Polygenic (or genetic) risk scores have become widely used in the study of common genetic variation and its role in disease... these risk scores are derived by combining the effects of the genetic variants identified in genome wide association (GWA) studies. GWA studies themselves are usually a comparison between the genetic variants that exist in a particular disease group (for example Parkinson's disease) compared with the variants seen in a healthy control group. Stringent levels of 'statistical significance' are applied to rule out false positive results and the regions that are identified are independent of one another. This independence means that the odds of the disease attributed to each variant/region can be multiplied together to give an overall genetic risk score for that disease. You can see how this might be useful for predicting who might get Parkinson's.
One can also calculate how much of the disease that the genetic risk score explains (usually only a very small amount). The genetic risk score for the present study came from here. There is now a bigger GWA study for Parkinson's that has been published too.
In the present study, the authors set out to see if the original genetic risk score that predicted the odds of getting PD also predicted the rate of disease progression in those that already have the disease, using cognitive and motor scores. It is not always the case that risk factors that are associated with getting a disease are also associated with more aggressive disease, but here we see evidence that this might be the case. Whether this is a reflection of common mechanisms underpinning risk and progression, or whether the original GWAS study contained an excess of patients with more aggressive forms of PD remains to be determined...
- Alastair Noyce
JAMA Neurol. 2018 Jan 16. doi: 10.1001/jamaneurol.2017.4206. [Epub ahead of print]
Paul KC, Schulz J, Bronstein JM, Lill CM, Ritz BR.
https://jamanetwork.com/journals/jamaneurology/article-abstract/2669922?redirect=true
IMPORTANCE:
Genetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance.
OBJECTIVE:
To assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD.
DESIGN, SETTING, AND PARTICIPANTS:
This longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression.
MAIN OUTCOMES MEASURES:
The combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring.
RESULTS:
Of the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01).
CONCLUSIONS AND RELEVANCE:
Susceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.
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