The Genetics RevolutionGenomics and theFuture of Medicine

The Genetics RevolutionGenomics and theFuture of Medicine

Matt BrownDirector | Professor of Immunogenetics,

University of Queensland Diamantina Institute,Translational Research Institute,

Princess Alexandra Hospital,Brisbane, Australia.

Matt.brown@uq.edu.au

Lessons learnt:• Current practice in rheumatology was of uncertainbenefit• Much more research was required to make progress.

• At risk

• Presymptomatic Disease

FUTURE?

• Symptomatic Early Disease

• Established Disease CURRENT

Sequencing – the next revolution

1977 1993 1998 2004 2009100bp 1000bp 96000bp 30Gb 600Gb

• Whole exome scan currently costs <1 MRIscan

•Whole genome sequence will cost• <$1000 within ~3 years• <1 MRI scan within 5 years.

UQ Centre for Clinical Genomics

Genetics and Medicine• Genes determine risk of disease

– Therapies targeting pathways identified by geneswill reduce the risk of developing disease.

• Genetic tests can identify those who will getdisease.

• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.

• Genes determine risk of disease– Therapies targeting pathways identified by genes

will reduce the risk of developing disease.

• Genetic tests can identify those who will getdisease.

• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.

Published GWA Reports, 2005 – 6/2012To

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IL-23 SignallingGene Diseases

IL23R AS, IBD, PS

IL12B AS, IBD, PS, MS

IL12RB2 AS, IBD

STAT3 IBD, PS, MS

Di Cesare et al, Jour Invest Dermatology 2009)

STAT3 IBD, PS, MS

JAK2 IBD

CARD9 AS, IBD

PTGER4 AS, IBD

TYK2 AS, IBD, PS, MS, RA,T1D, PBC

Osteoporosis Drug Targets and GeneticsDrug Class Drug Target Monogenic

ConditionCommon variantassociation

Bisphosphonates FarnesylPyrophosphate No No

SERMs Estrogen Receptor No Yes

Estrogen Estrogen Receptor No YesEstrogen Estrogen Receptor No Yes

DKK-1 Inhibitors DKK-1 No Yes

Cathepsin-K inhibitors Cathepsin-K Yes No

Denosumab RANKL Yes Yes

Sclerostin inhibitors Sclerostin Yes Yes

PTH analogues PTH receptor Yes Yes

Anti-sclerostinantibodies

Cathepsin Kantagonists

• Genes determine risk of disease– Therapies targeting pathways identified by genes

will reduce the risk of developing disease.

• Genetic tests can identify those who will getdisease.

• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.

Genetics and Medicine• Genes determine risk of disease

– Therapies targeting pathways identified by geneswill reduce the risk of developing disease.

• Genetic tests can identify those who will getdisease.

• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.

• Values of early diagnosis– Correct diagnosis for patient– Avoids harmful inappropriate treatments– Advent of anti-TNF agents means potential to retard

ankylosis.

0.5

0.6

0.7

0.8

0.9

1.0

TRUE

POSITIVE

RATE

0.0

0.1

0.2

0.3

0.4

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

TRUE

POSITIVE

RATE

FALSE POSITIVE RATE

MRI

0.5

0.6

0.7

0.8

0.9

1

TRUE

POSITIVE

RATE

B27 ALONE

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POSITIVE

RATE

FALSE POSITIVE RATE

B27-ERAP1-IL23R

MRI

• AUC genetic score 59%• AUC weight/age 75%

• Most diseases will not be predictable bygenetic testing– Exceptions include T1D, Alzheimer’s disease, male

coronary heart disease..

• 90% of individuals will be shown to be atabove average risk of at least one disease

• Most diseases will not be predictable bygenetic testing– Exceptions include T1D, Alzheimer’s disease, male

coronary heart disease..

• 90% of individuals will be shown to be atabove average risk of at least one disease

Science Transl Med, 2012

• Genes determine risk of disease– Therapies targeting pathways identified by genes

will reduce the risk of developing disease.

• Genetic tests can identify those who will getdisease.

• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.

Genetics and Medicine

• Genes determine risk of disease– Therapies targeting pathways identified by genes

will reduce the risk of developing disease.

• Genetic tests can identify those who will getdisease.

• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.

TNFRSF1A splice variants in AS and MS

The minor allele ofrs1800693 (MAF: 0.319)

TNFRSF1A

20

The minor allele ofrs1800693 (MAF: 0.319)

risk to AS

risk to MS

Associated with direct expression of anovel, soluble form of TNFR1 that canblock TNF akin to Etanercept

UQ Centre for Clinical Genomics

• Sequencing equipment– Four Illumina HiSeq2000 sequencers

• Each capable of sequencing 600Gigabases every 10 days

• Amounts to six 30x genomes every 10days per machine

• Per annum capacity currently >800genomes per annum.

– Two MiSeq sequencers• Run 5Gb sequence overnight

• Sequencing equipment– Four Illumina HiSeq2000 sequencers

• Each capable of sequencing 600Gigabases every 10 days

• Amounts to six 30x genomes every 10days per machine

• Per annum capacity currently >800genomes per annum.

– Two MiSeq sequencers• Run 5Gb sequence overnight

Translational Applications of Sequencing

• Providing definite genetic diagnosis of known monogenicdiseases– 1% of Australians have a clinically significant

monogenic disease– Enables appropriate follow-up/Rx of affected pts– Possibility of accurate antenatal screening.

• Diagnosis of genetic diseases of unknown aetiology• ?Improved prediction of common genetic diseases• Sequence based microbial profiling• Mutational screening for somatic diseases (e.g. cancer)

• Providing definite genetic diagnosis of known monogenicdiseases– 1% of Australians have a clinically significant

monogenic disease– Enables appropriate follow-up/Rx of affected pts– Possibility of accurate antenatal screening.

• Diagnosis of genetic diseases of unknown aetiology• ?Improved prediction of common genetic diseases• Sequence based microbial profiling• Mutational screening for somatic diseases (e.g. cancer)

248+1 G>AC111R

C166FC166SQ176X

C615RG1468TG1468+5AC476G

C587YC598W1836delAC661R

A705TC711Y

C816SC832Y

3208+5G>TC1032YC1039YK1043RI1048T1048del IC1053RC1055G1058insC3174insTGC3192delA3445insCdel Ex 25

D1113GC1117GC1117Y(2)G11127SN1131YR1137P(2)C1153Y

E1200G3623delGC1223Y(2)

3839-1G>TN1282SC1320SA3963Gdel Ex 31(2)

N1382S

C1497SC1513R

C1610G4857delA

5137ins4C1721Y5241ins5B

5672del117bN1893KG1910VC1928R C1977Y

R1997X

6163+2del16bR2057XR2057QY2062XC2099W6314del66C2111YY2113X

D2127EN2144SC2151W

C2258RQ2262XI2269TR2282W(2)E2447K

6513delT

7456del366C2489RC2511RC2522SR2680C(2)

C2686F8052-2A>G8051+5G>A

G4459+1A

R122C(2)C129Y

W217GR240C

1604delTR545C(3)N548IR565X

E616GR627C (2)

D723AY746C2293+2T>CC750G

C816SC832Y

R861XC862RC890R

C926R

G1013R(4)K1023NV984IC996R

3208+5G>TC1032YC1039YK1043RI1048T1048del IC1053RC1055G1058insC3174insTGC3192delA3445insCdel Ex 25

I1071SD1072GE1073DE1073K(3)C1074RS10779C1086W

D1113GC1117GC1117Y(2)G11127SN1131YR1137P(2)C1153Y

D1155N3464del17C1166YR1170H (2)C1171WN1173KI1175TC1182SC1182W

C1242YN1246SC1249SE1260X 3965-2A>G

del Ex 32 (2)A1337PN1341S4011delT4020delC

D1404YP1424AC1429S

C1589FE1605X

G4943-1CC1663RV1667I

C1818YE1823XR1832CP1837S

D1930N5788+5G>A(3)5898delA

D2127EN2144SC2151W

6739+1G>CC2221SC2232Y

C2307S6997+1G>A

7205-2A>G(2)

D2607GE2610KG8051+1AH2623PN2624SG2627R

R2680C(2)C2686F8052-2A>G8051+5G>A

R2726W8236delGAW2756XR2776X8525del5

755del8b2399delC C2017R

L2309VI2023T

I2585TC2577R

C423G

C2535X

COOHNH2

N- and C-termini

hybridEGF-like proline-rich TBcbEGF-like

WES in Marfans Disease and OsteogenesisImperfecta

• We identified 13/13 mutations in OI and 11/11 mutationsin MFS

– Non-synonymous SNPs and small indels (up to 10bp)

• Costs were ~%50 lower than current commercialsequencing

• Enables– antenatal diagnosis

– Diagnostic certainty

– Identification of phenocopies e.g MODY.

• We identified 13/13 mutations in OI and 11/11 mutationsin MFS

– Non-synonymous SNPs and small indels (up to 10bp)

• Costs were ~%50 lower than current commercialsequencing

• Enables– antenatal diagnosis

– Diagnostic certainty

– Identification of phenocopies e.g MODY.

Sequencing Based Microbial Profiling

• Allows species level sensitive and specificprofiling of viral, bacterial and fungalpathogens even culture free

• Potential clinical and research applicationsextensive

• Cost is low– 16S rRNA sequence lab cost in research is

currently $65.

• Allows species level sensitive and specificprofiling of viral, bacterial and fungalpathogens even culture free

• Potential clinical and research applicationsextensive

• Cost is low– 16S rRNA sequence lab cost in research is

currently $65.

Community profiling using 16SrRNA

Mary-Ellen Costello, submited, ISME Journal 2013

Lena Peltonen-Palotie (RIP)

• Head of Wellcome TrustSanger centre

• Died of metastaticmalignancy withunknown primary

• The first cancer genomesequenced– Guided her

chemotherapy regimen

• Head of Wellcome TrustSanger centre

• Died of metastaticmalignancy withunknown primary

• The first cancer genomesequenced– Guided her

chemotherapy regimen

Cancer Sequencing

• Already extensively used in blood cancers inclinical setting

• Increasing relevance in other cancers, and willbecome standard of care for seriousmalignancies

• Establishing this in clinical practice will take alot of work!

• Already extensively used in blood cancers inclinical setting

• Increasing relevance in other cancers, and willbecome standard of care for seriousmalignancies

• Establishing this in clinical practice will take alot of work!

The Genomics Revolution

• Technological advances in genomics haverevolutionised research and are ready fortranslation into clinical practice.

• Many areas of clinical practice will be affected,not just heritable disease investigation.

• Implementation of genomics into clinicalpractice requires further research and plannedroll out to maximise the potential benefit.

• Technological advances in genomics haverevolutionised research and are ready fortranslation into clinical practice.

• Many areas of clinical practice will be affected,not just heritable disease investigation.

• Implementation of genomics into clinicalpractice requires further research and plannedroll out to maximise the potential benefit.