Genetics of Alzheimer's disease
From work conducted during and just after Pat Kehoe's PhD at Cardiff he was the first to identify significant genetic association between variation in the Angiotensin-1 converting Enzyme (ACE1) gene and increased risk of Alzheimer's disease. On completing his PhD, Dr Kehoe then spearheaded for 3 years, the Cardiff contribution of what was then Phase I of the largest genome screen of sibling pairs with Alzheimer's disease, conducted in collaboration with the laboratories of Dr Alison Goate and Dr John Hardy and which yielded a number of novel candidate loci for late-onset (onset after 65years) Alzheimer's disease. Phase II of this project which involved refinement of the areas identified from Phase I in the original and additional samples went on to confirm the candidacy of loci on chromosome's 9, 10 and 12 in Alzheimer's disease as published by Myers et al. and by Holmans et al (as summarised and highlighted in table) along with other groups.
| Chromosome |
Pericak-
Vance |
Pericak-
Vance |
Curtis [2001] |
Olson [2002] |
Myers [2002] |
Li [2002] |
Blacker [2003] |
Scott [2003] |
Holmans [2005] |
Sillen [2005] |
Lee [2006] |
|
9p21
q22-34 |
- - |
4.3 2.0 |
1.4 1.6 |
- 2.6 |
1.8 1.8 |
- - |
- 2.9 |
4.6 - |
- 4.2 |
- - |
- 1.9 |
|
10q21-22
q25-26 |
- - |
- - |
2.0 - |
2.1 - |
4.1 - |
- 2.4 |
1.8 1.9 |
- - |
4.1 - |
- - |
- 2.5 |
| 12p11-13 |
3.9 |
- |
2.1 |
- |
1.4 |
- |
- |
- |
3.3 |
- |
- |
| Modified from data summarised on Alzgene (taken 24/05/2007) | |||||||||||
Table Legend: Data is presented from various linkage studies on overlapping sample sets (for further details see Alzgene). Chromosomal regions with lod scores >3 (suggestive of linkage and possibly harbouring an Alzheimer's disease associated gene) from >1 study are highlighted by red text. Lod scores >2 but < 3 (possibly denoting positive signals but may be underpowered statistically) are denoted by Italicised text. The studies following on from the Phase I genome screens are highlighted in yellow. For an enlarged view of this table with information on other chromosomal regions visit Alzgene.
Dr Kehoe then left the genetic work for a brief while to further his knowledge and training in Mental Health research by undertaking a split role as a Research and Development Manager and Research Associate in a joint funded post between the largest Mental Health NHS organisation in the United Kingdom (Avon and Wiltshire Mental Health Partnership NHS Trust - AWP) and the Division of Psychiatry, University of Bristol.
In 2002, Dr Kehoe returned to his unabated interest of Alzheimer's disease by joining the then Department of Care of the Elderly, to lead a Molecular Genetics laboratory that research Alzheimer's disease. It is this group that has since been renamed the Dementia Research Group, as a group in its own right in the Department of Clinical Science at North Bristol, and which is now headed jointly by both Dr Kehoe and Professor Seth Love. Within only one year Dr Kehoe had firmly re-established his position as a leading researcher in the role of the renin-angiotensin system of AD by spear-heading collaborative studies with Dr Jonathan Prince (Karolinska Institute, Stockholm), Professors Kaj Blennow (University of Göteborg) and Nancy Pedersen (Karolinska Institute, Stockholm). From this work they published the first ever haplotype study of ACE1 in Alzheimer's disease which supported Dr Kehoe's earlier findings of genetic association between ACE1 and Alzheimer's disease. Additional work on this found that variants associated with increased risk of Alzheimer's disease were associated with more detrimental levels (i.e. lower) of Aβ in cerebrospinal fluid taken from patients with Alzheimer's diseaseand also associated with earlier ages at onset of the disease. This work has been furthered by his spearheading (in collaboration with collaborators at the University of Oxford) one of the largest ever candidate gene meta-analyses conducted to date on Alzheimer's disease involving over 6,000 Alzheimer's disease patients and over 12,000 non-demented elderly and this too supported his original findings and his other findings with collaborators at the University of Bari on the existence of geographical differences in the distribution of ACE1 genotypes in which may be responsible to variable levels of association found with both Alzheimer's disease and longevity. To date the candidacy of ACE1 as a susceptibility gene for Alzheimer's disease still stands and he is currently involved in a number of projects to expand this work.