A cumulative genetic risk score predicts progression in Parkinson's disease

Abstract

We present results linking cumulative genetic risk to a motor outcome in Parkinson's disease. Our findings provide a valuable starting point for future large-scale efforts to map the genetic determinants of phenotypic variability.

Polygenic load: Earlier disease onset but similar longitudinal progression in Parkinson's disease

“…All of them found an association of an older age at onset with worse motor and nonmotor performance . Two recently published studies in 336 and 192 patients reported a higher genetic burden to be associated with faster motor and/or cognitive progression . However, the genetic risk score that was used comprised less variants from GWAS analyses than included in our analysis, and the researchers used a different approach defining outcome parameters.…”

“…[26][27][28][29][30] Two recently published studies in 336 and 192 patients reported a higher genetic burden to be associated with faster motor and/or cognitive progression. 31,32 However, the genetic risk score that was used comprised less variants from GWAS analyses than included in our analysis, and the researchers used a different approach defining outcome parameters. Furthermore, it is not reported whether or not patients with pathogenic PD-associated mutations have been excluded.…”

A paradoxical relationship between family history, onset age, and genetic risk in Parkinson's disease

“…The cumulative burden of common GWAS variants has been associated with earlier PD onset and higher rates of motor and cognitive progression . Presuming that common risk loci contribute to familial clustering in non‐Mendelian PD, one would expect cumulative genetic risk score (GRS) to be on average higher in patients with a positive family history.…”

Will genotype drive treatment options?

“…The concept of polygenic risk score (PRS), however, is increasingly being used to predict treatment outcomes in complex‐genetic disorders. In complex‐genetic PD, cumulative polygenic risk scores were shown to be associated with age at onset and faster motor and cognitive deterioration . Anticipating the possible disease course may help to inform treatment decisions, but the significance of PRS in predicting treatment outcome has to be investigated in prospective, longitudinal studies.…”