I have been terribly frustrated by trying to make any sense of how genetics fits into the etiology of sporadic or iodopathic PD the kind of PD that most people have. I stumbled across quite a find that answers a lot of questions about PD.

The genetic research has been focused on individual SNPs in our genome as indicators that we might be susceptible to PD; like genetic markers. 23andme tests for one of the more common markers LRRK2 but that only works with those who do not have YOPD. What they are finding is that for sporadic PD, researchers needed to look at the bigger picture; a person's entire genome.

Well researchers have done just that and found two very important things. In sporadic PD the only big genetic markers we have is with the MAPT and the SNCA genes (SNCA regulates alpha-syn, btw). Beyond that there seemed to be nothing until they started to overlay the genomes of PWP. Here is the the next big find: Researchers analyzed 5000 SNPS and found that PWP had 25 different different biological pathways to PD! Of that number three stand out because in all tested PD patients, the SNPs matched identically. The three standouts are:

Axonal guidance pathway -Rick, if you are still here...read up on this one cause they are singing your song. With this pathway, we are pre-wired for PD at birth. Something happens in utero to compromise our development and we are then born with the likelihood of getting PD.

Focal Adhesion path - Don't know much about this other than it involves faulty signaling between neurons and it can result in aptoptosis or cellular death but a very specific type called anoikis.

Calcium signaling pathway- Mitochondrial dysfunction results in calcium accumulation. The neurons of the Substantia Nigra are particularly at risk.
This would explain PWP response to calcium channel blockers.

I don't know what to make of all this. On the one hand it seems like we have a breakthrough in identifying markers. Our genomes can be scanned against these pathways for a match. And treatment would obviously be variable. Of course, I am oversimplifying but the foundation is there.

The down side is how freakin complex this is. The authors of these articles note how researchers have been misguided by focusing only on largely familial PD markers orsseelo like PINK1 and LRRK2. The sporadic version of PD depends on the interplay of over 1,000 SNPs not to mention the environmental and/or viral triggers. The three common pathways have been confirmed by two different GWAS (Genomic Wide Assoication Studies).

Other pathways to PD involve melanin and starts off toward melanoma to a point then diverges. Again there has been correlation between melanoma and PD reported. A rather alarming number show PD sharing a partial path with several cancers. One pathway even involves glucose and starch metabolism. I think links between PD and these things have all been discussed here.

Key articles:

Identifying Consensus Disease Pathways in Parkinson's Disease Using an Integrative Systems Biology Approach.

Towards a pathway definition of parkinson's disease: A complex disorder with links to cancer, diabetes and inflammation.