Three genes associated with Alzheimer’s Disease have been identified in 2 new studies published online today in Nature Genetics. Amouyel and colleagues conducted a two-part study (Amouyel et al, 2009). In the first part of the study they undertook a Genome-Wide Association Study involving 537,029 single nucleotide polymorphism’s (SNP’s) in a French sample of 2032 people with Alzheimer’s Disease and 5328 controls.As there were multiple comparisons, they needed to control for this (with a Bonferroni correction) and a marker in the CLU gene on chromosome 8 (8p21-p12) showed a statistically significant correlation just above the threshold.
They then attempted a replication in the second stage which involved 3978 probable cases of Alzheimer’s Disease and 3297 controls. This second stage involved subjects from Spain, Belgium and France. They confirmed a statistically significant association of CLU with the probable Alzheimer’s Disease subjects and additionally found a significant correlation with CR1 on chromosome 1 (1q32). The researchers then estimated the contribution of each gene to the risk of Alzheimer’s Disease and estimated that the attributable risk for APOE (a well established risk factor for Alzheimer’s Disease) was 25.5%, for CLU it was 8.9% and for CR1 it was 3.8%. Nevertheless the CR1 did not show up in the first stage of the study.
In the second study, Professor Julie Williams and colleagues (including Professor Michael Owen) undertook another two part study. This involved ‘up to 19,000 subjects’ in the initial stages of the study, these subjects being recruited from Europe and the United States. Again, this was a Genome Wide Association Study. After quality control measures, they looked at 529,205 autosomal single nucleotide polymorphisms in 3,941 people with Alzheimer’s Disease and 7,848 controls. They identified one marker in CLU (the same gene identified in the study above) and a second in the PICALM gene on chromosome 11. Importantly both of these findings were replicated in the second stage of the study which involved 2,023 people with Alzheimer’s Disease and 2,340 age-matched controls.They then looked further to see if they could identify which areas within the gene were significantly correlated and produces some candidate regions. The team point out that there are other significant genes which wouldn’t have been identified in this analysis.
Thus the three identified genes were CLU, PICALM and CR1.
The CLU gene (Clusterin) which was identified in both studies encodes an apolipoprotein which together with APOE is found in the central nervous system as well as other tissues. There are many suggested pathways for the involvement of CLU in the pathology of Alzheimer’s Disease. Thus CLU is found in the amyloid plaques found in Alzheimer’s Disease and there is evidence also suggesting that it may be involved in the removal of Beta Amyloid from the brain (by forming soluble complexes which can cross the blood brain barrier) and may play a role in inflammation in the brain.
The PICALM gene which was significantly associated with Alzheimer’s Disease in the second study encodes a protein that is involved in endocytosis. Mutations in PICALM (phosphatidylinositol-binding clathrin assembly protein) may therefore interfere with the transport of materials into the neurons and the team suggest that synaptic vesicle cycling may affected (for another study looking at vesicle cycling see the study below which involved a newly discovered protein – the Flower protein which may be involved in Calcium regulation within the neuron emphasising the importance of endocytosis in neuronal functioning).
The CR1 gene which was significantly associated with Alzheimer’s Disease in the second stage of the first study, encodes a receptor for C3b protein. The C3b protein forms part of the complement cascade and again there is some evidence suggesting that it may be involved in the removal of Beta Amyloid. The CR1 receptor may be involved in the process of phagocytosis – when material is ingested by the immune cells.
Now that these gene associations have been identified it will be interesting to see further replication studies as well as studies examining the possible roles of these genes in further detail.
Two large studies ( n=2978 and n=1760) published at PLOS Medicine, looked at how patients make choices regarding medications and amongst the findings, people were best able to understand medication outcome information if this was presented in simple frequencies (e.g. per 100 of the population). Further information on the trials can be found here and here together with a discussion of shared decision making here. The N60 region of the RanBP9 protein has been associated with an increased production of Beta-Amyloid production using post-mortem and cell culture data and these findings may lead to the development of novel therapeutic interventions for Alzheimer’s Disease. This protein binds to another protein which is involved in the movement of RNA through the pores in the nuclear membrane. RanBP9 interacts with several other proteins also. A new finding reported in the journal Cell is that cells are able to move using a newly identified mechanism which involves a folding of the membranes to form filopidia and this involves the use of a protein sRGAP2 which is associated with neurodevelopmental disorders. This may have important implications for the understanding of neurodevelopment. A new gene association with deafness has been identified. Loxhd1 mutations impair functioning of hair cells and subsequently with hearing. Mutations of this gene were found in some families with deafness (in a genetic database with genetic samples from hundreds of families with deafness). A protein – called the Flower protein – has been recently identified and found to play a role in the processes of endo and exocytosis whereby neurotransmitters are packaged into vesicles, released from the neuron and the membrane resorbed. Aggregates of the protein form channels which allow the entry of calcium into the cell and the research team suggest that this protein could be responsible for the close and necessary coupling of endocytosis and exocytosis.
Amouyel P et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s Disease. Nature Genetics. Advanced Online Publication (Published Online 6 September 2009).
Williams J et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s Disease. Nature Genetics. Advanced Online Publication (Published online 6 September 2009).
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