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Alzheimer’s Disease

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.

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Alzheimer’s Disease

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  1. Julie Williams Alzheimer’s Disease

  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 = 23 = 10 = 20 = 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. New gene 1 P=5x10-21 New Gene 2 P=1.8x10-14 PICALM P=1.6x10-19 APOE CR1 P=1.3x10-19 CLUP=2.6x10-22 New Gene 3 P=6.0x10-10 BIN1 P=5.8x10-15 New Gene 5 P=8.6x10-9 New Gene 4 P=1.6x10-9 MTHFD1L 1.9x10-10 P=5x10-8 20K cases, 40k controls Pericack-Vance, 2010 (OPS 5.3) Seshadri, 2010 Gierdratis 2009; Kamboh, 2010; ADGC; 2010; Carrasquillo, 2010

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

  9. 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 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 Dublin Michael Gill Brian Lawlor Aoibhinn Lynch Bristol Seth Love Patrick G. Kehoe Greece Magda Tsolaki Nottingham Kevin Morgan Kristelle Brown Edinburgh Ian Deary Belfast Peter Passmore David Craig Bernadette McGuinness Stephen Todd UK Sanger Institute Rhian Gwilliam Panagiotis Deloukas US Mayo Clinic Minerva M. Carrasquillo Shane V. Pankratz Steven G. Younkin Southampton Clive Holmes Manchester David Mann London (IOP) Simon Lovestone John Powell Petroula Proitsi Michelle K Lupton Ammar Al-Chalabi Christopher E. Shaw Caerphilly Prospective Study John Gallacher Yoav Ben-Shlomo Oxford A. David Smith US Washington Alison Goate John S.K. Kauwe Carlos Cruchaga Petra Nowotny John C. Morris Kevin Mayo London (UCL) John Hardy Simon Mead Nick Fox Martin Rossor John Collinge Gill Livingston Nicholas J. Bass Hugh Gurling Andrew McQuillin 1958 Birth Cohort Wellcome Trust Case-Control Consortium Cambridge, CFAS Carol Brayne David C. Rubinsztein Fiona Matthews GlaxoSmithKline US NIH Andrew Singleton Rita Guerreiro

  10. 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.

  11. Cholesterol in brain cells ABCA1 Bjorkhem, I. et al. Arterioscler Thromb Vasc Biol 2004;24:806-815

  12. C3 C5 C1 complex C1q CFI + - C1r C1s C3b C5b Inflammation:complement pathway genes Encoded in the GWAS and picked up in GO complement activation Adaptive immune response CLU - C3b + C9 C9 C5b CR1 CR2 MAC innate immune response C3b binds pathogen and to CR1 or CR2 receptors on B-lymphocytes

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

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

  15. 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

  16. 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

  17. 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 APP PS1 APOE Common variant :17.7% AD risk

  18. First Genome-wide Association Studies of Alzheimer’s Disease

  19. 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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