swr plenaire conferentie januari 2015 - gert jan van ommen
TRANSCRIPT
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SWR Leusden 30 januari 2015
Prof dr Gertjan van Ommen Biobanking and BioMolecular Research Infrastructure Centre for Medical Systems Biology
Leiden University Medical Centre
De groei(stuipen) van de genetica: Nederland als voortrekker
B
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TEST
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LATER: PERSONALIZED MEDICINE NOW: TRIAL AND ERROR
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PHARMACOGENOMICS: Genomics and biobank research into drug treatment outcomes
26-27 june 2000
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Title&
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Mammalian Genomes
Monodelphis, Opossum
Platypus!
Human Mouse, rat Chimpanzee Dog(s)
Photo seqsystem !
dec 2006
Sequencing in action
Human genomes
Craig Venter
James Watson
Individual genomes, may 2008:
ANONYMOUS: Yoruban male Yoruban trio
Asiatic genome Female Cancer
Marjolein Kriek, Clinical geneticist
Leiden
A human genome
By Academic Hospitalnot a large genome center, nor a company (sequence technology)
Marjolein KriekPhD, clinical geneticist (i.t.)
First : LUMC
Leiden Netherlands
EuropeFEMALE
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Australia&
Publieks&percep6e...&&
here the defective gene for parking a car backwards
Not everybody agreed…
Human and Clinical Genetics
Sequencing&kosten&
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Human and Clinical Genetics! © JT den Dunnen!
The human genome 2000
€ 2,000,000,000 in ~10 years
2008 € 50 - 100,000 in ~4 months
2010 € 5,000 in ~2 weeks
2013 € 2,000 in a day
...2020 ? € 10 ? ... in minutes ?
A million times cheaper AND 3000 x faster !!
Human and Clinical Genetics!
Oxford Nanopore3&
no labels !
~5% v.h. genoom onder selectie ~500,000 geconserveerde elementen
33%(=(eiwitcoderend((
67%(=(???(
DNA
Genen
GENEN
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DNA
Genen
GENEN
DNA
Genen
JUNK DNA?
Principal component analysis of European populations Simon Heath et al. (2008) EJHG 16, 1413 – 1429
1st principal component = 26% of variance
2nd p
rinci
pal c
omon
ent =
6%
of v
aria
nce
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Genomes in common diseases: What are we trying to accomplish?
Understand the biology behind any disease but also:
Improve diagnostic classification of common diseases
Understanding individual disease risks and response to therapies (positive and adverse)
Produce data useful for public health intervention strategies
Cumulative number of trait loci identified using GWA
0
100
200
300
400
500
600
700
800
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
year
loci
CDKN2B/AATG16L1
5p1310q21IRGM!
NKX2-3IL12B3p211q24
PTPN2TCF2
CDKN2B/AIGF2BP2CDKAL1
HHEXSLC30A8
MEIS1LBXCOR1BTBD9
C3ORMDL3
4q25TCF2GCKRFTO
C12orf30ERBB3
KIAA0350CD22616p13PTPN2SH2B3FGFR2TNRC9MAP3K1LSP1
LOXL1IL7R
TRAF1/C5STAT4ABCG8GALNT2PSRC1NCANTBL2TRIB1
KCTD10ANGLPT3GRIN3A
NOS1APIFIH1PCSK9CFB/C2
LOC3877158q24IL23RTCF7L2
CD25IRF5
PCSK9CFHPTPN22KCNJ11CTLA4IBD5
NOD2PPARγ
e.g.:High Cholesterol
ObesityStature
Myocardial infarctArrhythmias
Type 2 Diabetes Prostate cancerBreast cancerColon cancer
Bipolar disorderSchizophrenia
Age Related Macular DegenerationCrohns DiseaseType 1 Diabetes
Systemic Lupus ErythematosusAsthma
Restless leg syndromeGallstone diseaseMultiple sclerosis
Rheumatoid arthritisGlaucoma
NHGRI(GWA(Catalog(www.genome.gov/GWAStudies(www.ebi.ac.uk/fgpt/gwas/((
Published(GenomeJWide(AssociaKons(through(12/2013(Published(GWA(at(p≤5X10J8(for(17(trait(categories(
We need more studies of well characterized human populations
Help to expose both common and rare risk variants, highly relevant for human health
Guide us to novel functional domains in the landscape of human genome
Critical in efforts to define the significance of genetic and life style risk factors
Contribute to the functional annotation of genome Provide the basis for future health care decisions
by our societies
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Biobanking and Biomolecular Research Infrastructure - NL
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BBMRI#NL:&CONNECTIVITY&
TWIN(Registry(
MZ:$Environment$DZ:$Genes$
COHORTS(#&Outbred&#&Isolates&
Onset,$causality$Mul8$uses$$
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CaseJcontrol(Sample&sets&High$disease$$frequency$
The(Netherlands(:(200(biobanks(–(800.000(samples((~(5%!)(
c& Wageningen
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Table(of(Contents(for(The$American$Journal$of$Human$Gene3cs,(Volume(87,(Issue(3.(September(2010(Editors'(Corner(This(Month(in(The$Journal&K.D.&Bungartz&and&R.E.&Williamson(This(Month(in(GeneKcs&K.B.&Garber(Book(ReviewA(Guide(to(GeneKc(Counseling,(2nd(EdiKon&M.&Fox&((SEPTEMBER(2010(
Direct(Measure(of(the(De(Novo(MutaKon(Rate(in(AuKsm(and(Schizophrenia(CohortsP.&Awadalla,&J.&Gauthier,&R.A.&Myers,&F.&Casals,&F.F.&Hamdan,&A.R.&Griffing,&M.&Côté,&E.&Henrion,&D.&Spiegelman,&J.&Tarabeux,&A.&Piton,&Y.&Yang,&A.&Boyko,&C.&Bustamante,&L.&Xiong,&J.L.&Rapoport,&A.M.&Addington,&J.L.E.&DeLisi,&M.#O.&Krebs,&R.&Joober,&B.&Millet,&É&.&&Fombonne,&L.&Moaron,&M.&Zilversmit,&J.&Keebler,&H.&Daoud,&C.&Marineau,&M.#H.&Roy#Gagnon,&M.#P.&Dubé,&A.&Eyre#Walker,&P.&Drapeau,&E.A.&Stone,&R.G.&Lafrenière,&and&G.A.&Rouleau(BOOST:(A(Fast(Approach(to(DetecKng(GeneJGene(InteracKons(in(GenomeJwide(CaseJControl(StudiesX.&Wan,&C.&Yang,&Q.&Yang,&H.&Xue,&X.&Fan,&N.L.S.&Tang,&and&W.&Yu((Mutability(of(YJChromosomal(Microsatellites:(Rates,(CharacterisKcs,(Molecular(Bases,(and(Forensic(ImplicaKonsK.N.&Ballantyne,&M.&Goedbloed,&R.&Fang,&O.&Schaap,&O.&Lao,&A.&Wollstein,&Y.&Choi,&K.&van&Duijn,&M.&Vermeulen,&S.&Brauer,&R.&Decorte,&M.&Poetsch,&N.&von&Wurmb#Schwark,&P.&de&Knijff,&D.&Labuda,&H.&Vézina,&H.&Knoblauch,&R.&Lessig,&L.&Roewer,&R.&Ploski,&T.&Dobosz,&L.&Henke,&J.&Henke,&M.R.&Furtado,&and&M.&Kayser(Reports(
Recessive(MutaKons(in(the(Gene(Encoding(the(Tight(JuncKon(Protein(Occludin(Cause(BandJlike(CalcificaKon(with(Simplified(GyraKon(and(PolymicrogyriaM.C.&O'Driscoll,&S.B.&Daly,&J.E.&Urquhart,&G.C.M.&Black,&D.T.&Pilz,&K.&Brockmann,&M.&McEntagart,&G.&Abdel#Salam,&M.&Zaki,&N.I.&Wolf,&R.L.&Ladda,&S.&Sell,&S.&D'Arrigo,&W.&Squier,&W.B.&Dobyns,&J.H.&Livingston,&and&Y.J.&Crow&(TBC1D24,(an(ARF6JInteracKng(Protein,(Is(Mutated(in(Familial(InfanKle(Myoclonic(EpilepsyA.&Falace,&F.&Filipello,&V.&La&Padula,&N.&Vanni,&F.&Madia,&D.&De&Pietri&Tonelli,&F.A.&de&Falco,&P.&Striano,&F.&Dagna&Bricarelli,&C.&Minek,&F.&Benfena6,&A.&Fassio,&and&F.&Zara&&A(Focal(Epilepsy(and(Intellectual(Disability(Syndrome(Is(Due(to(a(MutaKon(in((TBC1D24$M.A.&Corbea,&M.&Bahlo,&L.&Jolly,&Z.&Afawi,&A.E.&Gardner,&K.L.&Oliver,&S.&Tan,&A.&Coffey,&J.C.&Mulley,&L.M.&Dibbens,&W.&Simri,&A.&Shalata,&S.&Kivity,&G.D.&Jackson,&S.F.&Berkovic,&and&J.&Gecz(Nonsense(MutaKons(in(FAM161A(Cause(RP28JAssociated(Recessive(ReKniKs(PigmentosaT.&Langmann,&S.A.&Di&Gioia,&I.&Rau,&H.&Stöhr,&N.S.&Maksimovic,&J.C.&Corbo,&A.B.&Renner,&E.&Zrenner,&G.&Kumaramanickavel,&M.&Karlsteaer,&Y.&Arsenijevic,&B.H.F.&Weber,&A.&Gal,&and&C.&Rivolta&&Homozygosity(Mapping(Reveals(Null(MutaKons(in&FAM161A(as(a(Cause(of(AutosomalJRecessive(ReKniKs(PigmentosaD.&Bandah#Rozenfeld,&L.&Mizrahi#Meissonnier,&C.&Farhy,&A.&Obolensky,&I.&Chowers,&J.&Pe'er,&S.&Merin,&T.&Ben#Yosef,&R.&Ashery#Padan,&E.&Banin,&and&D.&Sharon(((
MutaKons(in(DHDPSL(Are(Responsible(For(Primary(Hyperoxaluria(Type(IIIR.&Belostotsky,&E.&Seboun,&G.H.&Idelson,&D.S.&Milliner,&R.&Becker#Cohen,&C.&Rinat,&C.G.&Monico,&S.&Feinstein,&E.&Ben#Shalom,&D.&Magen,&I.&Weissman,&C.&Charon,&and&Y.&Frishberg(A(MutaKon(in(ZNF513,(a(PutaKve(Regulator(of(Photoreceptor(Development,(Causes(AutosomalJRecessive(ReKniKs(PigmentosaL.&Li,&N.&Nakaya,&V.R.M.&Chavali,&Z.&Ma,&X.&Jiao,&P.A.&Sieving,&S.&Riazuddin,&S.I.&Tomarev,&R.&Ayyagari,&S.A.&Riazuddin,&and&J.F.&Hejtmancik(MutaKons(in&ABHD12(Cause(the(NeurodegeneraKve(Disease(PHARC:(An(Inborn(Error(of(Endocannabinoid(MetabolismT.&Fiskerstrand,&D.&H'mida#Ben&Brahim,&S.&Johansson,&A.&M'zahem,&B.I.&Haukanes,&N.&Drouot,&J.&Zimmermann,&A.J.&Cole,&C.&Vedeler,&C.&Bredrup,&M.&Assoum,&M.&Tazir,&T.&Klockgether,&A.&Hamri,&V.M.&Steen,&H.&Boman,&L.A.&Bindoff,&M.&Koenig,&and&P.M.&Knappskog(Exome&Sequencing&Iden6fies&WDR35&Variants&Involved&in&Sensenbrenner&Syndrome&Chris6an&Gilissen,&Heleen&H.&Arts,&Alexander&Hoischen,&Liesbeth&Spruijt,&Dorus&A.&Mans,&Peer&Arts,&Bart&van&Lier,&Marloes&Steehouwer,&Jeroen&van&Reeuwijk,&Sarina&G.&Kant,&Ronald&Roepman,&Nine&V.A.M.&Knoers,&Joris&A.&Veltman,&Han&G.&Brunner&
Dominant(MutaKons(in&RP1L1(Are(Responsible(for(Occult(Macular(DystrophyM.&Akahori,&K.&Tsunoda,&Y.&Miyake,&Y.&Fukuda,&H.&Ishiura,&S.&Tsuji,&T.&Usui,&T.&atase,&M.&Nakamura,&H.&Ohde,&T.&Itabashi,&H.&Okamoto,&Y.&Takada,&and&T.&Iwata(A(Locus(on(Chromosome(1p36(Is(Associated(with(Thyrotropin(and(Thyroid(FuncKon(as(IdenKfied(by(GenomeJwide(AssociaKon(StudyV.&Panicker,&S.G.&Wilson,&J.P.&Walsh,&J.B.&Richards,&S.J.&Brown,&J.P.&Beilby,&A.P.&Bremner,&G.L.&Surdulescu,&E.&Qwei6n,&I.&Gillham#Nasenya,&N.&Soranzo,&E.M.&Lim,&S.J.&Fletcher,&and&T.D.&Spector(Protein(Tyrosine(Phosphatase(PTPN14(Is(a(Regulator(of(LymphaKc(FuncKon(and(Choanal(Development(in(HumansA.C.&Au,&P.A.&Hernandez,&E.&Lieber,&A.M.&Nadroo,&Y.#M.&Shen,&K.A.&Kelley,&B.D.&Gelb,&and&G.A.&Diaz&&JULY(2010(
Whole&Exome&Sequencing&and&Homozygosity&Mapping&Iden6fy&Muta6on&in&the&Cell&Polarity&Protein&GPSM2&as&the&Cause&of&Nonsyndromic&Hearing&Loss&DFNB82.&Tom&Walsh,&Hashem&Shahin,&Tal&Elkan#Miller,&Ming&K.&Lee,&Anne&M.&Thornton,&Wendy&Roeb,&Amal&Abu&Rayyan,&Suheir&Loulus,&Karen&B.&Avraham,&Mary#Claire&King,&Moien&Kanaan(
Terminal&Osseous&Dysplasia&Is&Caused&by&a&Single&Recurrent&Muta6on&in&the&FLNA&Gene&(Exome&Sequencing)&Yu&Sun,&Rowida&Almomani,&Emmelien&Aten,&Jacopo&Celli,&Jaap&van&der&Heijden,&Hanka&Venselaar,&Stephen&P.&Robertson,&Anna&Baroncini,&Brunella&Franco,&Lina&Basel#Vanagaite,&Emiko&Horii,&Ricardo&Drut,&Yavuz&Ariyurek,&Johan&T.&den&Dunnen,&Mar6jn&H.&Breuning&
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DIRECTE(BENEFIT(:(DIAGNOSTIEK(EN(BEGRIP(VAN(ZELDZAME(ZIEKTEN(((((((((((((((((((((((((((((((((((((
Bridging&common&and&rare&disease&Rare&to&common&• Excellent&human&models&for&therapy&development:&&• & #&one&knows&what&one&should&see&when&it&works&!&• & #&extended&use&later&&• Therapy&business&models&more&viable&than&thought&• Next&gen&sequencing&causes&rapid&advances,&new&therapies&• !&Large,$wellAinformed$and$organized$pa8ent$cons8tuency$&Common&to&rare&• Splikng&up&of&fields&in&rarer&subclasses&• More&homogeneous&subgroups:&
• Smaller,&cheaper,&shorter&trials&• Longer&cost&recovery&period&under&patent&
• !&Large$biobanks$needed$for$recruitment$of$small$subgroups$$
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After HumanGenome Project
Basic tools exist tocharacterize the biology
behind human diseases
DE TOEKOMST?
Trait Risk schizofrenie 2x Dopamine receptor D4.2+ rheuma >65j 18% hartfalen 22% hoge bloeddruk 8% long kanker 27% prostaat kanker 12% darm kanker 10% leukemie 7% huid kanker 4% borst/ovarium kanker 0% suicide 6% IQ A+B-C0D*...Q+…Z23a (etc.)
DETERMINISME -> PROBABILISME
SCHIZOPHRENIE
1% in de populatie
Erfelijke factor met 2x risico:
98% kans om het NIET te krijgen
… als je WEL het risico-gen hebt!
Data&Protec6on&..&
Acknowledgements(GoNL(team((
Paul&&de&Bakker&
Cornelia&Van&Duijn& Morris&
Swertz&
Cisca&Wijmenga&
Dorret&Boomsma&
Eline&Slagboom&
Gertjan&Van&Ommen&
Credits,&thanks,&acknowledgements:&Steering group UMCG: Cisca Wijmenga (PI), Morris Swertz; LUMC: Gertjan van Ommen, Eline Slagboom; Jasper Bovenberg (ELSI); EMC: Cornelia van Duijn; VUmc: Dorret Boomsma; UMCU: Paul de Bakker
Cohort collection and sample management LUMC: Eline Slagboom, Ton de Craen, Marian Beekman; VUmc: Dorret Boomsma; UMCG: Bruce Wolffenbuttel, Mathieu Platteel; EMC: Bert Hofman
Sequencing BGI: Yuanping Du, Ruoyan Chen, Hongzhi Cao, Rui Cao, Yushen Sun, Jeremy Sujie Cao
Data processing and Analysis (Rainbow project 2) UMCG: Morris Swertz (Co-Chair), Freerk van Dijk, Pieter Neerincx, Martijn Dijkstra; AMC: Mark Santcroos, Barbera van Schaik; LUMC: Jan Bot, Kai Ye, Eric-Wubbo Lameijer, Martijn Vermaat, Jeroen Laros; EMC: Slavik Koval, Lennart Karssen, Karol Estrada, Elisa van Leeuwen, Karol Estrada, Fernando Rivadeneira; UMCN: Jayne Hehir, Joep Ligt, VUmc: Jouke-Jan Hottenga, Matthijs Kattenberg; NBIC: David van Enckevort, Leon Mei; UMCU/Hubrecht: Laurent Francioli, Wigard Kloosterman, Ies Nijman, Victor Guryev, Paul de Bakker (Co-Chair)
Collaborators Broad: Shamil Sunyaev, Adam Kiezun, Steve McCarroll, Bob Handsaker, Mark Depristo and GSA Team; U Wash: Evan Eichler; Columbia: Itsik Pe’er; U Penn: Ben Voight
Other collaborators Target Consortium, CIT Rekencentrum, BigGrid