Enrichment of Minor Alleles of Common SNPs and Improved Risk Prediction for Parkinson's Disease

Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder in the aged population and thought to involve many genetic loci. While a number of individual single nucleotide polymorphisms (SNPs) have been linked with PD, many remain to be found and no known markers or combinations of them have a useful predictive value for sporadic PD cases. The collective effects of genome wide minor alleles of common SNPs, or the minor allele content (MAC) in an individual, have recently been shown to be linked with quantitative variations of numerous complex traits in model organisms with higher MAC more likely linked with lower fitness. Here we found that PD cases had higher MAC than matched controls. A set of 37564 SNPs with MA (MAF < 0.4) more common in cases (P < 0.05) was found to have the best predictive accuracy. A weighted risk score calculated by using this set can predict 2% of PD cases (100% specificity), which is comparable to using familial PD genes to identify familial PD cases. These results suggest a novel genetic component in PD and provide a useful genetic method to identify a small fraction of PD cases.

Modern human origins: multiregional evolution of autosomes and East Asia origin of Y and mtDNA

“…We examined 3 different sets of SNPs, the slow set as defined above, syn SNPs in the slow genes as defined above (Supplementary Table S3), and the random set as defined above. The results showed a clear pattern of more sharing in fast evolving SNPs (Table 1), indicating saturation level of genetic diversity, which further confirmed previous findings of higher genetic diversity in patients of complex diseases relative to normal matched controls (22,37,38).…”

“…The Neutral theory explains only the linear pattern, which however represents only a minority of any genome today. The link between traits/diseases and the amount of SNPs shows an optimum genetic diversity level maintained by selection, thereby providing direct experimental disproof for the neutral assumption for common SNPs (21,22,37,38). Other types of experimental evidence invalidating the neutral assumption have also been found (39,40).…”

“…In recent years, a more complete molecular evolutionary theory, the maximum genetic distance or diversity (MGD) hypothesis, has been making steady progress in solving both evolutionary and contemporary biomedical problems (20)(21)(22)(23)(24)(25)(26)(27). The core concept of the MGD theory, maximum genetic diversity, is a priori expected and supported by numerous facts (20,28,29).…”

Collective effects of common single nucleotide polymorphisms and genetic risk prediction in type 1 diabetes

“…By calculating the fraction of MAs in an individual, or minor allele contents (MAC) defined as the total number of MAs divided by the total number of SNPs examined, one can compare the average MAC scores of cases relative to controls. We have consistently found that the MAC scores are higher in several complex diseases relative to controls, including Parkinson's disease, lung cancer, type 2 diabetes, and schizophrenia . A subset of the MAs could be used to predict a fraction of these diseases.…”

“…For SNPs whose MAs were different in the control group vs the combined case and control groups were removed because their MAFs were too close to 0.5 to be informative on their MA status. MAC of an individual was calculated by dividing the number of MAs by the total number of SNPs examined . A custom script was used to calculate the MAC values of each sample (https://github.com/health1987/dist).…”