KT
Kiemeney Lambertus A LA
Krude Heiko H
Laakso Markku M
Lawlor Debbie A DA
Metspalu Andres A
Munroe Patricia B PB
Ouwehand Willem H WH
Pedersen Oluf O
Penninx Brenda W BW
Peters Annette A
Pramstaller Peter P PP
Quertermous Thomas T
Reinehr Thomas T
Rissanen Aila A
Rudan Igor I
Samani Nilesh J NJ
Schwarz Peter E H PE
Shuldiner Alan R AR
Spector Timothy D TD
Tuomilehto Jaakko J
Uda Manuela M
Uitterlinden André A
Valle Timo T TT
Wabitsch Martin M
Waeber Gérard G
Wareham Nicholas J NJ
Watkins Hugh H
Wilson James F JF
Wright Alan F AF
Zillikens M Carola M
Chatterjee Nilanjan N
McCarroll Steven A SA
Purcell Shaun S
Schadt Eric E EE
Visscher Peter M PM
Assimes Themistocles L TL
Borecki Ingrid B IB
Deloukas Panos P
Fox Caroline S CS
Groop Leif C LC
Haritunians Talin T
Hunter David J DJ
Kaplan Robert C RC
Mohlke Karen L KL
O'Connell Jeffrey R JR
Peltonen Leena L
Schlessinger David D
Strachan David P DP
Van Duijn Cornelia M CM
Wichmann H -Erich H-
Frayling Timothy M TM
Thorsteinsdottir Unnur U
Abecasis Gonçalo R GR
Barroso Inês I
Boehnke Michael M
Stefansson Kari K
North Kari E KE
McCarthy Mark I MI
Hirschhorn Joel N JN
Ingelsson Erik E
Loos Ruth J F RJ
Dehghan Abbas A
Dupuis Josée J
Barbalic Maja M
Bis Joshua C JC
Eiriksdottir Gudny G
Lu Chen C
Pellikka Niina N
Wallaschofski Henri H
Kettunen Johannes J
Henneman Peter P
Baumert Jens J
Strachan David P DP
Fuchsberger Christian C
Vitart Veronique V
Wilson James F JF
Paré Guillaume G
Naitza Silvia S
Rudock Megan E ME
Surakka Ida I
de Geus Eco J C EJ
Alizadeh Behrooz Z BZ
Guralnik Jack J
Shuldiner Alan A
Tanaka Toshiko T
Zee Robert Y L RY
Schnabel Renate B RB
Nambi Vijay V
Kavousi Maryam M
Ripatti Samuli S
Nauck Matthias M
Smith Nicholas L NL
Smith Albert V AV
Sundvall Jouko J
Scheet Paul P
Liu Yongmei Y
Ruokonen Aimo A
Rose Lynda M LM
Larson Martin G MG
Hoogeveen Ron C RC
Freimer Nelson B NB
Teumer Alexander A
Tracy Russell P RP
Launer Lenore J LJ
Buring Julie E JE
Yamamoto Jennifer F JF
Folsom Aaron R AR
Sijbrands Eric J G EJ
Pankow James J
Elliott Paul P
Keaney John F JF
Sun Wei W
Sarin Antti-Pekka AP
Fontes João D JD
Badola Sunita S
Astor Brad C BC
Hofman Albert A
Pouta Anneli A
Werdan Karl K
Greiser Karin H KH
Kuss Oliver O
Meyer zu Schwabedissen Henriette E HE
Thiery Joachim J
Jamshidi Yalda Y
Nolte Ilja M IM
Soranzo Nicole N
Spector Timothy D TD
Völzke Henry H
Parker Alexander N AN
Aspelund Thor T
Bates David D
Young Lauren L
Tsui Kim K
Siscovick David S DS
Guo Xiuqing X
Rotter Jerome I JI
Uda Manuela M
Schlessinger David D
Rudan Igor I
Hicks Andrew A AA
Penninx Brenda W BW
Thorand Barbara B
Gieger Christian C
Coresh Joe J
Willemsen Gonneke G
Harris Tamara B TB
Uitterlinden Andre G AG
Järvelin Marjo-Riitta MR
Rice Kenneth K
Radke Dörte D
Salomaa Veikko V
van Dijk Ko Willems KW
Boerwinkle Eric E
Vasan Ramachandran S RS
Ferrucci Luigi L
Gibson Quince D QD
Bandinelli Stefania S
Snieder Harold H
Boomsma Dorret I DI
Xiao Xiangjun X
Campbell Harry H
Hayward Caroline C
Pramstaller Peter P PP
van Duijn Cornelia M CM
Peltonen Leena L
Psaty Bruce M BM
Gudnason Vilmundur V
Ridker Paul M PM
Homuth Georg G
Koenig Wolfgang W
Ballantyne Christie M CM
Witteman Jacqueline C M JC
Benjamin Emelia J EJ
Perola Markus M
Chasman Daniel I DI
Furberg Helena H
Kim YunJung Y
Dackor Jennifer J
Boerwinkle Eric E
Franceschini Nora N
Ardissino Diego D
Bernardinelli Luisa L
Mannucci Pier M PM
Mauri Francesco F
Merlini Piera A PA
Absher Devin D
Assimes Themistocles L TL
Fortmann Stephen P SP
Iribarren Carlos C
Knowles Joshua W JW
Quertermous Thomas T
Ferrucci Luigi L
Tanaka Toshiko T
Bis Joshua C JC
Furberg Curt D CD
Haritunians Talin T
McKnight Barbara B
Psaty Bruce M BM
Taylor Kent D KD
Thacker Evan L EL
Almgren Peter P
Groop Leif L
Ladenvall Claes C
Boehnke Michael M
Jackson Anne U AU
Mohlke Karen L KL
Stringham Heather M HM
Tuomilehto Jaakko J
Benjamin Emelia J EJ
Hwang Shih-Jen SJ
Levy Daniel D
Preis Sarah Rosner SR
Vasan Ramachandran S RS
Duan Jubao J
Gejman Pablo V PV
Levinson Douglas F DF
Sanders Alan R AR
Shi Jianxin J
Lips Esther H EH
McKay James D JD
Agudo Antonio A
Barzan Luigi L
Bencko Vladimir V
Benhamou Simone S
Castellsagué Xavier X
Canova Cristina C
Conway David I DI
Fabianova Eleonora E
Foretova Lenka L
Janout Vladimir V
Healy Claire M CM
Holcátová Ivana I
Kjaerheim Kristina K
Lagiou Pagona P
Lissowska Jolanta J
Lowry Ray R
Macfarlane Tatiana V TV
Mates Dana D
Richiardi Lorenzo L
Rudnai Peter P
Szeszenia-Dabrowska Neonilia N
Zaridze David D
Znaor Ariana A
Lathrop Mark M
Brennan Paul P
Bandinelli Stefania S
Frayling Timothy M TM
Guralnik Jack M JM
Milaneschi Yuri Y
Perry John R B JR
Altshuler David D
Elosua Roberto R
Kathiresan Sek S
Lucas Gavin G
Melander Olle O
O'Donnell Christopher J CJ
Salomaa Veikko V
Schwartz Stephen M SM
Voight Benjamin F BF
Penninx Brenda W BW
Smit Johannes H JH
Vogelzangs Nicole N
Boomsma Dorret I DI
de Geus Eco J C EJ
Vink Jacqueline M JM
Willemsen Gonneke G
Chanock Stephen J SJ
Gu Fangyi F
Hankinson Susan E SE
Hunter David J DJ
Hofman Albert A
Tiemeier Henning H
Uitterlinden Andre G AG
van Duijn Cornelia M CM
Walter Stefan S
Chasman Daniel I DI
Everett Brendan M BM
Paré Guillaume G
Ridker Paul M PM
Li Ming D MD
Maes Hermine H HH
Audrain-McGovern Janet J
Posthuma Danielle D
Thornton Laura M LM
Lerman Caryn C
Kaprio Jaakko J
Rose Jed E JE
Ioannidis John P A JP
Kraft Peter P
Lin Dan-Yu DY
Sullivan Patrick F PF
JOURNAL
VOLUME: 9
ISSUE: 10
TITLE: PLoS genetics
ISOABBREVIATION: PLoS Genet.
YEAR: 2013
MONTH: Oct
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1553-7404
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: PLoS Genet
COUNTRY: United States
ISSNLINKING: 1553-7390
NLMUNIQUEID: 101239074
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
076467 Wellcome Trust United Kingdom
083431MA Wellcome Trust United Kingdom
085515 Wellcome Trust United Kingdom
090532 Wellcome Trust United Kingdom
092731 Wellcome Trust United Kingdom
095515 Wellcome Trust United Kingdom
AA07535 NIAAA NIH HHS United States
AA07728 NIAAA NIH HHS United States
AA11998 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA13326 NIAAA NIH HHS United States
AA14041 NIAAA NIH HHS United States
AA17688 NIAAA NIH HHS United States
DA012854 NIDA NIH HHS United States
DA019951 NIDA NIH HHS United States
G1000758 Medical Research Council United Kingdom
G9815508 Medical Research Council United Kingdom
MC_PC_15018 Medical Research Council United Kingdom
MC_UU_12013/1 Medical Research Council United Kingdom
MC_UU_12013/3 Medical Research Council United Kingdom
MC_UU_12013/5 Medical Research Council United Kingdom
MR/J012165/1 Medical Research Council United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adaptor Proteins, Vesicular Transport genetics
Alleles genetics
C-Reactive Protein genetics
Genetic Diseases, Inborn genetics
Genetic Predisposition to Disease genetics
Genome, Human genetics
Genome-Wide Association Study genetics
Genotype genetics
Humans genetics
Longitudinal Studies genetics
Phenotype genetics
Polymorphism, Single Nucleotide genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Adaptor Proteins, Vesicular Transport
160124-07-2 COG2 protein, human
9007-41-4 C-Reactive Protein
OTHER ID's
OTHERID SOURCE
PMC3814299 NLM