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If there is one factor common to genetic association studies it is their heterogeneity Bertram and Tanzi 2004 Shi et al, 2008 Dozen of confusing positive and negative studies blur the picture and suggest that many are related to artefact or insufficient statistical power. However, while at a global level these results are contentious, at a local level they can be quite homogenous, tending to cluster in positive or negative association hot and coldspots around the world.These examples are taken from data from the Alzgene and Szgene databases and are posted to illustrate this phenomenon.
This was done gene by gene, rather than by individual polymorphism, but this clustering could relate to several possibilities. Firstly, all polymorphisms/mutations have a single ancestral origin in a particular place at a particular time. For example a presenilin mutation has been tracked back to a family in Southern Italy prior to the 17th century Bruni at al, 2010 Their spread around the world will depend on their success (natural selection), their age and the migratory patterns of their bearers. Conquests, forced and voluntary expatriation will influence their distribution. Secondly, environmental factors may influence the risk promoting effects of many genes. For example many Alzheimer's disease related genes are related to cholesterol and lipoprotein function, and many related risk factors See risk factors (high cholesterol, saturated fat consumption) and protective factors (fish diets, polyunsaturated fat consumption, Mediterranean diet) may influence whether or not these genes are risk promoting. High fat consumption and APOE polymorphisms are a dangerous mix, but perhaps APOE is less risk promoting in countries with a high fish consumption (see negative APOE data from Japan). Thirdly, certain genes may also be related to infectious agents Carter 2009 Prasad et al, 2010 whose distribution varies around the globe. Each of these could influence positive and negative association data, which at a local level do not seem to be so heterogeneous.
Positive results are represented by filled black circles and negative results by open circles
Enhanced links to genes are provided by
web survey
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Apolipoprotein E: APOE4 is represented by the star
CR1 Complement receptor 1
Clusterin CLU
PICALM phosphatidylinositol binding clathrin assembly protein
Lipoprotein Receptor LRP1
Brain derived neurotrophic factor BDNF
Clusterin: Note the negative data from Spain and from a US study of Hispanic patients
Angiotensin converting enzyme ACE
No positive associations between MTHFR and Alzheimer’s disease have been reported in any European region. Positive association is exclusively localised to Iran, China and Korea,
and to an NIMH study in the USA. Maryland (the seat of NIMH) has a high proportion of Korean immigrants.
SORL1 sortilin-related receptor, L(DLR class)
APOE
COMT
Illinois settlers (mainly negative data) were originally French, German and Swedish , those in Minnesota, German and Nordic, and those in Iowa mainly French.. With the exception of 1 positive German study, most of these European areas return negative association data for COMT. In contrast, the population of Maryland derives from Latin America (and thus Spain), Asia and Korea, all of which possess fairly dense clusters of positive association data. Baltimore, Pittsburgh and New York are large multicultural cites, displaying both positive and negative association data.
BDNF
D-Amino acid oxidase DAO
DISC1
Neurogranin
Dopamine receptor DRD2
Dopamine receptor DRD3
DRD4: There are a large number of Japanese settlers in Mexico
Neuregulin NRG1
Dysbindin DTNB1
MTHFR
NOTCH4
PGBD1 piggyBac transposable element derived 1
TCF4 Transcription factor 4
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