Beginning the PGC3 grant Patrick Sullivan for the PGC University of North Carolina / Karolinska Institutet 1
BeginningthePGC3grant
PatrickSullivanforthePGCUniversityofNorthCarolina/Karolinska Institutet
1
PGC(briefly)
2
PGCoverview
• 2007-present• 9disorders• 900+scientistsinPGC,largestconsortiumever• Resultsfreelyavailable• Papers:17main,31secondary/methods,75+useourresults• Manyhighlycitedor“hot”papers
3
PGC3grant,6/2016– 4/2021
4
PGChistory
Aim PGC1 PGC2 PGC3
NIHfunding 2009-11 2011-16 2016-2021
NIH NIMH NIMH NIMH,NIDA
Co-funding – yes* yes*‡
Dataharmonization yes yes yes
Numberofcases 30K 264K 600K+
Aim:GWAS mega-analyses 5 disorders 9 disorders 9disorders
5disorders:ADHD,AUT,BIP,MDD,SCZ
9disorders:addeatingdisorder,OCD/TS,PTSD,SUDs
5
ScienceFoundationIreland&NorwegianResearchCouncil
6
Coordinatingcommittee(Sullivan)
ADHD(Faraone)
AN(Bulik,Breen)
AUT(Daly)
SUDs(Agrawal)
BIP(Kelsoe,Sklar)
MDD(Sullivan)
OCD/TS(Mathews)
PTSD(Koenen)
SCZ(O’Donovan)
Cross-Disorder(Smoller)
CNV(Sebat)
Statisticalanalysis(Daly)
NIMHGeetha SenthilThomasLehnerAnji Addington
900+investigators
“States’rightsmodel”
7
“Growingpains”fixesIn2009,noonethoughtthePGCwouldbearoundin2020…
8
Updatedwebpage
Thanks1e6to:KristaLatta,LeaDavis,GeromeBreen,CindyBulik,MichaelGill
Greatsectionsallaround
Inparticular,theextensiveFAQ&newbiesections
9
DataAccessCommittee
10
PGCtalks
Shifttodisseminationofmethods
11
Ricopili training
Ricopili isthePGCgwas pipeline,https://github.com/Nealelab/ricopiliTherehavebeen2trainingsessionsinLondon(June2015&2016)Trained24&45analysts.https://sites.google.com/a/broadinstitute.org/pgc-summer-school-2016
Hopetorepeatin2017
ThankstoCathryn Lewis&GeromeBreen(IOPPNorganizers)StanleyCenterformajorfunding
12
Communications
UNClistservs formostgroups
MultipleGoogleGroups
Keygooglegroupisthisone(N=968)https://groups.google.com/forum/?hl=en-GB#!forum/pgc-full-consortium
Pointperson=KristaLattŀ (UNC)
13
Bioinformatics
BuildingbioinformaticstoolsonLISAtounderstandoutput• Basicannotations(genes,GWAScatalog,OMIM,psychCNVs,ID/ASD)• Makinga”genematrix”(usingR,extensible,modifiable)• Geneticcorrelations&lookupvsallPGCresults• MakeinputdataforLD-Hub• MAGMApathwayanalysis;TWAS;causalSNPidentification;partitionedLDSC;etc
DoingpilotprojectwithpsychENCODE toaddfunctionalgenomicdata
14
PGC3grant
15
andBrisbaneAustralia ORCIDlistsADHD,AN,BIPMDDOCD/TSSUD
16
Structure
Site Site lead Note 1 2 3 4 5 6
Cardiff O’Donovan,Mick Largest site ✓
Dublin Gill,Michael Big peds ✓
Mass GenHosp Daly,Mark gma/brainstorm ✓✓ ✓
Mt Sinai Sklar, Pamela Targetedseq ✓
UCSD Sebat,Jonathan CNV ✓
UNC Sullivan,Patrick Coordination ✓
Wash UStLouis Agrawal,Arpana SUDs - NIDA ✓
Overall,65%ofbudgetà 9analysts+5datawranglers+coreadminstaff
ThePGCishiring!
17
“Findingactionablevariation”
Goalistodeliveractionablefindings,genomicresultsthata) revealthefundamentalbiology,b) informclinicalpractice,andc) delivernewtherapeutictargets
ThisisthecentralideaofthePGC:toconvertgeneticriskfactorsintobiologically,clinically,andtherapeuticallymeaningfulinsights.
18
Aim1(corebusiness)
SNPs(a)EnlargeGWASmega-analysestoincreaseunderstandingofdisordersforwhichmajorprogresshasbeenmadeandtoacceleratenewdiscoveries(b)Systematiccross-disorderanalyses(c)Pathwayanalyses.Includeacademicandindustryexpertsinpsychopharmacologytomaximizetherapeuticimplications– paperinpressinNatureNeuroscience
Goal– 100Kcasesforeachdisorder
Common
19
Inpreparation(datainPGCorsoon)
Disorder Newloci
SCZ- CLOZUK 50
BIP 12
MDD 9
ADHD- iPSYCH 9
AUT- iPSYCH 5
AN 1
SUDs 1
FingerscrossedforOCD/TS&PTSD
20
Ncase withGWAS.pgc1:initialPGCpapers.pgc2:currentNcases .pgc3:conservativeNcase estimatesforQ1/2019
PGC3samplesizes
21
What’stheendpoint?
Ncases
Associations
DeadzoneInflection
Linear
True#associations
“Goodenough”• Tagmostgenesonce• Tagmostgenesinkeypathways
Diminishingreturns
22
Aim2
Geneticriskscores(GRS)(a) Development:usingexistingdatafromlargelongitudinalcohorts,
evaluatethepleomorphiceffectsofGRSoverdevelopmentaltime(b) Extremes:analyzephenotypedatafromcaseswithveryhighorvery
lowGRStounderstandtheclinicalimpactofgeneticburden(c) Cross-disorder:developageneralGRSforpsychopathologyto
evaluateriskandresilienceacrossPGCdisorders(includesRDoC)
Common
23
Aim2– needtoformworkinggroup
Intentionistoformaworkinggroupofstudieswith:• Longitudinalcohortstudies• 2+measurementpoints• Multiplepsychiatricphenotypes(disorderand/orsymptomscales• HaveGWASnow&sharablewithPGC
EmailKristapleaseifyouwanttohearmore
24
Aim3BrainstormEstimategeneticcorrelationsamongallPGCdisordersandallCNS-relevantdiseases/quantitativetraitstodevelopacomprehensiveviewofgeneticinfluencesacrossabroadsetofbrainphenotypes.
Common
http://biorxiv.org/content/early/2016/04/16/048991
25
Aim4
CNVAnalyzerareCNVsinninepsychiatricdisordersviahigh-qualitymega-analyses,andperformcross-disorderanalysestorevealpleiotropicgeneticeffects.
WeneedtogetintensityfilesuploadedtoLISAThisisbeingcoordinatedbyCNVgroup(JSebat)&workinggroups
Rare
26
Aim5
SequencingCharacterizethefullspectrumofgeneticvariation(especiallyrarevariantsofstrongeffect)inregionsimplicatedbyPGCGWAS.Inexpensivelysequencecodingandregulatoryregionsof~200candidategenesin20,000independentsubjects.
Rare
27
Aim6
Pedigreesequencing(co-fundedbyScienceFoundationIreland)ThelargenetworkofPGCclinicianshaveidentifiedrare,denselyaffectedpedigrees.Usingwholegenomesequencing(30xcoverage),wewillsystematicallyevaluate~100suchpedigreestoenablesearchesforrarevariantsofstrongeffect.
Rare
28
“PGC3:findingactionablevariation”
29
Actionable
Goalistodeliveractionablefindings,genomicresultsthata) revealthefundamentalbiology,b) informclinicalpractice,andc) delivernewtherapeutictargets
ThisisthecentralideaofthePGC:toconvertgeneticriskfactorsintobiologically,clinically,andtherapeuticallymeaningfulinsights.
30
What’sthelogic?
Geneticfindings
Biology
Pathways/“readouts”
Rationaldrugdiscovery/clinicaluse
31
Actionable– rarevariantaims
Aim biol /clin /ther Comment
Rare– 6 – largepedigrees ✓ ✓ Abigswingfor thefence– even1wouldbenotable
Rare– 5 – targetedsequencing ✓ ✓ Canany genesgetovertheexomesigthreshold?
Rare– 4 – CNVs ✓ ✓ ✓ Especially singlegeneCNVs(e.g., NRXN1 &C4 CNP)
Common– 3 – brainstorm
Common– 2 – GRSoverdev
Common– 1 – corebusiness,gwas
Easytoconnectageneticfindingtoaspecificgenewithhypothesisofmechanism
32
Actionable– commonvariantaims
Aim biol /clin /ther Comment
Rare– 6 – largepedigrees ✓ ✓ Abigswingfor thefence– even1wouldbenotable
Rare– 5 – targetedsequencing ✓ ✓ Canany exonsgetovertheRVthreshold?
Rare– 4 – CNVs ✓ ✓ ✓ Especially singlegeneCNVs(e.g., NRXN1 &C4 CNP)
Common– 3 – brainstorm ✓ Nosology
Common– 2 – GRSoverdev ✓ Etiology,GxE,gen epi
Common– 1 – corebusiness,gwas ✓ ✓ ✓ Bread-and-butter ofthePGC
Connectionoffindingstogenesrequiresmultipleassumptions
33
Howtoconnectcommonvariantstogenes?
34
exactly
35
HowcanIgetinvolvedwiththePGC?
36
Thisisdo-able
MuchofPGCleadershipis55+.Turnoverisgoodforanorganization.ThepeoplewhoareinleadershiprolesinPGCsteppedup:• Volunteered,followedthrough,didtaskswell• Tookonsmallroles,didthemwell,gotmoretodo• Volunteeredtowritepartsofpapers• Wereconsistentlyoncalls PGCFAQ
37
N=418 who’ve done ORCID: Abdellaoui, Adkins, Adolfsson, Agartz, Agrawal, Air, Akil, Alda, Alliey-Rodriguez, Andlauer, Andreassen, Anjorin,Arnold, Arranz, Aschauer, Bacanu, Baker, Banaschewski, Barchas, Barta, Bass, Bau, Bauer, Baune, Beekman, Bergen, Berger, Bethell, Bienvenu,Biernacka, Bierut, Bigdeli, Blackwood, Boden, Boehnke, Boks, Boomsma, Boraska Perica, Børglum, Breen, Brown, Bulik, Bunney, Burmeister,Buttenschøn, Byrne, Cappi, Carracedo, Casas Bruguã, Casas Brugué, Castelao, Cath, Cervantes, Chen, Chou, Cichon, Clarke, Collier, Cook,Copeland, Corley, Cormand, Costello, Courtet, Couvy-Duchesne, Craddock, Crowley, Cruceanu, Cullen, Culverhouse, Curtis, Czerski, Dale,Dalsgaard, Dalvie, Dannlowski, Davis, De Geus, Degenhardt, Del Favero, Delorme, Dempfle, Denys, Depienne, Derks, Derringer, Di Florio, Direk,Djurovic, Dmitrzak-Weglarz, Domenici, Doyle, Duncan, Dunn, Eapen, Edenberg, Ehrlich, Elvsåshagen, Esko, Fan, Farrer, Favaro, Fernandez,Fernandez-Aranda, Figee, Fischer, Flickinger, Forstner, Forty, Frank, Fraser, Freimer, Frye, Fullerton, Gaddis, Gelernter, Geller, Gershon, Giegling,Gilbert, Gill, Goes, Gonidakis, Gordon, Gordon-Smith, Grabe, Grados, Green, Greenberg, Grevet, Grice, Grigoroiu-Serbanescu, Grove, Grünblatt,Guan, Guijarro, Guillaume, Guzman-Parra, Haavik, Hack, Hakonarson, Hamilton, Hammerschlag, Hamshere, Hancock, Hanna, Hansen,Hartmann, Hartz, Hatzikotoulas, Hauser, Hautzinger, Hayward, Heath, Heiman, Henders, Herms, Herpertz-Dahlmann, Hervas, Hewitt, Hickie,Hinney, Hoekstra, Hoffmann, Hofman, Hohmann, Holmans, Homuth, Hopfer, Horn, Horwood, Hottenga, Hultman, Hutz, Ibanez, Ising, Jankovic,Jansen, Jimenez-Murcia, Johansson, Johnson, Jones, Juréus, Kandaswamy, Kaprio, Karlsson, Kendler, Kennedy, Kent, Kiefer, King, Kirov, Kittel-Schneider, Kloiber, Klump, Knott, Knowles, Knudsen, Koen, Kogevinas, Konte, Kral, Krauter, Krogh, Kuntsi, Kupka, Kutalik, Landén, Lang, Langley,Lawrence, Leber, Lesch, Levinson, Levy, Lewis, Li, Lichtenstein, Lissowska, Liu, Loo, Lucae, Lynskey, Maaser, Macintyre, Madden, Maes,Magnusson, Maher, Malt, Martin, Mathews, Mattheisen, Mayoral-Cleries, Mcelroy, Mcgough, Mcgrath, Mcguffin, Mcintosh, Mckay, Mclaughlin,Mcqueen, Mcquillin, Medland, Mehta, Melle, Meng, Metspalu, Micali, Middeldorp, Mihailov, Milaneschi, Milani, Mitchell, Moessner,Monteleone, Montgomery, Morken, Mors, Mota, Mühleisen, Müller-Myhsok, Müller-Vahl, Munn-Chernoff, Myers, Nagy, Nauck, Nelson, Nestadt,Nicolini, Nigg, Nöthen, Nurmi, Nurnberger, Nyholt, O'donovan, Oedegaard, Olde Loohuis, Onnink, Ophoff, Ori, Oruc, Owen, Paciga, Pálmason,Papeå¾Ovã¡, Paschou, Pauls, Pearson, Pedersen, Penninx, Pergadia, Perlis, Perry, Peterson, Pettersson, Peyrot, Pfennig, Piras, Polderman,Porteous, Posthuma, Potash, Preisig, Quiroz, Ramos-Quiroga, Rasmussen, Regeer, Reichborn-Kjennerud, Reif, Reinbold, Rhee, Ribases, Rice,Richter, Ridinger, Rietschel, Riley, Ripke, Rivas, Rivera, Rizzo, Rommelse, Rothenberger, Rouleau, Rujescu, Sã Nchez-Mora, Saccone, Saeed Mirza,Samuels, Sànchez-Mora, Sandor, Scherag, Scherbaum, Schimmelmann, Schlögelhofer, Schoevers, Schofield, Schulze, Scott, Shi, Sinnamon, Sinzig,Slof-Op 'T Landt, Smalley, Smit, Smoller, Sonuga-Barke, Soyka, Spalletta, Spijker, Stallings, Steffens, Stein, Stordal, Strauss, Streit, Strohmaier,Stuhrmann, Sullivan, Szatkiewicz, Tansey, Tarnok, Tarter, Teumer, Thapar, Thompson, Thornton, Tiemeier, Tischfield, Todorov, Treutlein, Turecki,Uher, Uhlmann, Uitterlinden, Umbricht, Vaaler, Van Den Heuvel, Van Der Auwera, Van Furth, Van Grootheest, Van Hemert, Vanyukov, Viktorin,Vincent, Völzke, Vulink, Walitza, Wall, Walters, Wang, Wang, Watson, Webb, Weissman, Wellmann, Werge, Willemsen, Wilmot, Winslow, Witt,Wodarz, Worbe, Wray, Xi, Xu, Yanovski, Yao, Yilmaz, Yu, Zai, Zayats, Zeggini, Zerwas, Zill
THANKS
38