BeginningthePGC3grant

PatrickSullivanforthePGCUniversityofNorthCarolina/Karolinska Institutet

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PGC(briefly)

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PGCoverview

• 2007-present• 9disorders• 900+scientistsinPGC,largestconsortiumever• Resultsfreelyavailable• Papers:17main,31secondary/methods,75+useourresults• Manyhighlycitedor“hot”papers

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PGC3grant,6/2016– 4/2021

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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

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ScienceFoundationIreland&NorwegianResearchCouncil

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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”

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“Growingpains”fixesIn2009,noonethoughtthePGCwouldbearoundin2020…

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Updatedwebpage

Thanks1e6to:KristaLatta,LeaDavis,GeromeBreen,CindyBulik,MichaelGill

Greatsectionsallaround

Inparticular,theextensiveFAQ&newbiesections

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DataAccessCommittee

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PGCtalks

Shifttodisseminationofmethods

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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

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Communications

UNClistservs formostgroups

MultipleGoogleGroups

Keygooglegroupisthisone(N=968)https://groups.google.com/forum/?hl=en-GB#!forum/pgc-full-consortium

Pointperson=KristaLattŀ (UNC)

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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

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PGC3grant

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andBrisbaneAustralia ORCIDlistsADHD,AN,BIPMDDOCD/TSSUD

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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!

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“Findingactionablevariation”

Goalistodeliveractionablefindings,genomicresultsthata) revealthefundamentalbiology,b) informclinicalpractice,andc) delivernewtherapeutictargets

ThisisthecentralideaofthePGC:toconvertgeneticriskfactorsintobiologically,clinically,andtherapeuticallymeaningfulinsights.

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Aim1(corebusiness)

SNPs(a)EnlargeGWASmega-analysestoincreaseunderstandingofdisordersforwhichmajorprogresshasbeenmadeandtoacceleratenewdiscoveries(b)Systematiccross-disorderanalyses(c)Pathwayanalyses.Includeacademicandindustryexpertsinpsychopharmacologytomaximizetherapeuticimplications– paperinpressinNatureNeuroscience

Goal– 100Kcasesforeachdisorder

Common

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Inpreparation(datainPGCorsoon)

Disorder Newloci

SCZ- CLOZUK 50

BIP 12

MDD 9

ADHD- iPSYCH 9

AUT- iPSYCH 5

AN 1

SUDs 1

FingerscrossedforOCD/TS&PTSD

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Ncase withGWAS.pgc1:initialPGCpapers.pgc2:currentNcases .pgc3:conservativeNcase estimatesforQ1/2019

PGC3samplesizes

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What’stheendpoint?

Ncases

Associations

DeadzoneInflection

Linear

True#associations

“Goodenough”• Tagmostgenesonce• Tagmostgenesinkeypathways

Diminishingreturns

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Aim2

Geneticriskscores(GRS)(a) Development:usingexistingdatafromlargelongitudinalcohorts,

evaluatethepleomorphiceffectsofGRSoverdevelopmentaltime(b) Extremes:analyzephenotypedatafromcaseswithveryhighorvery

lowGRStounderstandtheclinicalimpactofgeneticburden(c) Cross-disorder:developageneralGRSforpsychopathologyto

evaluateriskandresilienceacrossPGCdisorders(includesRDoC)

Common

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Aim2– needtoformworkinggroup

Intentionistoformaworkinggroupofstudieswith:• Longitudinalcohortstudies• 2+measurementpoints• Multiplepsychiatricphenotypes(disorderand/orsymptomscales• HaveGWASnow&sharablewithPGC

EmailKristapleaseifyouwanttohearmore

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Aim3BrainstormEstimategeneticcorrelationsamongallPGCdisordersandallCNS-relevantdiseases/quantitativetraitstodevelopacomprehensiveviewofgeneticinfluencesacrossabroadsetofbrainphenotypes.

Common

http://biorxiv.org/content/early/2016/04/16/048991

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Aim4

CNVAnalyzerareCNVsinninepsychiatricdisordersviahigh-qualitymega-analyses,andperformcross-disorderanalysestorevealpleiotropicgeneticeffects.

WeneedtogetintensityfilesuploadedtoLISAThisisbeingcoordinatedbyCNVgroup(JSebat)&workinggroups

Rare

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Aim5

SequencingCharacterizethefullspectrumofgeneticvariation(especiallyrarevariantsofstrongeffect)inregionsimplicatedbyPGCGWAS.Inexpensivelysequencecodingandregulatoryregionsof~200candidategenesin20,000independentsubjects.

Rare

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Aim6

Pedigreesequencing(co-fundedbyScienceFoundationIreland)ThelargenetworkofPGCclinicianshaveidentifiedrare,denselyaffectedpedigrees.Usingwholegenomesequencing(30xcoverage),wewillsystematicallyevaluate~100suchpedigreestoenablesearchesforrarevariantsofstrongeffect.

Rare

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“PGC3:findingactionablevariation”

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Actionable

Goalistodeliveractionablefindings,genomicresultsthata) revealthefundamentalbiology,b) informclinicalpractice,andc) delivernewtherapeutictargets

ThisisthecentralideaofthePGC:toconvertgeneticriskfactorsintobiologically,clinically,andtherapeuticallymeaningfulinsights.

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What’sthelogic?

Geneticfindings

Biology

Pathways/“readouts”

Rationaldrugdiscovery/clinicaluse

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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

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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

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Howtoconnectcommonvariantstogenes?

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exactly

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HowcanIgetinvolvedwiththePGC?

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Thisisdo-able

MuchofPGCleadershipis55+.Turnoverisgoodforanorganization.ThepeoplewhoareinleadershiprolesinPGCsteppedup:• Volunteered,followedthrough,didtaskswell• Tookonsmallroles,didthemwell,gotmoretodo• Volunteeredtowritepartsofpapers• Wereconsistentlyoncalls PGCFAQ

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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

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