Paul KC, Schulz J, Bronstein JM, Lill CM, Ritz BR.
Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease.
JAMA Neurol. 2018 Jan 16;
PubMed.
The subclinical progression and age at onset, as well as clinical progression subsequent to diagnosis of complex age-related neurodegenerative diseases such as PD, is very likely to involve interactions not only between risk genes but also between genes that code for enzymes (e.g. glutathione-S-transferase) involved in the metabolism and detoxification of xenobiotics. The more we understand these complex interactions, the better will be our chances for identifying modifiable factors such as diet, occupation, and lifestyle that can be adjusted with relatively low risk to the patients while slowing subclinical disease progression and thus, delaying onset.
The rate of disease progression among Parkinson’s disease (PD) patients can be highly variable. Genome-wide association studies (GWAS) in PD have largely focused on the identification of risk alleles for PD and onset age. However, the identification of genetic factors influencing the rate of disease progression could have an important clinical relevance. This longitudinal population-based cohort study by Paul and coworkers addresses this important issue. The authors have genotyped 23 SNPs in 285 PD patients. Genome-wide independent and significant association with PD risk was observed for each of these 23 SNPs in a previously reported GWAS meta-analysis (Nalls et al., 2014). Subsequently, the authors have calculated a polygenic risk score for each patient (using the number of risk alleles and the effect size of each risk allele, based on the GWAS meta-analysis). The polygenic risk score was significantly associated with a more rapid decline of the Mini-Mental State Examination (MMSE). Additionally, significant association of the polygenic risk score with a faster progression of motor symptoms to Hoehn-and-Yahr stage 3 (HY stage 3) was observed. HY stage 3 defines the appearance of balance problems and is an important disease milestone in PD. Faster progression to HY stage 3 was also shown to be significantly associated with a polygenic score (calculation based on 19 GWAS SNPs) in a Norwegian longitudinal study with mean follow-up duration of more than 10 years (Pihlstrom et al., 2016).
Paul and coworkers highlight the influence of common genetic variants and of the polygenic architecture on the variability of disease progression rate in PD. These findings need to be replicated in studies with larger sample size and longer follow-up duration. Careful clinical characterization and periodic standardized clinical follow-up is mandatory for the accuracy of the phenotypical data in these studies. The development and validation of biomarkers to track the disease progression in PD patients will hopefully contribute to the identification of novel genetic determinants in future studies.
References:
Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, International Parkinson's Disease Genomics Consortium (IPDGC), Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI), 23andMe, GenePD, NeuroGenetics Research Consortium (NGRC), Hussman Institute of Human Genomics (HIHG), Ashkenazi Jewish Dataset Investigator, Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE), North American Brain Expression Consortium (NABEC), United Kingdom Brain Expression Consortium (UKBEC), Greek Parkinson's Disease Consortium, Alzheimer Genetic Analysis Group, Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB.
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.
Nat Genet. 2014 Sep;46(9):989-93. Epub 2014 Jul 27
PubMed.
Pihlstrøm L, Morset KR, Grimstad E, Vitelli V, Toft M.
A cumulative genetic risk score predicts progression in Parkinson's disease.
Mov Disord. 2016 Apr;31(4):487-90. Epub 2016 Feb 8
PubMed.
Comments
Boston University Chobanian & Avedisian School of Medicine
The subclinical progression and age at onset, as well as clinical progression subsequent to diagnosis of complex age-related neurodegenerative diseases such as PD, is very likely to involve interactions not only between risk genes but also between genes that code for enzymes (e.g. glutathione-S-transferase) involved in the metabolism and detoxification of xenobiotics. The more we understand these complex interactions, the better will be our chances for identifying modifiable factors such as diet, occupation, and lifestyle that can be adjusted with relatively low risk to the patients while slowing subclinical disease progression and thus, delaying onset.
View all comments by Marcia RatnerUniversity of Antwerp
The rate of disease progression among Parkinson’s disease (PD) patients can be highly variable. Genome-wide association studies (GWAS) in PD have largely focused on the identification of risk alleles for PD and onset age. However, the identification of genetic factors influencing the rate of disease progression could have an important clinical relevance. This longitudinal population-based cohort study by Paul and coworkers addresses this important issue. The authors have genotyped 23 SNPs in 285 PD patients. Genome-wide independent and significant association with PD risk was observed for each of these 23 SNPs in a previously reported GWAS meta-analysis (Nalls et al., 2014). Subsequently, the authors have calculated a polygenic risk score for each patient (using the number of risk alleles and the effect size of each risk allele, based on the GWAS meta-analysis). The polygenic risk score was significantly associated with a more rapid decline of the Mini-Mental State Examination (MMSE). Additionally, significant association of the polygenic risk score with a faster progression of motor symptoms to Hoehn-and-Yahr stage 3 (HY stage 3) was observed. HY stage 3 defines the appearance of balance problems and is an important disease milestone in PD. Faster progression to HY stage 3 was also shown to be significantly associated with a polygenic score (calculation based on 19 GWAS SNPs) in a Norwegian longitudinal study with mean follow-up duration of more than 10 years (Pihlstrom et al., 2016).
Paul and coworkers highlight the influence of common genetic variants and of the polygenic architecture on the variability of disease progression rate in PD. These findings need to be replicated in studies with larger sample size and longer follow-up duration. Careful clinical characterization and periodic standardized clinical follow-up is mandatory for the accuracy of the phenotypical data in these studies. The development and validation of biomarkers to track the disease progression in PD patients will hopefully contribute to the identification of novel genetic determinants in future studies.
References:
Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, International Parkinson's Disease Genomics Consortium (IPDGC), Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI), 23andMe, GenePD, NeuroGenetics Research Consortium (NGRC), Hussman Institute of Human Genomics (HIHG), Ashkenazi Jewish Dataset Investigator, Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE), North American Brain Expression Consortium (NABEC), United Kingdom Brain Expression Consortium (UKBEC), Greek Parkinson's Disease Consortium, Alzheimer Genetic Analysis Group, Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014 Sep;46(9):989-93. Epub 2014 Jul 27 PubMed.
Pihlstrøm L, Morset KR, Grimstad E, Vitelli V, Toft M. A cumulative genetic risk score predicts progression in Parkinson's disease. Mov Disord. 2016 Apr;31(4):487-90. Epub 2016 Feb 8 PubMed.
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