Polygenic risk of Parkinson disease is correlated with disease age at onset

Abstract

ObjectiveWe have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset.MethodsThis study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta‐analysis of PD genome‐wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset.ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome‐wide association cohorts (minimum p = 3.76 × 10−6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014).InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015;77:582–591

Genome-wide assessment of Parkinson's disease in a Southern Spanish population

“…Our study, in agreement with the literature, did not reveal any significant variant to be associated with this PD feature. However, recent studies have found that increasing genetic risk scores are related to earlier age at onset (Nalls, et al, 2015b, Lill, et al, 2015) suggesting that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be influenced by an accumulation of common polygenic alleles with relatively low effect sizes (Escott-Price, et al, 2015). We show no association between GRS and AAO in this study.…”

Genetic risk of Parkinson’s disease in the general population

“…These studies showed that a risk score based on these variants may contribute to discrimination of PD patients and healthy controls [10,11], and average genetic risk may be higher in patients with an early disease age at onset [12]. In a recent diagnostic case-control study of PD, the univariate C-statistic of a genetic risk score that comprised 30 genetic variants including the 26 used in our study ranged from 0.62 to 0.64 [11], which was slightly higher than in our predictive study (C-statistic ¼ 0.56).…”

“…In addition, we could only assess the predictive value of the risk score for incident PD in persons aged 55 years and older. Since high polygenic risk is associated with a lower age of onset of PD [12], this probably led to a slight underestimate of the predictive value of the genetic risk score, considering the relatively small proportion of PD patients aged younger than 55 at a population level [1].…”

“…In addition, genome-wide association studies have yielded a total of 28 independent risk variants that are common at a population level, 22 of which are genome-wide significant [9]. Recent case-control studies have shown that a risk score based on these variants may contribute to discrimination of PD patients and healthy controls [10,11], and average genetic risk may be higher in patients with an early disease age at onset [12]. However, the clinical usefulness of these variants in prospectively predicting PD remains untested.…”

Parkinson’s Disease: Insights from Drosophila Model

“…To date, the largest GWAS was performed in 2014 carrying out a meta-analysis in all existing European-ancestry PD GWAS data with 13,708 PD cases, 95,282 controls and a replication study using genotyping array called 'Neuro X' in an independent data set identified 26 independent SNPs which showed genome-wide risk for PD [145].The first papers about the potential impact of risk loci on age at onset (AAO) in PD were published in 2015. The results using polygenic score analysis showed that patients with an early AAO had a significantly higher polygenic score when compared to those with late AAO [146]. GWAS showed a genetic association with PD in the HLA region (chromosome 6p21.3), which was designated PARK18 and the common variant associated with late onset sporadic PD was rs3129882 in intron 1 of HLA-DRA [147] GWAS sporadic PD was performed and sterol regulatory element binding transcription factor 1 (SREBF1) was identified as risk factor for PD [148].…”