Rare Genetic Variants Linked to Familial Parkinson’s Disease Risk

Using whole-exome sequencing, researchers identified 2 genes with potentially damaging genetic variants that could affect familial Parkinson's susceptibility.

Potentially deleterious genetic variants in TNK2 and TNR have been identified in individuals with familial Parkinson’s disease, according to study data published in JAMA Neurology.

Parkinson’s disease (PD) susceptibility is thought to be linked to both environmental and genetic factors. However, PD is genetically heterogeneous, and there are many genes that have yet to be discovered.

In order to identify genetic variants involved in familial PD, Janice L. Farlow, PhD, of the Department of Medical and Molecular Genetics at Indiana University School of Medicine in Indianapolis, and colleagues conducted a 2-stage study in which they compared genetic variants identified through whole-exome sequencing from a discovery cohort of multiplex families with PD with a replication cohort of sequenced probands with familial PD.

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The discovery cohort included 32 families with 93 individuals with Parkinson’s disease without a known causative mutation who underwent whole-exome sequencing. The researchers identified 3 genes, TNK2, TNR, and TOPORS, which contained 13 rare and potentially damaging variants, to be prioritized for whole-exome sequencing in the replication cohort, which consisted of 49 unrelated participants with familial PD. Two of these genes, TNK2 and TNR, were found to have 9 distinct and possibly functional variants in the replication cohort, which was confirmed by targeted polymerase chain reaction and Sanger sequencing.

“Using whole-exome sequencing in discovery and replication cohorts of individuals with familial PD, we detected 9 likely deleterious, rare exonic variants in 2 genes (TNK2 and TNR) that may have a role in PD susceptibility,” the authors wrote. “To our knowledge, neither TNK2 nor TNR has previously been implicated in PD susceptibility from genetic investigation of large pedigrees or from genome-wide association studies in population cohorts.”

In an accompanying editorial, Mathias Toft, MD, PhD, of the Department of Neurology at Oslo University Hospital in Norway and Owen A. Ross, PhD, of the Department of Neurosciences at the Mayo Clinic in Jacksonville, Florida note that this study used an interesting strategy that could increase the chance of identifying genetic variants. However, they note that the results should be treated with “cautious enthusiasm” while awaiting independent assessments.

“It is critical that results such as those published by Farlow and colleagues are made available to other investigators,” they wrote. “This represents an important step forward in assessing the role that rare variants play in the genetic architecture underlying PD susceptibility.”


  1. Farlow JL, Robak LA, Hetrick, K, Bowling K, et al. Whole-Exome Sequencing in Familial Parkinson Disease. JAMA Neurol. 2015. doi:10.1001/jamaneurol.2015.3266.
  2. Toft M, Ross O. Exome Variant Mining in Familial Parkinson Disease: Will Replication Find the Gold? JAMA Neurol. 2015. doi:10.1001/jamaneurol.2015.3536.