© FIMM - Institute for Molecular Medicine Finland www.fimm.fi

Thermo-Fisher ESHG 2019 Seminar

Gothenburg, June 16, 2019

FinnGen: a platform for drug targetdevelopment and precision medicine

Samuli Ripatti

Institute For Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki

Public Health, Faculty of Medicine, University of Helsinki

The Broad Institute of MIT and Harvard

@samrip

@CoECDG

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Y O U R T E S T B E D F O R N E X T G E N E R A T I O N R E S E A R C H & I N N O V A T I O N

INNOVATIVE STUDY DESIGNS

POPULATION ISOLATE

HEALTHREGISTERS

BIOBANKS GENOME DATA

+ ++

4

EARLY SETTLEMENT • 2000-10 000 years ago• South and Coast

LATE SETTLEMENT• 16th century• multiple bottle necks

EXPANSION • 18th century – population 250 000• Today – population 5.4 million

EARLY

SETTLEMENT

LATE

SETTLEMENT

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GRACILE (death in infancy)

LAAHD (intrauterine death)

FSH-RO (fertility disturbance)

EPMR (progressive retardation)

PEHO (progressive retardation)

TMD (muscle disease) dominant

RAPADILINO (growth disturbance with malformations)

LCCS (intrauterine death)

IOSCA, OHAHA (progressive retardation)

CHS (progressive retardation)

vLINCL (progressive retardation)

HYDROLET (intrauterine death)

SALLA (progressive retardation)

MKS (intrauterine death)

MEB (severe retardation)

TCD, CHM (eye disease), X -recessive

INCL (progressive retardation)

HOGA (eye disease)

DTD (growth disturbance)

JNCL (progressive retardation)

CHH (growth disturbance)

MUL (growth disturbance)

FAF (eye, nerve and skin disease) dominant

USH3 (ear and eye disease)

PLOSL (progressive retardation)

AGU (progressive retardation)

CLD (watery diarrhea)

NKH (severe retardation)

LPI (metabolic disease)

CCD (watery diarrhea)

APECED (autoimmune polyendocrinopathy)

RESCH, RS (eye disease), X- recessive

PME (neurological disease)

SMB12 (anemia)

CNA2 (eye disease)

CNF (kidney disease)

56... 58... 60... 62... 64... 66... 68... 70... 72... 74... 76... 78... 80... 82... 84 ...86... 88... 90... 92... 94... 96... 98

Finnish Disease Heritage

Recessive diseases enriched in

Finland

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Finnish bottleneck boosts the frequency of a subset of high impact variants

• Risk effects• Tens of Mendelian diseases

• AKT2 knockouts ↑insulin level and ↑T2D risk

• TOP3B and SETD1A in schizophrenia and learning disabilities

• Protective effects• Knockouts of SLC30A8 T2D risk ↓ by 65%

• Knockouts of LPA CAD risk ↓ by 20%

• RNF186 truncating variant with ulcerative colitis risk ↓ by 70%

POPULATION ISOLATE

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500 000 individuals

~1O % of the population

500 000 individualsCombined

genotype and register data

National Health Register data

Association analyses

Axiom GWA array

Imputation

FinnGen

8

FinnGen partners

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National registers

Hospital discharge

Hospital procedure

Outpatient visit

Outpatient procedure

Primary care

Primary care procedure

Cancer register

Cause of death

Drug purchase

Drug reimbursement

Register data for

administration

Register data for

administration

Register data for

administration

All data harmonized

Interconnected by the 11 digit person number

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Constructing disease endpoints

Hospital or outpatientdischarge registry

Hospital or outpatient discharge registry

Procedure code:

Cause of death

Drug reimbursement

Cause of death

ICD: I21, I22

Coronary bypass surgery

ICD: I20-I25

ICD: G30, F00

ATC: NO6D

ICD: G30, F00contributing

Case

Coronary heart disease Alzheimer’s

Existing hospital labvalues

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FINNGEN1 Chip

540,008

Imputation grid

57,008

Partner content

116,402

Finnish rare coding

14,900

Clinvar pathogenic

10,800

HLA + KIR

4,600

Pharmacogenetic

736,145

FINNGEN1

Thermo Fisher, Axiom

12

• Latest data freeze 146 000 individuals• Imputed to a Finnish reference panel 8000 haplotypes

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Breast cancerLocus does not exist in 37 build

Known:IGFBP5, same lead

Info 0.74

Known: KCNU1Risk for T2D

Known.long LD

Novel rare Finn enriched

Known.FGFR2

Known.CCDN1.Same lead variant

Known.NTN4.Same lead variant

Not in GWAS but clinvar!!Finn specific PTV

Known.TOX3

Known.ZNRF3. Same lead

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PALB2 locus

Top variant intronic

Frameshift in perfect LD

PRS

PALB2

NoneCHEK2

CHEK2 + PRS

PALB2 + PRS

PRS = PRS >90th percentile, only women

HR 95% CI

None 1.00

CHEK2 1.94 1.45-2.61

PRS 2.41 2.19-2.65

PALB2 4.89 3.34-7.17

CHEK2 & PRS 6.32 4.37-9.13

PALB2 & PRS 14.17 4.54-44.20

Nina Mars: C16.4, Monday @ 13-14:30

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UK Biobank ~400k (another 80k non-European)

Biobank Japan ~200k

FinnGen ~150k (+50k every 6 months)

HUNT ~70k

Estonian Biobank ~50k (soon 100k)

Generation Scotland ~30k

Michigan ~40k

BioME (MSSM) ~32k

Colorado ~32k

Partners ~20k (soon 25k)

UCLA ~14k

Likely additional participants:

BioVU (120K)

deCODE (250K)

China Kadoorie (100K)

Wei Zhou, Masa Kanai, Juha KarjalainenCristen Willer, Ben Neale

Looking forward:Global Biobank Meta-Analysis

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Asthma

Biobank Japan8,204 cases, 10 loci

UK Biobank 26,332 cases, 31 loci Combined

52,194 cases, 52 loci

Finngen12,071 cases, 8 loci

HUNT 5,587 cases, 3 loci

Wei Zhou, Masa Kanai, Juha Karjalainen

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Towards next steps in population health

• Finnish medical data, genomes and technology combined with global collaboration will advance

• Genetic discoveries

• Public health interventions that prevent disease

• Identifying individuals at high-risk to make early detection and prevention more efficient

19

Acknowledgements