Alzheimer’s DiseaseJulie Williams

Finding Susceptibility Genes for Alzheimer’s Disease

• Pinpoint primary events in disease development

• Help us understand the biological pathways to disease development

• Provide the basis for future treatments or preventative therapies

Genetic Association Alzheimer’s Cases

Well Controls

= 10

= 20

= 23

= 7

Genome-wide Association

Stage 1Cases: 3,941 Controls: 7,848

Stage 2Cases: 2,023 Controls: 2,340

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MRC Genetic Resource for Late-onset AD• 1400 AD cases• 1400 matched controls• Validated case interview-

92%ppv

• Controls screened: including U3A

• Longitudinal follow-up: 600

• Breadth phenotypic data: AAO, ROD, symptoms

• MRI imaging: 150 • Brain banking

APOE

P=5x10-8

CR1P=1.3x10-19

CLUP=2.6x10-22

PICALM P=1.6x10-19

New Gene 5P=8.6x10-9

New Gene 3P=6.0x10-10

New Gene 2P=1.8x10-14

New gene 1P=5x10-21

New Gene 4P=1.6x10-9

20K cases, 40k controls

MTHFD1L 1.9x10-10

BIN1P=5.8x10-15

Gierdratis 2009; Kamboh, 2010; ADGC; 2010; Carrasquillo, 2010

Seshadri, 2010

Pericack-Vance, 2010 (OPS 5.3)

Collaboration

• Data-base: large complex, interactive

• Capacity for complex analyses in large datasets: sequence data

• Research-NHS database

CardiffJulie WilliamsMichael J.OwenMichael O’DonovanDenise HaroldRichard AbrahamRebecca SimsAmy GerrishMarian HamshereJaspreet Singh PahwaValentina MoskvinaNicola JonesCharlene ThomasAlexandra StrettonPeter HolmansLondon (IOP)Simon LovestoneJohn PowellPetroula ProitsiMichelle K LuptonAmmar Al-ChalabiChristopher E. ShawCambridge, CFASCarol BrayneDavid C. RubinszteinFiona Matthews

DublinMichael GillBrian LawlorAoibhinn LynchNottinghamKevin MorganKristelle BrownBelfastPeter PassmoreDavid CraigBernadette McGuinnessStephen Todd

SouthamptonClive HolmesManchesterDavid Mann

OxfordA. David Smith

BristolSeth LovePatrick G. Kehoe

London (UCL)John HardySimon MeadNick FoxMartin RossorJohn CollingeGill LivingstonNicholas J. BassHugh GurlingAndrew McQuillin

GermanyWolfgang MaierFrank JessenBritta SchürmannHendrik van den BusscheIsabella HeuserJohannes KornhuberJens WiltfangMartin DichgansLutz FrölichThomas W. MühleisenMarkus M. NöthenSusanne MoebusKarl-Heinz JöckelNorman KloppH-Erich WichmannDan RujescuMatthias RiemenschneiderUS WashingtonAlison GoateJohn S.K. KauweCarlos CruchagaPetra NowotnyJohn C. MorrisKevin Mayo

UK Sanger InstituteRhian GwilliamPanagiotis Deloukas

GreeceMagda Tsolaki

US NIHAndrew SingletonRita Guerreiro

US Mayo ClinicMinerva M. CarrasquilloShane V. PankratzSteven G. Younkin

EdinburghIan Deary

1958 Birth Cohort

Wellcome Trust Case-Control Consortium

Caerphilly Prospective StudyJohn GallacherYoav Ben-Shlomo

GlaxoSmithKline

Clearance of A

In most of these pathways clearance when in lipoprotein particle with E3 more efficient than with E4. CLU also affects A clearance.

Cholesterol in brain cells

Bjorkhem, I. et al. Arterioscler Thromb Vasc Biol 2004;24:806-815

ABCA1

Inflammation:complement pathway genes

C1q

C1rC1s

C1 complex

+ -

C3 C5

CFI

C3b C5bC3b

CR1 CR2

C3b binds pathogen and to CR1 or CR2 receptors on B-lymphocytes

+ C9 C9C5b

MAC

-CLU

Encoded in the GWAS and picked up in GO complement activation

Adaptive immune response

innate immune response

Both PICALM and BIN1play a role in Clathrin Mediated Endocytosis (CME)

• Clatherin mediated endocytosis A process by which large molecules enter cells

without passing through membrane.

Summary

• 3 rare variants: 0.5% variance

• 10 (+1) common variants: 20.5% variance

• 32% genetic variance

• Common variants implicate endocytosis, immunity and lipid processing

Future collaboration

• Identify extreme samples at high and low genetic risk for AD in ALSPAC, Caerphilly cohorts.

• Test for biological correlates: fishing expedition/ hypotheses based upon predicted mechanism (immunity, lipid processing).

• Replicate in independent samples

Alzheimer’s Disease:Early Findings

APOE APPPS1

PS2

Mutations:PS1: > 150PS2: < 20APP: < 200.5% AD cases

Rare variants

Copy number variantCNV

Common variant :17.7% AD risk

Heritability of AD 56 - 79%

First Genome-wide Association Studies of Alzheimer’s Disease

Study YearGWAS Cases

GWAS Controls Gene GWAS P

Grupe et al. 2007 380 396 GALP 8.4x10-3

Coon et al. 2007 664 422 APOE 5.3x10-34

Reiman et al. 2007 861 550 GAB2 4.6X10-7 *

Li et al. 2008 753 736 Intergenic 4.5x10-6

Abraham et al. 2008 1082 1239 LRAT 2x10-5

Bertram et al. 2008 410 families Intergenic 1x10-3

Beecham et al. 2009 492 498 FAM113B 1.43x10-6

Carrasquillo et al. 2009 844 1255 PCDH11X 1.2x10-5

           

* 527 4-positive cases, 117 APOE 4-positive controls R Replication P only# Adjusted for sex

Stage 1Cases: 3,941 Controls: 7,848

Stage 2Cases: 2,023 Controls: 2,340

Stage 1Cases: 2,025Controls: 5,328

Stage 2Cases: 3,978Controls: 3,297