Abstract
Parkinson’s disease (PD) is a common, disabling neurodegenerative disorder with significant genetic underpinnings. Multiple genome-wide association studies (GWAS) have been conducted with identification of several PD loci. However, these only explain about 25% of PD genetic risk indicating that additional loci of modest effect remain to be discovered. Association clustering methods such as gene-based tests are more powerful than single-variant analysis for identifying modest genetic effects. Combined with the locus-based algorithm, OASIS, the most significant association signals can be homed in. Here, two dbGAP GWAS datasets (7415 subjects (2750 PD and 4845 controls) genotyped for 0.78 million SNPs) were analyzed using combined clustering algorithms to identify 88 PD candidate genes in 24 loci. These were further investigated for gene expression in substantia nigra (SN) of PD and control subjects on GEO datasets. Expression differences were also assessed in normal brains SN versus white matter on BRAINEAC datasets. This genetic and functional analysis identified AXIN1, a key regulator of Wnt/β-catenin signaling, as a novel PD gene. This finding links PD with inflammation. Other significantly associated genes were CSMD1, CLDN1, ZNF141, ZNF721, RHOT2, RICTOR, KANSL1, and ARHGAP27. Novel PD genes were identified using genomic convergence of gene-wide and locus-based tests and expression studies on archived datasets.
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Acknowledgements
All GWAS data was obtained from dbGAP.
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OASIS [https://github.com/dr-saeed/OASIS/blob/master/OASIS.py], SNIPPER [https://csg.sph.umich.edu/boehnke/snipper], KGG [http://grass.cgs.hku.hk/limx/kgg], BRAINEAC [http://www.braineac.org] and STRING [https://string-db.org/cgi/input.pl], LDlink [https://analysistools.nci.nih.gov/LDlink/?tab=ldmatrix]
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ESM 1
Table S1. OASIS identified PD loci in two GWAS datasets, shows the 24 replicated PD loci and their candidate genes in the two datasets (db1, db2). Data regarding the chromosomal location and the strength of the association signal (−log (P), OASIS scores and Quadrants [A, B or C]) is shown. The genes shown are based on their significant association in GATES analysis at the respective locus. Table S2: SNIPPER derived candidate genes in 24 OASIS loci, Lists the 379 genes located in the 24 OASIS loci that overlapped in db1 and db2. Table S3. Gene-wide associations of OASIS identified PD loci in db1, Shows the genes that were significantly associated in db1 (sporadic PD) on GATES analysis. PBH indicate the Benjamini & Hochberg (BH) correction P-value. Table S4. Gene-wide associations of OASIS identified PD loci in db2, Shows the genes that were significantly associated in db2 (familial PD) on GATES analysis. Table S5. Single-variant replication of OASIS identified PD loci in three datasets, Shows the single variant replication statistics of SNPs with the highest −log [P] values (Max_SNP) in OASIS identified loci in db3, db4 and db5. Gene name and location is according to PDGene (db4). (XLSX 45 kb). Table S6 BRAINEAC eQTL analysis of significant SNPs at locus 22 containing AXIN1, shows the SNPs, their genomic location, the eQTL P-value for the probe t3675047 (AXIN1), the tissue in which AXIN1 expression is significantly altered by the SNP and the db1, db2 genetic association P-values. OCXT – occipital cortex; WHMT – white matter; SNIG – substantia nigra; PUTM – putamen; THAL – thalamus; NA – data not available. (XLSX 13 kb)
ESM 2
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ESM 2
Figure S1: OASIS quadrants, describes the OASIS quadrants A, B and C diagrammatically. The scatter graph shows −log [P] values plotted against OASIS scores for db1. Figure S2: Flow chart of the study methodology. The methods and study organization are graphically summarized in this flow chart. (PPTX 293 kb)
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Saeed, M. Genomic convergence of locus-based GWAS meta-analysis identifies AXIN1 as a novel Parkinson’s gene. Immunogenetics 70, 563–570 (2018). https://doi.org/10.1007/s00251-018-1068-0
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DOI: https://doi.org/10.1007/s00251-018-1068-0