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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