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Alzheimer’s Disease Julie Williams. Finding Susceptibility Genes for Alzheimer’s Disease Pinpoint primary events in disease development Help us understand.

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Presentation on theme: "Alzheimer’s Disease Julie Williams. Finding Susceptibility Genes for Alzheimer’s Disease Pinpoint primary events in disease development Help us understand."— Presentation transcript:

1 Alzheimer’s Disease Julie Williams

2 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

3 Genetic Association Alzheimer’s Cases Well Controls = 10 = 20 = 23 = 7

4 Genome-wide Association

5 Stage 1 Cases: 3,941 Controls: 7,848 Stage 2 Cases: 2,023 Controls: 2,340

6 ▲ 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

7

8 APOE P=5x10 -8 CR1 P=1.3x CLU P=2.6x PICALM P=1.6x New Gene 5 P=8.6x10 -9 New Gene 3 P=6.0x New Gene 2 P=1.8x New gene 1 P=5x New Gene 4 P=1.6x K cases, 40k controls MTHFD1L 1.9x BIN1 P=5.8x Gierdratis 2009; Kamboh, 2010; ADGC; 2010; Carrasquillo, 2010 Seshadri, 2010 Pericack-Vance, 2010 (OPS 5.3)

9 Collaboration Data-base: large complex, interactive Capacity for complex analyses in large datasets: sequence data Research-NHS database

10 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 Bristol Seth Love Patrick G. Kehoe 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 UK Sanger Institute Rhian Gwilliam Panagiotis Deloukas Greece Magda Tsolaki US NIH Andrew Singleton Rita Guerreiro US Mayo Clinic Minerva M. Carrasquillo Shane V. Pankratz Steven G. Younkin Edinburgh Ian Deary 1958 Birth Cohort Wellcome Trust Case-Control Consortium Caerphilly Prospective Study John Gallacher Yoav Ben-Shlomo GlaxoSmithKline

11 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.

12 Cholesterol in brain cells Bjorkhem, I. et al. Arterioscler Thromb Vasc Biol 2004;24: ABCA1

13 Inflammation:complement pathway genes C1q C1r C1s C1 complex +- C3C5 CFI C3bC5b C3b CR1CR2 C3b binds pathogen and to CR1 or CR2 receptors on B- lymphocytes + C9 C5b MAC - CLU Encoded in the GWAS and picked up in GO complement activation Adaptive immune response innate immune response

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

15 Clatherin mediated endocytosis A process by which large molecules enter cells without passing through membrane.

16 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

17 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

18 Alzheimer’s Disease: Early Findings APOE APP PS1 PS2 Mutations: PS1: > 150 PS2: < 20 APP: < % AD cases Rare variants Copy number variant CNV Common variant :17.7% AD risk Heritability of AD %

19 First Genome-wide Association Studies of Alzheimer’s Disease StudyYear GWAS Cases GWAS ControlsGeneGWAS P Grupe et al GALP8.4x10 -3 Coon et al APOE5.3x Reiman et al GAB24.6X10 -7 * Li et al Intergenic4.5x10 -6 Abraham et al LRAT2x10 -5 Bertram et al familiesIntergenic1x10 -3 Beecham et al FAM113B1.43x10 -6 Carrasquillo et al PCDH11X1.2x10 -5 * 527  4-positive cases, 117 APOE  4-positive controls R Replication P only # Adjusted for sex

20 Stage 1 Cases: 3,941 Controls: 7,848 Stage 2 Cases: 2,023 Controls: 2,340 Stage 1 Cases: 2,025 Controls: 5,328 Stage 2 Cases: 3,978 Controls: 3,297


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