All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs
| Title: | All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs |
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| Authors: | Schork AJ; Thompson WK; Pham P; Torkamani A; Roddey JC; Sullivan PF; Kelsoe JR; O'Donovan MC; Furberg H; Tobacco; Genetics Consortium; Bipolar Disorder Psychiatric Genomics Consortium; Schizophrenia Psychiatric Genomics Consortium; Schork NJ; Andreassen OA; Dale AM; Absher D; Agudo A; Almgren P; Ardissino D; Assimes TL; Bandinelli S; Barzan L; Bencko V; Benhamou S; Benjamin EJ; Bis J; Boehnke M; Boerwinkle E; Boomsma DI; Brennan P; Canova C; Castellsagué X; Chanock S; Chasman D; Conway DI; Dackor J; de Geus EJ; Duan J; Elosua R; Everett B; Fabianova E; Ferrucci L; Foretova L; Fortmann SP; Franceschini N; Frayling T; Furberg C; Gejman PV; Groop L; Gu F; Guralnik J; Hankinson SE; Haritunians T; Healy C; Hofman A; Holcátová I; Hunter DJ; Hwang SJ; Ioannidis JP; Iribarren C; Jackson AU; Janout V; Kaprio J; Kim Y; Kjaerheim K; Knowles JW; Kraft P; Ladenvall C; Lagiou P; Lanthrop M; Lerman C; Levinson DF; Levy D; Li MD; Lin DY; Lips EH; Lissowska J; Lowry R; Lucas G; Macfarlane TV; Maes H; Mannucci PM; Mates D; Mauri F; McGovern JA; McKay JD; McKnight B; Melander O; Merlini PA; Milaneschi Y; Mohlke KL; O'Donnell CJ; Pare G; Penninx BW; Perry J; Posthuma D; Preis SR; Psaty B; Quertermous T; Ramachandran VS; Richiardi L; Ridker P; Rose J; Rudnai P; Salomaa V; Sanders AR; Schwartz SM; Shi J; Smit JH; Stringham HM; Szeszenia Dabrowska N; Tanaka T; Taylor K; Thacker E; Thornton L; Tiemeier H; Tuomilehto J; Uitterlinden AG; van Duijn CM; Vink JM; Vogelzangs N; Voight BF; Walter S; Willemsen G; Zaridze D; Znaor A; Akil H; Anjorin A; Backlund L; Badner JA; Barchas JD; Barrett TB; Bass N; Bauer M; Bellivier F; Bergen SE; Berrettini W; Blackwood D; Bloss CS; Breen G; Breuer R; Bunner WE; Burmeister M; Byerley W; Caesar S; Chambert K; Cichon S; St Clair D; Collier DA; Corvin A; Coryell WH; Craddock N; Craig DW; Daly M; Day R; Degenhardt F; Djurovic S; Dudbridge F; Edenberg HJ; Elkin A; Etain B; Farmer AE; Ferreira MA; Ferrier I; Flickinger M; Foroud T; Frank J; Fraser C; Frisén L; Gershon ES; Gill M; Gordon Smith K; Green EK; Greenwood TA; Grozeva D; Guan W; Gurling H; Gustafsson Ó; Hamshere ML; Hautzinger M; Herms S; Hipolito M; Holmans PA; Hultman CM; Jamain S; Jones EG; Jones I; Jones L; Kandaswamy R; Kennedy JL; Kirov GK; Koller DL; Kwan P; Landén M; Langstrom N; Lathrop M; Lawrence J; Lawson WB; Leboyer M; Lee PH; Li J; Lichtenstein P; Lin D; Liu C; Lohoff FW; Lucae S; Mahon PB; Maier W; Martin NG; Mattheisen M; Matthews K; Mattingsdal M; McGhee KA; McGuffin P; McInnis MG; McIntosh A; McKinney R; McLean AW; McMahon FJ; McQuillin A; Meier S; Melle I; Meng F; Mitchell PB; Montgomery GW; Moran J; Morken G; Morris DW; Moskvina V; Muglia P; Mühleisen TW; Muir WJ; Müller Myhsok B; Myers RM; Nievergelt CM; Nikolov I; Nimgaonkar V; Nöthen MM; Nurnberger JI; Nwulia EA; O'Dushlaine C; Osby U; Óskarsson H; Owen MJ; Petursson H; Pickard BS; Porgeirsson P; Potash JB; Propping P; Purcell SM; Quinn E; Raychaudhuri S; Rice J; Rietschel M; Ruderfer D; Schalling M; Schatzberg AF; Scheftner WA; Schofield PR; Schulze TG; Schumacher J; Schwarz MM; Scolnick E; Scott LJ; Shilling PD; Sigurdsson E; Sklar P; Smith EN; Stefansson H; Stefansson K; Steffens M; Steinberg S; Strauss J; Strohmaier J; Szelinger S; Thompson RC; Tozzi F; Treutlein J; Vincent JB; Watson SJ; Wienker TF; Williamson R; Witt SH; Wright A; Xu W; Young AH; Zandi PP; Zhang P; Zöllner S; Agartz I; Albus M; Alexander M; Amdur RL; Amin F; Bitter I; Black DW; Børglum AD; Brown MA; Bruggeman R; Buccola NG; Byerley WF; Cahn W; Cantor RM; Carr VJ; Catts SV; Choudhury K; Cloninger C; Cormican P; Danoy PA; Datta S; DeHert M; Demontis D; Dikeos D; Donnelly P; Donohoe G; Duong L; Dwyer S; Fanous A; Fink Jensen A; Freedman R; Freimer NB; Friedl M; Georgieva L; Giegling I; Glenthøj B; Godard S; Golimbet V; de Haan L; Hansen M; Hansen T; Hartmann AM; Henskens FA; Hougaard DM; Ingason A; Jablensky AV; Jakobsen KD; Jay M; Jönsson EG; Jürgens G; Kahn RS; Keller MC; Kendler KS; Kenis G; Kenny E; Konnerth H; Konte B; Krabbendam L; Krasucki R; Lasseter VK; Laurent C; Lencz T; Lerer F; Liang KY; Lieberman JA; Linszen DH; Lönnqvist J; Loughland CM; Maclean AW; Maher BS; Malhotra AK; Mallet J; Malloy P; McGrath JJ; McLean DE; Michie PT; Milanova V; Mors O; Mortensen PB; Mowry BJ; Myin Germeys I; Neale B; Nertney DA; Nestadt G; Nielsen J; Nordentoft M; Norton N; O'Neill F; Olincy A; Olsen L; Ophoff RA; Ørntoft TF; van Os J; Pantelis C; Papadimitriou G; Pato CN; Pato MT; Peltonen L; Pickard B; Pietiläinen OP; Pimm J; Pulver AE; Puri V; Quested D; Rasmussen HB; Réthelyi JM; Ribble R; Riley BP; Rossin L; Ruggeri M; Rujescu D; Schall U; Schwab SG; Scott RJ; Silverman JM; Spencer CC; Strange A; Strengman E; Stroup T; Suvisaari J; Terenius L; Thirumalai S; Timm S; Toncheva D; Tosato S; van den Oord EJ; Veldink J; Visscher PM; Walsh D; Wang AG; Werge T; Wiersma D; Wildenauer DB; Williams HJ; Williams NM; van Winkel R; Wormley B.; BERNARDINELLI, LUISA |
| Contributors: | Schork, Aj; Thompson, Wk; Pham, P; Torkamani, A; Roddey, Jc; Sullivan, Pf; Kelsoe, Jr; O'Donovan, Mc; Furberg, H; Tobacco; Genetics, Consortium; Bipolar Disorder Psychiatric Genomics, Consortium; Schizophrenia Psychiatric Genomics, Consortium; Schork, Nj; Andreassen, Oa; Dale, Am; Absher, D; Agudo, A; Almgren, P; Ardissino, D; Assimes, Tl; Bandinelli, S; Barzan, L; Bencko, V; Benhamou, S; Benjamin, Ej; Bernardinelli, Luisa; Bis, J; Boehnke, M; Boerwinkle, E; Boomsma, Di; Brennan, P; Canova, C; Castellsagué, X; Chanock, S; Chasman, D; Conway, Di; Dackor, J; de Geus, Ej; Duan, J; Elosua, R; Everett, B; Fabianova, E; Ferrucci, L; Foretova, L; Fortmann, Sp; Franceschini, N; Frayling, T; Furberg, C; Gejman, Pv; Groop, L; Gu, F; Guralnik, J; Hankinson, Se; Haritunians, T; Healy, C; Hofman, A; Holcátová, I; Hunter, Dj; Hwang, Sj; Ioannidis, Jp; Iribarren, C; Jackson, Au; Janout, V; Kaprio, J; Kim, Y; Kjaerheim, K; Knowles, Jw; Kraft, P; Ladenvall, C; Lagiou, P; Lanthrop, M; Lerman, C; Levinson, Df; Levy, D; Li, Md; Lin, Dy; Lips, Eh; Lissowska, J; Lowry, R; Lucas, G; Macfarlane, Tv; Maes, H; Mannucci, Pm; Mates, D; Mauri, F; Mcgovern, Ja; Mckay, Jd; Mcknight, B; Melander, O; Merlini, Pa; Milaneschi, Y; Mohlke, Kl; O'Donnell, Cj; Pare, G; Penninx, Bw; Perry, J; Posthuma, D; Preis, Sr; Psaty, B |
| Publication Year: | 2013 |
| Collection: | IRIS UNIPV (Università degli studi di Pavia) |
| Subject Terms: | Genetic Predisposition to Disease; Human; Linkage Disequilibrium; Phenotype; Schizophrenia; Genome-Wide Association Study; Polymorphism; Single Nucleotide; Ecology; Evolution; Behavior and Systematic; Molecular Biology; Genetic; Genetics (clinical); Cancer Research |
| Description: | Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1-FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci. |
| Document Type: | article in journal/newspaper |
| File Description: | ELETTRONICO |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/23637621; info:eu-repo/semantics/altIdentifier/wos/WOS:000318073300042; volume:9; issue:4; firstpage:e1003449; journal:PLOS GENETICS; http://hdl.handle.net/11571/1182105; http://www.plosgenetics.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1003449&representation=PDF |
| DOI: | 10.1371/journal.pgen.1003449 |
| Availability: | http://hdl.handle.net/11571/1182105; https://doi.org/10.1371/journal.pgen.1003449; http://www.plosgenetics.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1003449&representation=PDF |
| Accession Number: | edsbas.995E847E |
| Database: | BASE |