Download Stage 1 Cases

Julie Williams
Alzheimer’s Disease
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 1
Cases: 3,941
Controls: 7,848
Stage 2
Cases: 2,023
Controls: 2,340
MRC Genetic Resource for Late-onset AD
• 1400 AD cases
• 1400 matched controls
• Validated case interview92%ppv
• Controls screened:
including U3A
• Longitudinal follow-up:
600
• Breadth phenotypic data:
▲ AAO, ROD, symptoms
• MRI imaging: 150
• Brain banking
PICALM P=1.6x10-19
New gene 1
P=5x10-21
New Gene 2
CLU
P=1.8x10-14
-22
P=2.6x10
CR1
P=1.3x10-19
BIN1
P=5.8x10-15
New Gene 3
P=6.0x10-10
New Gene 5
P=8.6x10-9
New Gene 4
P=1.6x10-9
P=5x10-8
MTHFD1L
1.9x10-10
20K cases, 40k controls
Pericack-Vance, 2010 (OPS 5.3)
Seshadri, 2010
Gierdratis 2009; Kamboh, 2010; ADGC; 2010; Carrasquillo, 2010
APOE
Collaboration
• Data-base: large complex, interactive
• Capacity for complex analyses in large
datasets: sequence data
• Research-NHS database
Cardiff
Julie Williams
Michael J.Owen
Michael O’Donovan
Denise Harold
Richard Abraham
Rebecca Sims
Amy Gerrish
Marian Hamshere
Jaspreet Singh Pahwa
Valentina Moskvina
Nicola Jones
Charlene Thomas
Alexandra Stretton
Peter Holmans
London (IOP)
Simon Lovestone
John Powell
Petroula Proitsi
Michelle K Lupton
Ammar Al-Chalabi
Christopher E. Shaw
Cambridge, CFAS
Carol Brayne
David C. Rubinsztein
Fiona Matthews
Dublin
Michael Gill
Brian Lawlor
Aoibhinn Lynch
Nottingham
Kevin Morgan
Kristelle Brown
Belfast
Peter Passmore
David Craig
Bernadette McGuinness
Stephen Todd
Southampton
Clive Holmes
Manchester
David Mann
Oxford
A. David Smith
London (UCL)
John Hardy
Simon Mead
Nick Fox
Martin Rossor
John Collinge
Gill Livingston
Nicholas J. Bass
Hugh Gurling
Andrew McQuillin
Germany
Wolfgang Maier
Frank Jessen
Britta Schürmann
Hendrik van den Bussche
Isabella Heuser
Johannes Kornhuber
Jens Wiltfang
Martin Dichgans
Lutz Frölich
Thomas W. Mühleisen
Markus M. Nöthen
Susanne Moebus
Karl-Heinz Jöckel
Norman Klopp
H-Erich Wichmann
Dan Rujescu
Matthias Riemenschneider
US Washington
Alison Goate
John S.K. Kauwe
Carlos Cruchaga
Petra Nowotny
John C. Morris
Kevin Mayo
US NIH
Andrew Singleton
Rita Guerreiro
Bristol
Seth Love
Patrick G. Kehoe
Greece
Magda Tsolaki
Edinburgh
Ian Deary
UK Sanger Institute
Rhian Gwilliam
Panagiotis Deloukas
US Mayo Clinic
Minerva M. Carrasquillo
Shane V. Pankratz
Steven G. Younkin
Caerphilly Prospective Study
John Gallacher
Yoav Ben-Shlomo
1958 Birth Cohort
Wellcome Trust Case-Control Consortium
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
ABCA1
Bjorkhem, I. et al. Arterioscler Thromb Vasc Biol 2004;24:806-815
Inflammation:complement pathway
genes
Encoded in
C1
complex
C3
C5
the GWAS
and picked
up in GO
complement
activation
C1q
C1s
C1r
+
-
CFI
C3b
Adaptive immune response
CR1 CR2
CLU
C3b
C5b
+
C9
-
C5bC9
MAC
innate immune response
C3b binds pathogen and to
CR1 or CR2 receptors on Blymphocytes
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
Rare variants
Heritability of AD 56 - 79%
PS2
Mutations:
PS1: > 150
PS2: < 20
APP: < 20
0.5% AD
cases
Copy number variant
CNV
PS1
APOE
Common variant :17.7% AD risk
First Genome-wide Association Studies of
Alzheimer’s Disease
Study
Year
GWAS
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 e4-positive cases, 117 APOE e4-positive controls
R
Replication P only
#
Adjusted for sex
Stage 1
Cases: 3,941
Controls: 7,848
Stage 1
Cases: 2,025
Controls: 5,328
Stage 2
Cases: 2,023
Controls: 2,340
Stage 2
Cases: 3,978
Controls: 3,297