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New Alzheimer risk gene discovered

adsp ap-2 digital pathology gwas scanscope whole-exome sequencing

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#1 Engadin

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Posted 21 November 2019 - 12:40 PM


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S O U R C E :    MedicalXpress

 

F U L L   T E X T   P R I M A L   S O U R C E :   Oxford Academic [Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene]

 

 

 

 

 

A new paper in the Journal of Neuropathology & Experimental Neurology finds a gene that may help explain a large part of the genetic risk for developing Alzheimer disease.

 
Late-onset Alzheimer disease, the most common form of the illness, is a devastating neurological condition with aspects of heritable risk that are incompletely understood. Unfortunately, the complexity of the human genome and shortcomings of earlier research are limiting factors, so that some genetic phenomena were not surveyed completely in prior studies. For example, there are many incompletely mapped genomic regions, and areas with repetitive sequences, that could not be studied previously.
 
Although Alzheimer's is known to be largely heritable, a substantial proportion of the actual genetic risk for the disease has remained unexplained, despite extensive studies. This knowledge gap is known to researchers are the "missing (or hidden) heritability" problem. For example, while heritability explained 79% of late-onset Alzheimer disease risk in a Swedish twin study, common risk variants identified by pervious genetic studies explained only 20% to 50% of late-onset Alzheimer disease. In other words, a relatively large amount of genetic influence on late-onset Alzheimer disease risk was not explained by prior genetic studies.
 
Recent advances in sequencing technologies have enabled more comprehensive studies. Such developments allow for more precise and accurate identification of genetic material than was available in earlier gene variant studies.
 
In the present study, researchers analyzed Alzheimer's Disease Sequencing Project data derived from over 10,000 people (research volunteers who agreed to have their genetic data evaluated in combination with their disease status), with the goal of identifying genetic variation associated with late-onset Alzheimer disease.
 
Preliminary results found evidence of late-onset Alzheimer disease -linked genetic variation within a segment of a gene called Mucin 6. Although the underlying mechanisms are mostly still unknown, researchers here believe that it's possible to draw credible and testable hypotheses based on these results. For example, the genetic variant that was associated with Alzheimer's disease risk may implicate a biochemical pathway in the brain that then represents a potential therapeutic target, a topic for future studies.
 
 
 
 
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#2 xEva

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Posted 25 November 2019 - 06:40 AM

Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene, 2019

 

 

I skimmed the source, looking for SNPs, and found 3, but because  "VNTR regions have been at least partly omitted from high-throughput genomic research for technical reasons, and therefore not included in many genotype-phenotype correlation analyses", they don't show up on 23andme.

 

Some quotes I found interesting:

 

The term VNTR describes end-to-end iterations of repetitive genomic sequences >= 6 bp in length

 

Unfortunately, the MUC6 VNTR region is extremely difficult to sequence, for technical reasons, related to the size, number, and interindividual differences of the tandem repeats
 

The MUC6 gene is a member of the mucin gene family. An interesting feature of this gene family is that tandem repeats reside in exons, and therefore they are transcribed and translated.

 

The repetitive polypeptide domains help constitute the “main components of mucus” and, when glycosylated, these amino acid motifs provide a basis for the “gelforming” characteristics of mucin proteins.

 

MUC6 is expressed preferentially in epithelial tissues, particularly in the gastrointestinal tract. Hence, a major focus in prior work has been on how the MUC6 VNTR polymorphism is associated with risk for gastrointestinal diseases—ulcers, gut infections, and stomach or intestinal cancers. However, this unique tandem repeat region may have broader impact. The MUC6 VNTR polymorphism may affect 2 organ systems—brain and digestive tract—through influencing the expression of at least 2 separate genes.

 

We also speculate that the MUC6 VNTR polymorphism is a possible reason why some individuals (those with more MUC6 VNTR repeats) may be relatively vulnerable to tauopathy with a given burden of Aβ plaques.

 


Edited by xEva, 25 November 2019 - 06:45 AM.


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