Alzheimer's disease and age-related macular degeneration have different genetic models for complement gene variation

Proitsi, Petroula; Lupton, Michelle K.; Dudbridge, Frank; Tsolaki, Magda; Hamilton, Gillian; Daniilidou, Makrina; Pritchard, Megan; Lord, Kathryn; Martin, Belinda M.; Craig, David; Todd, Stephen; McGuinness, Bernadette; Hollingworth, Paul; Harold, Denise; Kloszewska, Iwona; Soininen, Hilkka; Mecocci, Patrizia; Velas, Bruno; Gill, Michael; Lawlor, Brian; Rubinsztein, David C.; Brayne, Carol; Passmore, Peter A.; Williams, Julie; Lovestone, Simon; Powell, John F.

doi:10.1016/j.neurobiolaging.2011.12.036

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Alzheimer's disease and age-related macular degeneration have different genetic models for complement gene variation

Petroula Proitsi
- King's College London, Institute of Psychiatry, De Crespigny Park, London, UK
- Corresponding author at: Institute of Psychiatry, KCL, De Crespigny Park, Department of Neuroscience, MRC, Centre for Neurodegeneration Research, PO55, London, SE5 8AF, UK. Tel.: +44 2078485244; fax: +44 2077080017
Michelle K. Lupton
- King's College London, Institute of Psychiatry, De Crespigny Park, London, UK
Frank Dudbridge
- Department of Non-communicable Disease Epidemiology, Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK
Magda Tsolaki
- Memory and Dementia Centre, Aristotle University of Thessaloniki, Thessaloniki, Greece
Gillian Hamilton
- Molecular Medicine Centre, Medical Genetics, Western General Hospital, University of Edinburgh, Edinburgh, UK
Makrina Daniilidou
- Memory and Dementia Centre, Aristotle University of Thessaloniki, Thessaloniki, Greece
Megan Pritchard
- King's College London, Institute of Psychiatry, De Crespigny Park, London, UK
Kathryn Lord
- King's College London, Institute of Psychiatry, De Crespigny Park, London, UK
Belinda M. Martin
- King's College London, Institute of Psychiatry, De Crespigny Park, London, UK
David Craig
- Ageing Group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
Stephen Todd
- Ageing Group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
Bernadette McGuinness
- Ageing Group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
Paul Hollingworth
- MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
Denise Harold
- MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
Iwona Kloszewska
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
Hilkka Soininen
- Department of Neurology, Kuopio University and University Hospital, Kuopio, Finland
Patrizia Mecocci
- Section of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
Bruno Velas
- Department of Internal and Geriatrics Medicine, Hôpitaux de Toulouse, Toulouse, France
Michael Gill
- Institute of Molecular Medicine, Trinity College, Dublin, Ireland
Brian Lawlor
- Mercer's Institute for Research on Aging, St. James's Hospital and Trinity College, Dublin, Ireland
David C. Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
Carol Brayne
- Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK
Peter A. Passmore
- Ageing Group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
Julie Williams
- MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
Simon Lovestone
- King's College London, Institute of Psychiatry, De Crespigny Park, London, UK
John F. Powell
- King's College London, Institute of Psychiatry, De Crespigny Park, London, UK

Received 1 March 2011; received in revised form 12 December 2011; accepted 28 December 2011. published online 03 February 2012.
Corrected Proof

Abstract

Alzheimer's disease (AD) and age-related macular degeneration (AMD) are both neurodegenerative disorders which share common pathological and biochemical features of the complement pathway. The aim of this study was to investigate whether there is an association between well replicated AMD genetic risk factors and AD. A large cohort of AD (n = 3898) patients and controls were genotyped for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), the Age-related maculopathy susceptibility protein 2 (ARMS2) the complement component 2 (C2), the complement factor B (CFB), and the complement component 3 (C3) genes. While significant but modest associations were identified between the complement factor H, the age-related maculopathy susceptibility protein 2, and the complement component 3 single nucleotide polymorphisms and AD, these were different in direction or genetic model to that observed in AMD. In addition the multilocus genetic model that predicts around a half of the sibling risk for AMD does not predict risk for AD. Our study provides further support to the hypothesis that while activation of the alternative complement pathway is central to AMD pathogenesis, it is less involved in AD.

Keywords: Alzheimer's disease (AD) , Age-related macular degeneration (AMD) , Complement pathway , Single nucleotide polymorphisms (SNPs) , Genetic models