Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

Abstract

Summary Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. Findings The discovery phase consisted of 5333 case and 12-019 control samples, with genotyped and imputed data at 7-689-524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5×10−8). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60·3% (95% CI 43·7–69·3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2·51 (95% CI 2·23–2·83) compared with 1·00 in the lowest quintile of disease risk. Interpretation These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. Funding Wellcome Trust, National Institute on Aging, and US Department of Defense.

<b><i>CCDC62</i></b> Variant rs12817488 Is Associated with the Risk of Parkinson's Disease in a Han Chinese Population

“…In the current Chinese population, we found that the A allele is a major allele of rs12817488 (54.2% in all subjects), rather than a minor allele as reported in Caucasians (46.0%) [8] and in NCBI dbSNP (39.9%), suggesting a differential presence of the variant's allele frequencies across ethnicities. Interestingly, gender-stratified analysis demonstrated that the association of rs12817488 with PD existed only in females, but not in males, suggesting an involvement of hormonal regulating factors.…”

“…rs10847864 in the HIP1R gene with linkage disequilibrium to rs12817488 (r 2 = 0.85), was used to compensate for probe design to reflect the signal of the initial locus [8]. The association of rs10847864/ HIP1R with PD was later confirmed by other groups [6,9,10].…”

“…Recently, 5 new variants were identified as PD-susceptible genes ( ACMSD, STK39, MCCC1/LAMP3, SYT11 , and CCDC62/HIP1R ) in a GWAS meta-analysis by the International Parkinson's Disease Genomics Consortium (IPDGC) [8]. These newly identified loci were thereafter investigated in different populations, except for the variant rs12817488 of CCDC62 which was substituted by a proxy SNP rs10847864/ HIP1R in these studies [6,9,10].…”

A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

“…Of these 16, all but 3 (rs4073221, rs10906923, and rs9468199) were also nominally associated in the NeuroX study (one-sided P < 0.05). A genetic risk score 8,18,19 defined by these 16 loci, in addition to the previously reported loci, had a non-negligible ability to predict PD case status (area under the curve, 0.6518; 95% CI, 0.6419–0.6616). This represents a significant improvement over the predictive power of risk scores defined by previously reported loci alone ( P = 6 × 10 −8 ) (Supplementary Note 1).…”

Use of support vector machines for disease risk prediction in genome-wide association studies: Concerns and opportunities

“…With the release of the 1000 Genomes data (www.1000genomes.org), it is anticipated that future genetic studies will fill the gap between known and yet-to-be defined heritability in complex disorders [Altshuler et al, 2010; Olsen et al, 2007]. For example, a recent study on Parkinson disease using 1000 Genomes data revealed new putative loci that were overlooked in previous genome scans [Nalls et al, 2011]. Apart from identifying risk factors for complex diseases, geneticists are also interested in disease risk prediction for multifactorial disorders, such as Diabetes, Crohn’s disease, and neurodegenerative disorders, to provide patients with an early diagnosis that is based on their genetic architecture, as determined by array-based genotyping technologies.…”