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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PMID
23637621
TITLE
All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs.
ABSTRACT
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.
DATE PUBLISHED
2013 Apr
HISTORY
PUBSTATUS PUBSTATUSDATE
ppublish 2013/04
received 2012/08/28
accepted 2013/02/28
epublish 2013/04/25
entrez 2013/05/03 06:00
pubmed 2013/05/03 06:00
medline 2016/04/23 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Schork AJ Schork Andrew J AJ Cognitive Sciences Graduate Program, University of California San Diego, La Jolla, California, United States of America.
Thompson WK Thompson Wesley K WK
Pham P Pham Phillip P
Torkamani A Torkamani Ali A
Roddey JC Roddey J Cooper JC
Sullivan PF Sullivan Patrick F PF
Kelsoe JR Kelsoe John R JR
O'Donovan MC O'Donovan Michael C MC
Furberg H Furberg Helena H
Tobacco and Genetics Consortium
Bipolar Disorder Psychiatric Genomics Consortium
Schizophrenia Psychiatric Genomics Consortium
Schork NJ Schork Nicholas J NJ
Andreassen OA Andreassen Ole A OA
Dale AM Dale Anders M AM
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Absher Devin D
Agudo Antonio A
Almgren Peter P
Ardissino Diego D
Assimes Themistocles L TL
Bandinelli Stephania S
Barzan Luigi L
Bencko Vladimir V
Benhamou Simone S
Benjamin Emelia J EJ
Bernardinelli Luisa L
Bis Joshua J
Boehnke Michael M
Boerwinkle Eric E
Boomsma Dorret I DI
Brennan Paul P
Canova Cristina C
Castellsagué Xavier X
Chanock Stephen S
Chasman Daniel D
Conway David I DI
Dackor Jennifer J
de Geus Eco J C EJ
Duan Jubao J
Elosua Roberto R
Everett Brendan B
Fabianova Eleonora E
Ferrucci Luigi L
Foretova Lenka L
Fortmann Stephen P SP
Franceschini Nora N
Frayling Timothy T
Furberg Curt C
Gejman Pablo V PV
Groop Leif L
Gu Fangyi F
Guralnik Jack J
Hankinson Susan E SE
Haritunians Talin T
Healy Claire C
Hofman Albert A
Holcátová Ivana I
Hunter David J DJ
Hwang Shih-Jen SJ
Ioannidis John P A JP
Iribarren Carlos C
Jackson Anne U AU
Janout Vladimir V
Kaprio Jaakko J
Kim Yunjung Y
Kjaerheim Kristina K
Knowles Joshua W JW
Kraft Peter P
Ladenvall Claes C
Lagiou Pagona P
Lanthrop Mark M
Lerman Caryn C
Levinson Douglas F DF
Levy Daniel D
Li Ming D MD
Lin Dan Yu DY
Lips Esther H EH
Lissowska Jolanta J
Lowry Ray R
Lucas Gavin G
Macfarlane Tatiana V TV
Maes Hermine H
Mannucci Pier Mannuccio PM
Mates Dana D
Mauri Francesco F
McGovern Janet Audrain JA
McKay James D JD
McKnight Barbara B
Melander Olle O
Merlini Piera Angelica PA
Milaneschi Yuri Y
Mohlke Karen L KL
O'Donnell Christopher J CJ
Pare Guillaume G
Penninx Brenda W BW
Perry John J
Posthuma Danielle D
Preis Sarah Rosner SR
Psaty Bruce B
Quertermous Thomas T
Ramachandran Vasan S VS
Richiardi Lorenzo L
Ridker Paul P
Rose Jed J
Rudnai Peter P
Salomaa Veikko V
Sanders Alan R AR
Schwartz Stephen M SM
Shi Jianxin J
Smit Johannes H JH
Stringham Heather M HM
Szeszenia-Dabrowska Neonilia N
Tanaka Toshiko T
Taylor Kent K
Thacker Evan E
Thornton Laura L
Tiemeier Henning H
Tuomilehto Jaakko J
Uitterlinden Andre G AG
van Duijn Cornelia M CM
Vink Jacqueline M JM
Vogelzangs Nicole N
Voight Benjamin F BF
Walter Stefan S
Willemsen Gonneke G
Zaridze David D
Znaor Ariana A
Absher Devin D
Akil Huda H
Anjorin Adebayo A
Backlund Lena L
Badner Judith A JA
Barchas Jack D JD
Barrett Thomas B TB
Bass Nick N
Bauer Michael M
Bellivier Frank F
Bergen Sarah E SE
Berrettini Wade W
Blackwood Douglas D
Bloss Cinnamon S CS
Boehnke Michael M
Breen Gerome G
Breuer René R
Bunner William E WE
Burmeister Margit M
Byerley William W
Caesar Sian S
Chambert Kim K
Cichon Sven S
St Clair David D
Collier David A DA
Corvin Aiden A
Coryell William H WH
Craddock Nicholas N
Craig David W DW
Daly Mark M
Day Richard R
Degenhardt Franziska F
Djurovic Srdjan S
Dudbridge Frank F
Edenberg Howard J HJ
Elkin Amanda A
Etain Bruno B
Farmer Anne E AE
Ferreira Manuel A MA
Ferrier I Nicol I
Flickinger Matthew M
Foroud Tatiana T
Frank Josef J
Fraser Christine C
Frisén Louise L
Gershon Elliot S ES
Gill Michael M
Gordon-Smith Katherine K
Green Elaine K EK
Greenwood Tiffany A TA
Grozeva Detelina D
Guan Weihua W
Gurling Hugh H
Gustafsson Ómar Ó
Hamshere Marian L ML
Hautzinger Martin M
Herms Stefan S
Hipolito Maria M
Holmans Peter A PA
Hultman Christina M CM
Jamain Stéphane S
Jones Edward G EG
Jones Ian I
Jones Lisa L
Kandaswamy Radhika R
Kennedy James L JL
Kirov George K GK
Koller Daniel L DL
Kwan Phoenix P
Landén Mikael M
Langstrom Niklas N
Lathrop Mark M
Lawrence Jacob J
Lawson William B WB
Leboyer Marion M
Lee Phil H PH
Li Jun J
Lichtenstein Paul P
Lin Danyu D
Liu Chunyu C
Lohoff Falk W FW
Lucae Susanne S
Mahon Pamela B PB
Maier Wolfgang W
Martin Nicholas G NG
Mattheisen Manuel M
Matthews Keith K
Mattingsdal Morten M
McGhee Kevin A KA
McGuffin Peter P
McInnis Melvin G MG
McIntosh Andrew A
McKinney Rebecca R
McLean Alan W AW
McMahon Francis J FJ
McQuillin Andrew A
Meier Sandra S
Melle Ingrid I
Meng Fan F
Mitchell Philip B PB
Montgomery Grant W GW
Moran Jennifer J
Morken Gunnar G
Morris Derek W DW
Moskvina Valentina V
Muglia Pierandrea P
Mühleisen Thomas W TW
Muir Walter J WJ
Müller-Myhsok Bertram B
Myers Richard M RM
Nievergelt Caroline M CM
Nikolov Ivan I
Nimgaonkar Vishwajit V
Nöthen Markus M MM
Nurnberger John I JI
Nwulia Evaristus A EA
O'Dushlaine Colm C
Osby Urban U
Óskarsson Högni H
Owen Michael J MJ
Petursson Hannes H
Pickard Benjamin S BS
Porgeirsson Porgeir P
Potash James B JB
Propping Peter P
Purcell Shaun M SM
Quinn Emma E
Raychaudhuri Soumya S
Rice John J
Rietschel Marcella M
Ruderfer Douglas D
Schalling Martin M
Schatzberg Alan F AF
Scheftner William A WA
Schofield Peter R PR
Schulze Thomas G TG
Schumacher Johannes J
Schwarz Markus M MM
Scolnick Ed E
Scott Laura J LJ
Shilling Paul D PD
Sigurdsson Engilbert E
Sklar Pamela P
Smith Erin N EN
Stefansson Hreinn H
Stefansson Kari K
Steffens Michael M
Steinberg Stacy S
Strauss John J
Strohmaier Jana J
Szelinger Szabocls S
Thompson Robert C RC
Tozzi Federica F
Treutlein Jens J
Vincent John B JB
Watson Stanley J SJ
Wienker Thomas F TF
Williamson Richard R
Witt Stephanie H SH
Wright Adam A
Xu Wei W
Young Allan H AH
Zandi Peter P PP
Zhang Peng P
Zöllner Sebastian S
Agartz Ingrid I
Albus Margot M
Alexander Madeline M
Amdur Richard L RL
Amin Farooq F
Bass Nicholas N
Bitter István I
Black Donald W DW
Børglum Anders D AD
Brown Matthew A MA
Bruggeman Richard R
Buccola Nancy G NG
Byerley William F WF
Cahn Wiepke W
Cantor Rita M RM
Carr Vaughan J VJ
Catts Stanley V SV
Choudhury Khalid K
Cloninger C Robert C
Cormican Paul P
Danoy Patrick A PA
Datta Susmita S
DeHert Marc M
Demontis Ditte D
Dikeos Dimitris D
Donnelly Peter P
Donohoe Gary G
Duan Jubao J
Duong Linh L
Dwyer Sarah S
Fanous Ayman A
Fink-Jensen Anders A
Freedman Robert R
Freimer Nelson B NB
Friedl Marion M
Gejman Pablo V PV
Georgieva Lyudmila L
Giegling Ina I
Glenthøj Birte B
Godard Stephanie S
Golimbet Vera V
de Haan Lieuwe L
Hansen Mark M
Hansen Thomas T
Hartmann Annette M AM
Henskens Frans A FA
Hougaard David M DM
Ingason Andrés A
Jablensky Assen V AV
Jakobsen Klaus D KD
Jay Maurice M
Jönsson Erik G EG
Jürgens Gesche G
Kahn René S RS
Keller Matthew C MC
Kendler Kenneth S KS
Kenis Gunter G
Kenny Elaine E
Kim Yunjung Y
Konnerth Heike H
Konte Bettina B
Krabbendam Lydia L
Krasucki Robert R
Lasseter Virginia K VK
Laurent Claudine C
Lencz Todd T
Lerer F Bernard F
Levinson Douglas F DF
Liang Kung-Yee KY
Lieberman Jeffrey A JA
Linszen Don H DH
Lönnqvist Jouko J
Loughland Carmel M CM
Maclean Alan W AW
Maher Brion S BS
Malhotra Anil K AK
Mallet Jacques J
Malloy Pat P
McGrath John J JJ
McLean Duncan E DE
Michie Patricia T PT
Milanova Vihra V
Mors Ole O
Mortensen Preben B PB
Mowry Bryan J BJ
Myin-Germeys Inez I
Neale Benjamin B
Nertney Deborah A DA
Nestadt Gerald G
Nielsen Jimmi J
Nordentoft Merete M
Norton Nadine N
O'Neill F Anthony F
Olincy Ann A
Olsen Line L
Ophoff Roel A RA
Ørntoft Torben F TF
van Os Jim J
Pantelis Christos C
Papadimitriou George G
Pato Carlos N CN
Pato Michele T MT
Peltonen Leena L
Pickard Ben B
Pietiläinen Olli P H OP
Pimm Jonathan J
Posthuma Danielle D
Pulver Ann E AE
Puri Vinay V
Quested Digby D
Rasmussen Henrik B HB
Réthelyi János M JM
Ribble Robert R
Riley Brien P BP
Rossin Lizzy L
Ruggeri Mirella M
Rujescu Dan D
Sanders Alan R AR
Schall Ulrich U
Schwab Sibylle G SG
Scolnick Edward E
Scott Rodney J RJ
Shi Jianxin J
Silverman Jeremy M JM
Spencer Chris C A CC
Strange Amy A
Strengman Eric E
Stroup T Scott T
Suvisaari Jaana J
Terenius Lars L
Thirumalai Srinivasa S
Timm Sally S
Toncheva Draga D
Tosato Sarah S
van den Oord Edwin J C G EJ
Veldink Jan J
Visscher Peter M PM
Walsh Dermot D
Wang August G AG
Werge Thomas T
Wiersma Durk D
Wildenauer Dieter B DB
Williams Hywel J HJ
Williams Nigel M NM
van Winkel Ruud R
Wormley Brandon B
Zammit Stan S
JOURNAL
VOLUME: 9
ISSUE: 4
TITLE: PLoS genetics
ISOABBREVIATION: PLoS Genet.
YEAR: 2013
MONTH: Apr
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
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GRANTS
GRANTID AGENCY COUNTRY
090532 Wellcome Trust United Kingdom
G0701420 Medical Research Council United Kingdom
P50MH081755 NIMH NIH HHS United States
P50NS022343 NINDS NIH HHS United States
R01 HD061414 NICHD NIH HHS United States
R01 MH083094 NIMH NIH HHS United States
R01AG022381 NIA NIH HHS United States
R01AG031224 NIA NIH HHS United States
R01EB000790 NIBIB NIH HHS United States
R01HD061414 NICHD NIH HHS United States
RC2DA029475 NIDA NIH HHS United States
SR01AG022381-09 NIA NIH HHS United States
U19 AG023122 NIA NIH HHS United States
U54NS056883 NINDS NIH HHS United States
UL1 RR025774 NCRR NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Phenotype
Polymorphism, Single Nucleotide
Schizophrenia genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
OTHERID SOURCE
PMC3636284 NLM
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