COLD SPRING HARBOR, NY (GenomeWeb) – Members of the International Parkinson's Disease Genomics Consortium have used whole-exome sequencing as part of their ongoing search for new genetic contributors to the neurodegenerative disease.
Iris Jansen, from the VU University Medical Center in the Netherlands, outlined the effort and findings so far during a Saturday session at the Biology of Genomes meeting.
By sequencing and comparing the exomes of 1,190 individuals with familial or sporadic Parkinson's disease and nearly 500 unaffected controls, she and her colleagues identified common variants, rare variants, and combinations of the two that contribute to Parkinson's disease risk.
When they looked at genes and pathways that were particularly prone to alterations in the protein-coding portion of Parkinson's disease patients, the researchers saw an over-representation of genes from three inter-connected pathways contributing to mitophagy, autophagy, and endocytosis-related processes.
Those results hint that dysfunctions affecting those pathways may be contribute to Parkinson's disease development rather than being a consequence of it, Jansen noted.
The IPDGC team — which has access to samples from some 14,000 Parkinson's disease patients in all — plans to do array-based profiling on thousands more Parkinson's disease patients using the so-called NeuroX exome chip to verify genetic results from the current exome sequencing study. Consortium members are also in the process of resequencing apparent Parkinson's disease loci detected through past studies of the condition.
Jansen and her co-authors noted that dozens of genes have been implicated in familial or sporadic forms of Parkinson's disease through past linkage and genome-wide association studies.
To learn more about genetic mechanisms contributing to Parkinson's Disease, the researchers did exome sequencing on 1,190 individuals with familial or sporadic Parkinson's disease and 490 unaffected controls.
In selecting study participants, Jansen noted that the group aimed for higher-than-usual representation from individuals with Parkinson's disease onset prior to the age of 55 years old. That early-onset form of the disease tends to be inherited in a recessive manner — a pattern the team exploited in its search for homozygous and compound heterozygous mutations contributing to the condition.
When they analyzed the exome sequence data under a recessive model of Parkinson's disease inheritance, for example, the researchers found 57 suspicious homozygous mutations and 74 apparent instances of compound heterozygous loss-of-function gene changes affecting more than 80 genes in all.
The team's analysis of common variant contributors to Parkinson's disease pointed to SNPs at more than 30 loci, while gene-based association tests highlighted 169 genes with potential Parkinson's contributions.
Finally, by focusing in on frequently affected pathways, the researchers found evidence for involvement by mitophagy, autophagy, and endocytosis pathways in Parkinson's disease development.
The group is continuing to look for new genetic contributors to the condition, while attempting to verify candidate associations from the exome sequencing study using lab models such as Caenorhabditis elegans and Drosophila and cell cultures generated from human neuronal cells.