Cumulative genetic risk may underlie many Parkinson’s cases

By Eleanor McDermid, Senior medwireNews Reporter

Genetic risk for Parkinson’s disease (PD) may be due as much to multiple genes with small individual effects as to single high-risk genes, research suggests.

Nigel Williams (Cardiff University School of Medicine, UK) and colleagues used data from five PD genome-wide association studies, involving 5333 PD cases and 12,298 controls. The team tested 259,577 single nucleotide polymorphism (SNPs) in a subset of 1705 PD cases and 6200 controls from the UK, identifying between nine and 30,157 SNPs that were significantly enriched among the PD patients, depending on the significance threshold of association used.

Applying a polygenic score based on these SNPs to two subsets of patients from the USA and one from Germany revealed significant enrichment of the SNPs identified in the UK patients in these independent cohorts.

Similar to studies of other polygenic diseases, the most robust evidence was gained using relatively lax significance thresholds, in line with the hypothesis of a large number of polymorphisms with small individual effects.

In a subset of 4111 patients, the researchers found that higher polygenic scores were associated with a younger age at PD onset. The association held after the team excluded SNPs linked to genomic regions with previously reported strong associations with PD.

Patients in the lowest 5% of age at onset (<40 years) had an average polygenic score of 0.14, which was significantly more than the average score of –0.05 among patients in the highest 5% of age at onset (≥80 years). Among patients with a polygenic score greater than 1.5, 13% had PD onset when they were younger than 40 years, whereas just 3% had onset when aged 80 years or older.

Patients lacking single high-risk genetic mutations who nevertheless develop the condition at a young age would be expected to have an increased polygenic risk, say the researchers. “Our study has identified compelling evidence that supports this hypothesis”, they write in the Annals of Neurology.

They caution that “the derived polygenic scores have little value for predicting an individual's risk of developing PD”, but add that “measures of polygenic burden could prove useful in distinguishing PD patients whose disease liability is most likely to carry the largest or smallest genetic component.”

This would therefore facilitate efforts to identify environmental risk factors and gene–environment interactions.

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