Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson’s Disease Risk
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data
2.2. Quality Control (QC)
2.3. Imputation and Post Imputation QC
2.4. Association Analysis and Conditional Analysis
2.5. Interaction Analysis
3. Results
3.1. Genome-Wide Association Analysis
3.2. Comparison of Association Results with Nalls et al. (2014) Findings
3.3. Novel Low-Frequency Variants Associated with PD
3.4. Joint Genetic Effects on PD Risk
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Region | MAF | Before Imputation | After Imputation | Before Imputation (%) | After Imputation (%) |
---|---|---|---|---|---|
Exonic | <0.05 | 68,026 | 62,829 | 61.56 | 4.29 |
≥0.05 | 12,581 | 38,282 | 11.39 | 2.61 | |
>0 | 80,607 | 101,111 | 72.95 | 6.90 | |
Intronic | <0.05 | 2385 | 393,633 | 2.16 | 26.85 |
≥0.05 | 12,085 | 378,058 | 10.94 | 25.79 | |
>0 | 14,470 | 771,691 | 13.10 | 52.64 | |
Intergenic | <0.05 | 3181 | 275,900 | 2.88 | 18.82 |
≥0.05 | 12,246 | 317,236 | 11.08 | 21.64 | |
>0 | 15,427 | 593,136 | 13.96 | 40.46 | |
Total | <0.05 | 73,592 | 732,362 | 66.60 | 49.96 |
≥0.05 | 36,912 | 733,576 | 33.40 | 50.04 | |
>0 | 110,504 | 1,465,938 | 100 | 100 |
SNP | CHR | BP | Nearest Gene | EA | NEA | EAF | MAF | OR (95% CI) | p-Value |
---|---|---|---|---|---|---|---|---|---|
Novel PD Risk Loci | |||||||||
rs187989831 | 2 | 95,560,505 | TEKT4 | C | G | 0.005 | 0.005 | 0.001 (3 × 10−5–0.004) | 7.56 × 10−10 |
rs137887044 | 5 | 76,912,498 | WDR41 | C | T | 0.972 | 0.028 | 1.85 (1.49–2.27) | 2.41 × 10−8 |
rs78837976 | 7 | 100,647,511 | MUC12 | C | T | 0.989 | 0.011 | 16.67 (9.09–33.33) | 2.98 × 10−18 |
rs74125032 | 13 | 111,329,589 | CARS2 | T | C | 0.002 | 0.002 | 4.5 × 10−10 (6 × 10−13–4 × 10−7) | 2.36 × 10−10 |
rs117672332 | 17 | 3,606,117 | HASPIN | T | C | 0.989 | 0.011 | 7.69 (4.76–12.5) | 2.20 × 10−15 |
PD Risk Loci Reported in Other GWAS | |||||||||
rs983361 | 4 | 90,761,944 | SNCA | T | G | 0.217 | 0.217 | 0.820 (0.77–0.88) | 6.29 × 10−9 |
rs7221167 | 17 | 43,933,307 | MAPT | C | T | 0.396 | 0.396 | 0.848 (0.80–0.90) | 3.08 × 10−8 |
Secondary SNP | CHR | BP | Nearest Gene | EA | EAF | Index SNP | r2 | OR | p-Value | ORcond | p-Valuecond |
---|---|---|---|---|---|---|---|---|---|---|---|
rs112344141 | 1 | 154,983,036 | GBA | G | 0.0491 | rs35749011 | 0.001 | 1.3142 | 7.93 × 10−4 | 1.3337 | 4.18 × 10−4 |
rs113319394 | 2 | 95,555,635 | LOC442028 | C | 0.0045 | rs187989831 | 0.985 | 1.64 × 10−11 | 2.94 × 10−5 | 7.76 × 10−12 | 2.05 × 10−5 |
rs181580861 | 4 | 958,812 | GAK/DGKQ | G | 0.0013 | rs34311866 | 0.0003 | 6.4117 | 4.88 × 10−3 | 7.0166 | 3.43 × 10−3 |
rs3806789 | 4 | 90,759,556 | SNCA | C | 0.4951 | rs356182 | 0.174 | 0.9373 | 2.10 × 10−2 | 0.8265 | 9.13 × 10−10 |
rs72765119 | 5 | 76,363,276 | WDR41 | G | 0.2345 | rs137887044 | 0.0003 | 1.1172 | 2.90 × 10−3 | 1.1135 | 3.92 × 10−3 |
rs28645997 | 7 | 100,352,470 | MUC12 | G | 0.4134 | rs78837976 | 9.87 × 10−5 | 1.0935 | 2.06 × 10−3 | 1.0870 | 4.26 × 10−3 |
rs74125084 | 13 | 111,372,680 | CARS2 | T | 0.0058 | rs74125032 | 0.499 | 1.058 × 10−4 | 9.63 × 10−8 | 1.31 × 10−4 | 1.05 × 10−6 |
rs11653889 | 17 | 3,627,456 | HASPIN | A | 0.0072 | rs117672332 | 0.747 | 0.0499 | 1.13 × 10−14 | 0.0340 | 1.79 × 10−10 |
rs3851784 | 17 | 45,040,117 | NSF | A | 0.4376 | rs117300236 | 0.0115 | 0.8860 | 1.68 × 10−5 | 0.9081 | 6.78 × 10−4 |
SNP Information | Nalls et al. Results | Reanalysis of NeuroX Dataset | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Discovery Phase | Replication Phase | |||||||||||
SNP | CHR | BP | Nearest Gene | EA | EAF | OR | p-Value | OR | p-Value | Imp_rsq | OR | p-Value |
rs35749011 | 1 | 155,135,036 | GBA-SYT11 | A | 0.017 | 1.762 | 6.09 × 10−23 | 2.307 * | 7.48 × 10−9 * | 0.969 | 2.241 | 5.03 × 10−11 |
rs1474055 | 2 | 169,110,394 | STK39 | T | 0.128 | 1.213 | 7.12 × 10−16 | 1.218 * | 1.07 × 10−6 * | 0.961 | 1.241 | 2.82 × 10−7 |
rs115185635 | 3 | 87,520,857 | KRT8P25 | C | 0.035 | 1.789 | 2.18 × 10−8 | 0.931 * | 0.846 * | 0.999 | 0.983 | 0.802 |
rs117896735 | 10 | 121,536,327 | INPP5F | A | 0.014 | 1.767 | 1.21 × 10−11 | 1.404 * | 1.10 × 10−3 * | 0.776 | 1.525 | 4.64 × 10−4 |
rs3793947 | 11 | 83,544,472 | DLG2 | A | 0.443 | 0.912 | 2.59 × 10−8 | 0.976 * | 0.201 * | 0.998 | 0.983 | 0.538 |
rs11158026 | 14 | 55,348,869 | GCH1 | T | 0.335 | 0.889 | 7.13 × 10−11 | 0.948 | 0.039 | 0.999 | 1.048 | 0.186 |
rs1555399 | 14 | 67,984,370 | TMEM229B | A | 0.468 | 0.872 | 5.53 × 10−16 | 0.971 * | 0.144 * | 0.902 | 1.033 | 0.239 |
rs62120679 | 19 | 2,363,319 | SPPL2B | T | 0.314 | 1.141 | 2.53 × 10−9 | 0.999 * | 0.518 * | 0.919 | 1.074 | 0.031 |
rs8118008 | 20 | 3,168,166 | DDRGK1 | A | 0.657 | 1.111 | 2.32 × 10−8 | 1.113 * | 1.18 × 10−4 * | 0.955 | 1.120 * | 1.13 × 10−4 * |
SNP1 | SNP2 | Genotype freq | Nearest Gene | OR | p-Value | ||
---|---|---|---|---|---|---|---|
rsID | Chr:bp_Genotype | rsID | Chr:bp_Genotype | ||||
rs11248057 | 4:906131_GG | rs11734449 | 4:921733_CC | 0.101 | GAK | 1.412 | 4.70 × 10−7 |
rs6599388 | 4:939087_TT | rs1051613 | 4:951179_GG | 0.096 | TMEM175 | 1.431 | 3.01 × 10−7 |
rs356167 | 4:90673770_GG | rs34320254 | 4:90705606_TT | 0.478 | SNCA | 0.771 | 1.54 × 10−6 |
rs2965400 | 7:21733475_GG | rs6461595 | 7:21758045_GG | 0.132 | DNAH11 | 0.750 | 3.77 × 10−6 |
rs2521819 | 17:43543830_TC | rs7224890 | 17:43548778_GC | 0.299 | PLEKHM1 | 1.260 | 5.55 × 10−6 |
rs34186148 | 17:43854655_CC | rs242941 | 17:43892520_CC | 0.120 | CRHR1 | 0.576 | 4.78 × 10−10 |
rs1294776 | 17:44004442_TT | rs6503453 | 17:44062603_AA | 0.296 | MAPT | 0.798 | 9.25 × 10−6 |
rs200403 | 17:44781143_CA | rs35937770 | 17:44808360_GG | 0.205 | NSF | 0.752 | 1.57 × 10−7 |
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Rodrigo, L.M.; Nyholt, D.R. Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson’s Disease Risk. Genes 2021, 12, 689. https://doi.org/10.3390/genes12050689
Rodrigo LM, Nyholt DR. Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson’s Disease Risk. Genes. 2021; 12(5):689. https://doi.org/10.3390/genes12050689
Chicago/Turabian StyleRodrigo, Linduni M., and Dale R. Nyholt. 2021. "Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson’s Disease Risk" Genes 12, no. 5: 689. https://doi.org/10.3390/genes12050689
APA StyleRodrigo, L. M., & Nyholt, D. R. (2021). Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson’s Disease Risk. Genes, 12(5), 689. https://doi.org/10.3390/genes12050689