All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs

Autor: Aj, Schork, Wk, Thompson, Pham P, Torkamani A, Jc, Roddey, Pf, Sullivan, Jr, Kelsoe, Donovan Mc, O., Furberg H, Tobacco and Genetics Consortium, Bipolar Disorder Psychiatric Genomics Consortium, Schizophrenia Psychiatric Genomics Consortium, Nj, Schork, Oa, Andreassen, Am, Dale, Absher D, Agudo A, Almgren P, Ardissino D, Tl, Assimes, Bandinelli S, Barzan L, Bencko V, Benhamou S, Ej, Benjamin, Bernardinelli L, Bis J, Boehnke M, Boerwinkle E, Di, Boomsma, Brennan P, Canova C, Castellsagué X, Chanock S, Chasman D, Di, Conway, Dackor J, Ej, Geus, Duan J, Elosua R, Everett B, Fabianova E, Ferrucci L, Foretova L, Sp, Fortmann, Franceschini N, Frayling T, Furberg C, Pv, Gejman, Groop L, Gu F, Guralnik J, Se, Hankinson, Haritunians T, Healy C, Hofman A, Holcátová I, Dj, Hunter, Sj, Hwang, Jp, Ioannidis, Iribarren C, Au, Jackson, Janout V, Kaprio J, Kim Y, Kjaerheim K, Jw, Knowles, Kraft P, Ladenvall C, Lagiou P, Lanthrop M, Lerman C, Df, Levinson, Levy D, Md, Li, Dy, Lin, Eh, Lips, Lissowska J, Lowry R, Lucas G, Tv, Macfarlane, Maes H, Pm, Mannucci, Mates D, Mauri F, Ja, Mcgovern, Jd, Mckay, McKnight B, Melander O, Pa, Merlini, Milaneschi Y, Kl, Mohlke, Donnell Cj, O., Pare G, Bw, Penninx, Perry J, Posthuma D, Sr, Preis, Psaty B, Quertermous T, Vs, Ramachandran, Richiardi L, Ridker P, Rose J, Rudnai P, Salomaa V, Ar, Sanders, Sm, Schwartz, Shi J, Jh, Smit, Hm, Stringham, Szeszenia-Dabrowska N, Tanaka T, Taylor K, Thacker E, Thornton L, Tiemeier H, Tuomilehto J, Ag, Uitterlinden, Cm, Duijn, Jm, Vink, Vogelzangs N, Bf, Voight, Walter S, Willemsen G, Zaridze D, Znaor A, Akil H, Anjorin A, Backlund L, Ja, Badner, Jd, Barchas, Tb, Barrett, Bass N, Bauer M, Bellivier F, Se, Bergen, Berrettini W, Blackwood D, Cs, Bloss, Breen G, Breuer R, We, Bunner, Burmeister M, Byerley W, Caesar S, Chambert K, Cichon S, St Clair D, Da, Collier, Corvin A, Wh, Coryell, Craddock N, Dw, Craig, Daly M, Day R, Degenhardt F, Djurovic S, Dudbridge F, Hj, Edenberg, Elkin A, Etain B, Ae, Farmer, Ma, Ferreira, Ferrier I, Flickinger M, Foroud T, Frank J, Fraser C, Frisén L, Es, Gershon, Gill M, Gordon-Smith K, Ek, Green, Ta, Greenwood, Grozeva D, Guan W, Gurling H, Ó, Gustafsson, Ml, Hamshere, Hautzinger M, Herms S, Hipolito M, Pa, Holmans, Cm, Hultman, Jamain S, Eg, Jones, Jones I, Jones L, Kandaswamy R, Jl, Kennedy, Gk, Kirov, Dl, Koller, Kwan P, Landén M, Langstrom N, Lathrop M, Lawrence J, Wb, Lawson, Leboyer M, Ph, Lee, Li J, Lichtenstein P, Lin D, Liu C, Fw, Lohoff, Lucae S, Pb, Mahon, Maier W, Ng, Martin, Mattheisen M, Matthews K, Mattingsdal M, Ka, Mcghee, McGuffin P, Mg, Mcinnis, McIntosh A, McKinney R, Aw, Mclean, Fj, Mcmahon, McQuillin A, Meier S, Melle I, Meng F, Pb, Mitchell, Gw, Montgomery, Moran J, Morken G, Dw, Morris, Moskvina V, Muglia P, Tw, Mühleisen, Wj, Muir, Müller-Myhsok B, Rm, Myers, Cm, Nievergelt, Nikolov I, Nimgaonkar V, Mm, Nöthen, Ji, Nurnberger, Ea, Nwulia, O'Dushlaine C, Osby U, Óskarsson H, Mj, Owen, Petursson H, Bs, Pickard, Porgeirsson P, Jb, Potash, Propping P, Sm, Purcell, Quinn E, Raychaudhuri S, Rice J, Rietschel M, Ruderfer D, Schalling M, Af, Schatzberg, Wa, Scheftner, Pr, Schofield, Tg, Schulze, Schumacher J, Mm, Schwarz, Scolnick E, Lj, Scott, Pd, Shilling, Sigurdsson E, Sklar P, En, Smith, Stefansson H, Stefansson K, Steffens M, Steinberg S, Strauss J, Strohmaier J, Szelinger S, Rc, Thompson, Tozzi F, Treutlein J, Jb, Vincent, Sj, Watson, Tf, Wienker, Williamson R, Sh, Witt, Wright A, Xu W, Ah, Young, Pp, Zandi, Zhang P, Zöllner S, Agartz I, Albus M, Alexander M, Rl, Amdur, Amin F, Bitter I, Dw, Black, Ad, Børglum, Ma, Brown, Bruggeman R, Ng, Buccola, Wf, Byerley, Cahn W, Rm, Cantor, Vj, Carr, Sv, Catts, Choudhury K, Cloninger C, Cormican P, Pa, Danoy, Datta S, DeHert M, Demontis D, Dikeos D, Donnelly P, Donohoe G, Duong L, Dwyer S, Fanous A, Fink-Jensen A, Freedman R, Nb, Freimer, Friedl M, Georgieva L, Giegling I, Glenthøj B, Godard S, Golimbet V, de Haan L, Hansen M, Hansen T, Am, Hartmann, Fa, Henskens, Dm, Hougaard, Ingason A, Av, Jablensky, Kd, Jakobsen, Jay M, Eg, Jönsson, Jürgens G, Rs, Kahn, Mc, Keller, Ks, Kendler, Kenis G, Kenny E, Konnerth H, Konte B, Krabbendam L, Krasucki R, Vk, Lasseter, Laurent C, Lencz T, Lerer F, Ky, Liang, Ja, Lieberman, Dh, Linszen, Lönnqvist J, Cm, Loughland, Aw, Maclean, Bs, Maher, Ak, Malhotra, Mallet J, Malloy P, Jj, Mcgrath, McLean DE, Pt, Michie, Milanova V, Mors O, Pb, Mortensen, Bj, Mowry, Myin-Germeys I, Neale B, Da, Nertney, Nestadt G, Nielsen J, Nordentoft M, Norton N, O'Neill F, Olincy A, Olsen L, Ra, Ophoff, Tf, Ørntoft, van Os J, Pantelis C, Papadimitriou G, Cn, Pato, Mt, Pato, Peltonen L, Pickard B, Op, Pietiläinen, Pimm J, Ae, Pulver, Puri V, Digby Quested, Hb, Rasmussen, Jm, Réthelyi, Ribble R, Bp, Riley, Rossin L, Ruggeri M, Rujescu D, Schall U, Sg, Schwab, Rj, Scott, Jm, Silverman, Cc, Spencer, Strange A, Strengman E, Stroup T, Suvisaari J, Terenius L, Thirumalai S, Timm S, Toncheva D, Tosato S, Ej, Den Oord, Veldink J, Pm, Visscher, Walsh D, Ag, Wang, Werge T, Wiersma D, Db, Wildenauer, Hj, Williams, Nm, Williams, van Winkel R, Wormley B.
Přispěvatelé: Biological Psychology, Functional Genomics, Educational Neuroscience, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, ANS - Amsterdam Neuroscience, Adult Psychiatry, Psychiatry, Human genetics, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Gibson, Greg, Germeys, Inez, van Winkel, Ruud, De Hert, Marc
Rok vydání: 2013
Předmět:
False discovery rate
Netherlands Twin Register (NTR)
Cancer Research
Linkage disequilibrium
Genome-wide association study
Linkage Disequilibrium
0302 clinical medicine
2.1 Biological and endogenous factors
Aetiology
Genetics (clinical)
Genetics
0303 health sciences
Statistics
Genomics
Single Nucleotide
Genome Scans
Tobacco and Genetics Consortium
Functional Genomics
Phenotype
complex trait
Research Article
Bipolar Disorder Psychiatric Genomics Consortium
lcsh:QH426-470
SNP
Single-nucleotide polymorphism
Computational biology
Biostatistics
Biology
Polymorphism
Single Nucleotide
03 medical and health sciences
"genome-wide association study"
Genome Analysis Tools
Clinical Research
Schizophrenia Psychiatric Genomics Consortium
Genome-Wide Association Studies
Humans
Genetic Predisposition to Disease
Statistical Methods
Polymorphism
Molecular Biology
Genetic Association Studies
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Genetic association
Linkage (software)
Human Genome
Computational Biology
Human Genetics
Heritability
R1
schizophrenia
lcsh:Genetics
Schizophrenia
Mathematics
030217 neurology & neurosurgery
Genome-Wide Association Study
Developmental Biology
Zdroj: PLoS genetics, vol 9, iss 4
PLoS Genetics
Schork, AJ; Thompson, WK; Pham, P; Torkamani, A; Roddey, JC; Sullivan, PF; et al.(2013). All SNPs are not created equal: Genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. PLoS Genetics, 9(4). doi: 10.1371/journal.pgen.1003449. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/9xc7s4vr
Schork, A J, Thompson, W K, Pham, P, Torkamani, A, Roddey, J C, Sullivan, P F, Kelsoe, J, O'Donovan, M C, Furberg, H, Absher, D, Agudo, A, Almgren, P, Ardissino, D, Assimes, T L, Bandinelli, S, Barzan, L, Bencko, V, Benhamou, S, Benjamin, E J, Bernardinelli, L, Bis, J, Boehnke, M, Boerwinkle, E, Boomsma, D I, Brennan, P, Canova, C, Castellsagué, X, Chanock, S, Chasman, D I, Conway, D I, Dackor, J, de Geus, E J C, Duan, J, Elosua, R, Everett, B, Fabianova, E, Ferrucci, L, Foretova, L, Fortmann, S P, Franceschini, N, Frayling, T M, Furberg, C, Gejman, P V, Groop, L, Gu, F, Guralnik, J, Hankinson, S E, Haritunians, T, Healy, C, Hofman, A, Holcátová, I, Hunter, D J, Hwang, S J, Ioannidis, J P A, Iribarren, C, Jackson, A U, Janout, V, Kaprio, J, Kim, Y, Kjaerheim, K, Knowles, J W, Kraft, P, Ladenvall, C, Lagiou, P, Lanthrop, M, Lerman, C, Levinson, D F, Levy, D, Li, M D, Lin, D Y, Lips, E H, Lissowska, J, Lowry, R B, Lucas, G, Macfarlane, T V, Maes, H H M, Mannucci, P M, Mates, D, Mauri, F, McGovern, J A, McKay, J D, McKnight, B, Melander, O, Merlini, P A, Milaneschi, Y, Mohlke, K L, O'Donnell, C J, Pare, G, Penninx, B W J H, Perry, J R B, Posthuma, D, Preis, S R, Psaty, B, Quertermous, T, Ramachandran, V S, Richiardi, L, Ridker, P M, Rose, J, Rudnai, P, Salomaa, V, Sanders, A R, Schwartz, S M, Shi, J, Smit, J H, Stringham, H M, Szeszenia-Dabrowska, N, Tanaka, T, Taylor, K, Thacker, E E, Thornton, L, Tiemeier, H, Tuomilehto, J, Uitterlinden, A G, van Duijn, C M, Vink, J M, Vogelzangs, N, Voight, B F, Walter, S, Willemsen, G, Zaridze, D, Znaor, A, Akil, H, Anjorin, A, Backlund, L, Badner, J A, Barchas, J D, Barrett, T, Bass, N, Bauer, M, Bellivier, F, Bergen, S E, Berrettini, W, Blackwood, D, Bloss, C S, Breen, G, Breuer, R, Bunner, W E, Burmeister, M, Byerley, W F, Caesar, S, Chambert, K, Cichon, S, St Clair, D, Collier, D A, Corvin, A, Coryell, W H, Craddock, N, Craig, D W, Daly, M, Day, R, Degenhardt, F, Djurovic, S, Dudbridge, F, Edenberg, H J, Elkin, A, Etain, B, Farmer, A E, Ferreira, M A, Ferrier, I, Flickinger, M, Foroud, T, Frank, J, Fraser, C, Frisén, L, Gershon, E S, Gill, M, Gordon-Smith, K, Green, E K, Greenwood, T A, Grozeva, D, Guan, W, Gurling, H, Gustafsson, O, Hamshere, M L, Hautzinger, M, Herms, S, Hipolito, M, Holmans, P A, Hultman, C M, Jamain, S, Jones, E G, Jones, I, Jones, L, Kandaswamy, R, Kennedy, J L, Kirov, G K, Koller, D L, Kwan, P, Landén, M, Langstrom, N, Lathrop, M, Lawrence, J, Lawson, W B, Leboyer, M, Lee, P H, Li, J, Lichtenstein, P, Lin, D, Liu, C, Lohoff, F W, Lucae, S, Mahon, P B, Maier, W, Martin, N G, Mattheisen, M, Matthews, K, Mattingsdal, M, McGhee, K A, McGuffin, P, McInnis, M G, McIntosh, A, McKinney, R, McLean, A W, McMahon, F J, McQuillin, A, Meier, S, Melle, I, Meng, F, Mitchell, P B, Montgomery, G W, Moran, J, Morken, G, Morris, D W, Moskvina, V, Muglia, P, Mühleisen, T W, Muir, W J, Müller-Myhsok, B, Myers, R M, Nievergelt, C M, Nikolov, I, Nimgaonkar, V L, Nöthen, M M, Nurnberger, J I, Nwulia, E A, O'Dushlaine, C, Osby, U, Óskarsson, H, Owen, M J, Petursson, H, Pickard, B S, Porgeirsson, P, Potash, J B, Propping, P, Purcell, S M, Quinn, E, Raychaudhuri, S, Rice, J, Rietschel, M, Ruderfer, D, Schalling, M, Schatzberg, A F, Scheftner, W A, Schofield, P R, Schulze, T G, Schumacher, J, Schwarz, M M, Scolnick, E, Scott, L J, Shilling, P D, Sigurdsson, E, Sklar, P, Smith, E N, Stefansson, H, Stefansson, K, Steffens, M, Steinberg, S, Strauss, J, Strohmaier, J, Szelinger, S, Thompson, R C, Tozzi, F, Treutlein, J, Vincent, J B, Watson, S J, Wienker, T F, Williamson, R, Witt, S H, Wright, A, Xu, W, Young, A H, Zandi, P P, Zhang, P, Zöllner, S, Agartz, I, Albus, M, Alexander, M, Amdur, R L, Amin, F, Bitter, I, Black, D W, Børglum, A D, Brown, M A, Bruggeman, R, Buccola, N G, Cahn, W, Cantor, R M, Carr, V J, Catts, S V, Choudhury, K, Cloninger, C R, Cormican, P, Danoy, P A, Datta, S, DeHert, M, Demontis, D, Dikeos, D, Donnelly, P, Donohoe, G, Duong, L, Dwyer, S, Fanous, A, Fink-Jensen, A, Freedman, R, Freimer, N B, Friedl, M, Georgieva, L, Giegling, I, Glenthoj, B, Godard, S, Golimbet, V, de Haan, L, Hansen, M, Hansen, T, Hartmann, A M, Henskens, F A, Hougaard, D M, Ingason, A, Jablensky, A V, Jakobsen, K D, Jay, M, Jönsson, E G, Jürgens, G, Kahn, R S, Keller, M C, Kendler, K S, Kenis, G, Kenny, E, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, V K, Laurent, C, Lencz, T, Lerer, F B, Liang, K Y, Lieberman, J A, Linszen, D H, Lönnqvist, J, Loughland, C M, Maclean, A W, Maher, B S, Malhotra, A K, Mallet, J, Malloy, P, McGrath, J J, McLean, D E, Michie, P T, Milanova, V, Mors, O, Mortensen, P B, Mowry, B J, Myin-Germeys, I, Neale, B, Nertney, D A, Nestadt, G, Nielsen, J, Nordentoft, M, Norton, N, O'Neill, F, Olincy, A, Olsen, L, Ophoff, R A, Orntoft, T F, van Os, J, Pantelis, C, Papadimitriou, G, Pato, C N, Peltonen, L, Pickard, B, Pietilainen, O P, Pimm, J, Pulver, A E, Puri, V, Quested, D, Rasmussen, H B, Rethelyi, J M, Ribble, R, Riley, B P, Rossin, L, Ruggeri, M, Rujescu, D, Schall, U, Schwab, S G, Scott, R J, Silverman, J M, Spencer, C C, Strange, A, Strengman, E, Stroup, T S, Suvisaari, J, Terenius, L, Thirumalai, S, Timm, S, Toncheva, D, Tosato, S, van den Oord, E J, Veldink, J, Visscher, P M, Walsh, D, Wang, A G, Werge, T, Wiersma, D, Wildenauer, D B, Williams, H J, Williams, N M, van Winkel, R, Wormley, B, Zammit, S, Schork, N J, Andreassen, O A & Dale, A M 2013, ' All SNPs are not created equal: Genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs ', PLoS Genetics, vol. 9, no. 4, e1003449, pp. e1003449 . https://doi.org/10.1371/journal.pgen.1003449
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PLoS Genetics, Vol 9, Iss 4, p e1003449 (2013)
PLoS Genetics, 9(4):e1003449. Public Library of Science
PLoS genetics, 9(4). Public Library of Science
Plos Genetics, 9(4):e1003449. Public Library of Science
ISSN: 1553-7390
1553-7404
DOI: 10.1371/journal.pgen.1003449.
Popis: 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.
Author Summary Modern genome-wide association studies (GWAS) have failed to identify large portions of the genetic basis of common, complex traits. Recent work suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS. Moreover, these variants appear more abundantly in and near genes. Using genome annotations, summary statistics from several of the largest GWAS, and established statistical methods for quantifying distributions of test statistics, we show a consistency across studies. Namely, we show that, across all assessed traits, the test statistics resulting from SNPs that are related to the 5′ UTR of genes show the largest abundance of associations, while SNPs related to exons and the 3′UTR are also enriched. SNPs related to introns are only moderately enriched, and intergenic SNPs show a depletion of associations relative to the average SNP. This enrichment corresponds directly to increased replication across independent samples and can be incorporated a priori into statistical methods to improve discovery and prediction. Our results contribute to on-going debates about the functional nature of the genetic architecture of complex traits and point to avenues for leveraging existing GWAS data for discovery in future GWA and sequencing studies.
Databáze: OpenAIRE
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