Mining the human phenome using allelic scores that index biological intermediates.
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UNIL restricted access
State: Public
Version: Final published version
License: Not specified
Serval ID
serval:BIB_E0129038662F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mining the human phenome using allelic scores that index biological intermediates.
Journal
PLoS genetics
Working group(s)
GIANT Consortium, CRP Consortium, TAG Consortium
Contributor(s)
Speliotes E.K., Willer C.J., Berndt S.I., Monda K.L., Thorleifsson G., Jackson A.U., Allen H.L., Lindgren C.M., Luan J., Mägi R., Randall J.C., Vedantam S., Winkler T.W., Qi L., Workalemahu T., Heid I.M., Steinthorsdottir V., Stringham H.M., Weedon M.N., Wheeler E., Wood A.R., Ferreira T., Weyant R.J., Segré A.V., Estrada K., Liang L., Nemesh J., Park J.H., Gustafsson S., Kilpeläinen T.O., Yang J., Bouatia-Naji N., Esko T., Feitosa M.F., Kutalik Z., Mangino M., Raychaudhuri S., Scherag A., Smith A.V., Welch R., Zhao J.H., Aben K.K., Absher D.M., Amin N., Dixon A.L., Fisher E., Glazer N.L., Goddard M.E., Heard-Costa N.L., Hoesel V., Hottenga J.J., Johansson Å., Johnson T., Ketkar S., Lamina C., Li S., Moffatt M.F., Myers R.H., Narisu N., Perry J.R., Peters M.J., Preuss M., Ripatti S., Rivadeneira F., Sandholt C., Scott L.J., Timpson N.J., Tyrer J.P., van Wingerden S., Watanabe R.M., White C.C., Wiklund F., Barlassina C., Chasman D.I., Cooper M.N., Jansson J.O., Lawrence R.W., Pellikka N., Prokopenko I., Shi J., Thiering E., Alavere H., Alibrandi M.T., Almgren P., Arnold A.M., Aspelund T., Atwood L.D., Balkau B., Balmforth A.J., Bennett A.J., Ben-Shlomo Y., Bergman R.N., Bergmann S., Biebermann H., Blakemore A.I., Boes T., Bonnycastle L.L., Bornstein S.R., Brown M.J., Buchanan T.A., Busonero F., Campbell H., Cappuccio F.P., Cavalcanti-Proença C., Chen Y.D., Chen C.M., Chines P.S., Clarke R., Coin L., Connell J., Day I.N., den Heijer M., Duan J., Ebrahim S., Elliott P., Elosua R., Eiriksdottir G., Erdos M.R., Eriksson J.G., Facheris M.F., Felix S.B., Fischer-Posovszky P., Folsom A.R., Friedrich N., Freimer N.B., Fu M., Gaget S., Gejman P.V., Geus E.J., Gieger C., Gjesing A.P., Goel A., Goyette P., Grallert H., Gräßler J., Greenawalt D.M., Groves C.J., Gudnason V., Guiducci C., Hartikainen A.L., Hassanali N., Hall A.S., Havulinna A.S., Hayward C., Heath A.C., Hengstenberg C., Hicks A.A., Hinney A., Hofman A., Homuth G., Hui J., Igl W., Iribarren C., Isomaa B., Jacobs K.B., Jarick I., Jewell E., John U., Jørgensen T., Jousilahti P., Jula A., Kaakinen M., Kajantie E., Kaplan L.M., Kathiresan S., Kettunen J., Kinnunen L., Knowles J.W., Kolcic I., König I.R., Koskinen S., Kovacs P., Kuusisto J., Kraft P., Kvaløy K., Laitinen J., Lantieri O., Lanzani C., Launer L.J., Lecoeur C., Lehtimäki T., Lettre G., Liu J., Lokki M.L., Lorentzon M., Luben R.N., Ludwig B., Manunta P., Marek D., Marre M., Martin N.G., McArdle W.L., McCarthy A., McKnight B., Meitinger T., Melander O., Meyre D., Midthjell K., Montgomery G.W., Morken M.A., Morris A.P., Mulic R., Ngwa J.S., Nelis M., Neville M.J., Nyholt D.R., O'Donnell C.J., O'Rahilly S., Ong K.K., Oostra B., Paré G., Parker A.N., Perola M., Pichler I., Pietiläinen K.H., Platou C.G., Polasek O., Pouta A., Rafelt S., Raitakari O., Rayner N.W., Ridderstråle M., Rief W., Ruokonen A., Robertson N.R., Rzehak P., Salomaa V., Sanders A.R., Sandhu M.S., Sanna S., Saramies J., Savolainen M.J., Scherag S., Schipf S., Schreiber S., Schunkert H., Silander K., Sinisalo J., Siscovick D.S., Smit J.H., Soranzo N., Sovio U., Stephens J., Surakka I., Swift A.J., Tammesoo M.L., Tardif J.C., Teder-Laving M., Teslovich T.M., Thompson J.R., Thomson B., Tönjes A., Tuomi T., van Meurs J.B., van Ommen G.J., Vatin V., Viikari J., Visvikis-Siest S., Vitart V., Vogel C.I., Voight B.F., Waite L.L., Wallaschofski H., Walters G., Widen E., Wiegand S., Wild S.H., Willemsen G., Witte D.R., Witteman J.C., Xu J., Zhang Q., Zgaga L., Ziegler A., Zitting P., Beilby J.P., Farooqi I., Hebebrand J., Huikuri H.V., James A.L., Kähönen M., Levinson D.F., Macciardi F., Nieminen M.S., Ohlsson C., Palmer L.J., Ridker P.M., Stumvoll M., Beckmann J.S., Boeing H., Boerwinkle E., Boomsma D.I., Caulfield M.J., Chanock S.J., Collins F.S., Cupples L., Smith G.D., Erdmann J., Froguel P., Grönberg H., Gyllensten U., Hall P., Hansen T., Harris T.B., Hattersley A.T., Hayes R.B., Heinrich J., Hu F.B., Hveem K., Illig T., Jarvelin M.R., Kaprio J., Karpe F., Khaw K.T., Kiemeney L.A., Krude H., Laakso M., Lawlor D.A., Metspalu A., Munroe P.B., Ouwehand W.H., Pedersen O., Penninx B.W., Peters A., Pramstaller P.P., Quertermous T., Reinehr T., Rissanen A., Rudan I., Samani N.J., Schwarz P.E., Shuldiner A.R., Spector T.D., Tuomilehto J., Uda M., Uitterlinden A., Valle T.T., Wabitsch M., Waeber G., Wareham N.J., Watkins H., Wilson J.F., Wright A.F., Zillikens M., Chatterjee N., McCarroll S.A., Purcell S., Schadt E.E., Visscher P.M., Assimes T.L., Borecki I.B., Deloukas P., Fox C.S., Groop L.C., Haritunians T., Hunter D.J., Kaplan R.C., Mohlke K.L., O'Connell J.R., Peltonen L., Schlessinger D., Strachan D.P., Van Duijn C.M., Wichmann H-, Frayling T.M., Thorsteinsdottir U., Abecasis G.R., Barroso I., Boehnke M., Stefansson K., North K.E., McCarthy M.I., Hirschhorn J.N., Ingelsson E., Loos R.J., Dehghan A., Dupuis J., Barbalic M., Bis J.C., Eiriksdottir G., Lu C., Pellikka N., Wallaschofski H., Kettunen J., Henneman P., Baumert J., Strachan D.P., Fuchsberger C., Vitart V., Wilson J.F., Paré G., Naitza S., Rudock M.E., Surakka I., de Geus E.J., Alizadeh B.Z., Guralnik J., Shuldiner A., Tanaka T., Zee R.Y., Schnabel R.B., Nambi V., Kavousi M., Ripatti S., Nauck M., Smith N.L., Smith A.V., Sundvall J., Scheet P., Liu Y., Ruokonen A., Rose L.M., Larson M.G., Hoogeveen R.C., Freimer N.B., Teumer A., Tracy R.P., Launer L.J., Buring J.E., Yamamoto J.F., Folsom A.R., Sijbrands E.J., Pankow J., Elliott P., Keaney J.F., Sun W., Sarin A.P., Fontes J.D., Badola S., Astor B.C., Hofman A., Pouta A., Werdan K., Greiser K.H., Kuss O., Meyer zu Schwabedissen H.E., Thiery J., Jamshidi Y., Nolte I.M., Soranzo N., Spector T.D., Völzke H., Parker A.N., Aspelund T., Bates D., Young L., Tsui K., Siscovick D.S., Guo X., Rotter J.I., Uda M., Schlessinger D., Rudan I., Hicks A.A., Penninx B.W., Thorand B., Gieger C., Coresh J., Willemsen G., Harris T.B., Uitterlinden A.G., Järvelin M.R., Rice K., Radke D., Salomaa V., van Dijk K.W., Boerwinkle E., Vasan R.S., Ferrucci L., Gibson Q.D., Bandinelli S., Snieder H., Boomsma D.I., Xiao X., Campbell H., Hayward C., Pramstaller P.P., van Duijn C.M., Peltonen L., Psaty B.M., Gudnason V., Ridker P.M., Homuth G., Koenig W., Ballantyne C.M., Witteman J.C., Benjamin E.J., Perola M., Chasman D.I., Furberg H., Kim Y., Dackor J., Boerwinkle E., Franceschini N., Ardissino D., Bernardinelli L., Mannucci P.M., Mauri F., Merlini P.A., Absher D., Assimes T.L., Fortmann S.P., Iribarren C., Knowles J.W., Quertermous T., Ferrucci L., Tanaka T., Bis J.C., Furberg C.D., Haritunians T., McKnight B., Psaty B.M., Taylor K.D., Thacker E.L., Almgren P., Groop L., Ladenvall C., Boehnke M., Jackson A.U., Mohlke K.L., Stringham H.M., Tuomilehto J., Benjamin E.J., Hwang S.J., Levy D., Preis S.R., Vasan R.S., Duan J., Gejman P.V., Levinson D.F., Sanders A.R., Shi J., Lips E.H., McKay J.D., Agudo A., Barzan L., Bencko V., Benhamou S., Castellsagué X., Canova C., Conway D.I., Fabianova E., Foretova L., Janout V., Healy C.M., Holcátová I., Kjaerheim K., Lagiou P., Lissowska J., Lowry R., Macfarlane T.V., Mates D., Richiardi L., Rudnai P., Szeszenia-Dabrowska N., Zaridze D., Znaor A., Lathrop M., Brennan P., Bandinelli S., Frayling T.M., Guralnik J.M., Milaneschi Y., Perry J.R., Altshuler D., Elosua R., Kathiresan S., Lucas G., Melander O., O'Donnell C.J., Salomaa V., Schwartz S.M., Voight B.F., Penninx B.W., Smit J.H., Vogelzangs N., Boomsma D.I., de Geus E.J., Vink J.M., Willemsen G., Chanock S.J., Gu F., Hankinson S.E., Hunter D.J., Hofman A., Tiemeier H., Uitterlinden A.G., van Duijn C.M., Walter S., Chasman D.I., Everett B.M., Paré G., Ridker P.M., Li M.D., Maes H.H., Audrain-McGovern J., Posthuma D., Thornton L.M., Lerman C., Kaprio J., Rose J.E., Ioannidis J.P., Kraft P., Lin D.Y., Sullivan P.F.
ISSN
1553-7404 (Electronic)
ISSN-L
1553-7390
Publication state
Published
Issued date
10/2013
Peer-reviewed
Oui
Volume
9
Number
10
Pages
e1003919
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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.
Keywords
Adaptor Proteins, Vesicular Transport/genetics, Alleles, C-Reactive Protein/genetics, Genetic Diseases, Inborn/genetics, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Longitudinal Studies, Phenotype, Polymorphism, Single Nucleotide/genetics
Pubmed
Web of science
Open Access
Yes
Create date
05/02/2014 17:34
Last modification date
09/08/2024 15:52