A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Populations and Genetic Data
Longevity Studies
2.2. Definition of Extreme Longevity Phenotype
2.3. Replication Cohorts
2.3.1. UKB Father and Mother
2.3.2. UKB+LifeGen
2.4. Statistical Analysis
2.5. Replication Criteria
2.6. Protein Quantitative Trait Loci (pQTL) Analysis
Discovery GWAS | UKB-F | UKB-M | UKB+LifeGen | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
rsID | Gene | Chr | Pos | EA/NEA | EAF in Cases | EAF in Controls | Beta | SE | p | Beta | SE | p | Beta | SE | p | Beta | SE | p |
rs429358 | APOE | 19 | 45411941 | T/C | 0.95 | 0.88 | 0.84 | 0.065 | 1.94 × 10−36 | 0.020 | 0.0034 | 3.27 × 10−9 | 0.019 | 0.0036 | 2.58 × 10−7 | 0.106 | 0.0055 | 3.14 × 10−83 |
rs6475609 | CDKN2B-AS1 | 9 | 22106271 | A/G | 0.49 | 0.42 | 0.21 | 0.039 | 7.13 × 10−8 | 0.019 | 0.0025 | 1.41 × 10−14 | 0.006 | 0.0027 | 0.03 | 0.024 | 0.0039 | 9.98 × 10−10 |
rs145265196 | RPLP0P2 | 11 | 61401362 | G/T | 0.007 | 0.002 | 1.74 | 0.347 | 6.29 × 10−7 | −0.022 | 0.0405 | 0.59 | 0.025 | 0.0443 | 0.57 | NA | NA | NA |
rs9657521 | OR7E161P| DEFB136 | 8 | 11830502 | A/C | 0.76 | 0.71 | 0.20 | 0.044 | 3.86 × 10−6 | 0.009 | 0.0027 | 0.0012 | 0.005 | 0.0029 | 0.07 | 0.013 | 0.0043 | 0.0021 |
rs145282854 * | ZBED1P1| ENPEP | 4 | 111244992 | A/G | 0.022 | 0.013 | 0.72 | 0.157 | 5.47 × 10−6 | −0.013 | 0.0124 | 0.29 | −0.014 | 0.0134 | 0.30 | 0.003 | 0.0195 | 0.89 |
2.7. Gene Set Enrichment Analysis
2.8. Phenome-Wide Association Study (PheWAS) Search
3. Results
3.1. Locus on Chromosome 9: CDKN2B-AS1
3.2. Locus on Chromosome 11: RPLPOP2
3.3. Locus on Chromosome 8
3.4. Locus on Chromosome 4
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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rs6475609 (CDKN2B-AS1) | ||||||||
---|---|---|---|---|---|---|---|---|
SomaScan ID | UniProt ID | Gene | beta | se | t | p-Value | FC ** | AdjP *** |
6227-1_3 | O43240 | KLK10 | −0.09431 | 0.025082 | −3.75987 | 0.00022 | 1.244114 | 0.004196 |
11157-35_3 | Q9GZY8 | MFF | 0.034337 | 0.009403 | 3.651539 | 0.000328 | 0.96116 | 0.112067 |
3509-1_1 | Q16663 | CCL15 | −0.07418 | 0.020842 | −3.55895 | 0.00046 | 1.309531 | 9.30 × 10−7 |
11184-51_3 | P10645 | CHGA | −0.20668 | 0.058159 | −3.55364 | 0.000467 | 2.041239 | 7.03 × 10−7 |
8397-147_3 | Q6ZRP7 | QSOX2 | −0.06864 | 0.019382 | −3.54119 | 0.000488 | 0.894969 | 0.075736 |
14122-132_3 | Q9ULT6 | ZNRF3 | −0.04099 | 0.01168 | −3.50934 | 0.00055 | 0.976452 | 0.424986 |
14109-15_3 | Q16663 | CCL15 | −0.08507 | 0.024385 | −3.48852 | 0.000591 | 1.245471 | 0.000548 |
8330-1_3 | Q86VZ4 | LRP11 | −0.07416 | 0.021678 | −3.42106 | 0.000746 | 1.361808 | 2.42 × 10−9 |
2790-54_2 | P02775 | PPBP | 0.06303 | 0.018485 | 3.40968 | 0.000777 | 0.873098 | 0.006294 |
rs9657521 (OR7E161P|DEFB136) | ||||||||
5128-53_3 | Q96DU3 | SLAMF6 | −0.09213 | 0.025586 | −3.60081 | 0.000395 | 1.174195 | 0.006707 |
3073-51_2 | O95998 | IL18BP * | −0.08158 | 0.02414 | −3.37965 | 0.000862 | 1.313291 | 1.73 × 10−8 |
9391-60_3 | Q9UHG2 | PCSK1N * | 0.034867 | 0.010381 | 3.358835 | 0.000929 | 1.044992 | 0.163917 |
14101-2_3 | P26992 | CNTFR * | −0.05845 | 0.017439 | −3.35168 | 0.000949 | 1.149051 | 3.33 × 10−5 |
rs145282854 (ZBED1P1|ENPEP) | ||||||||
12626-6_3 | Q9BQF6 | SENP7 | 0.185977 | 0.044871 | 4.144741 | 4.93 × 10−5 | 0.973749 | 0.619881 |
12341-8_3 | Q16828 | DUSP6 | −0.11968 | 0.030611 | −3.90953 | 0.000124 | 0.905893 | 4.91 × 10−7 |
12431-13_3 | Q9BRX2 | PELO | −0.12712 | 0.032736 | −3.88324 | 0.000138 | 0.899788 | 5.94 × 10−6 |
6606-61_3 | Q15726 | KISS1 | −0.20633 | 0.054011 | −3.82019 | 0.000178 | 0.936344 | 0.141048 |
14624-51_3 | P49711 | CTCF | 0.13336 | 0.035568 | 3.749403 | 0.000228 | 0.992483 | 0.129235 |
9870-17_3 | P23381 | WARS | 0.228915 | 0.061876 | 3.699553 | 0.000275 | 1.092315 | 0.041444 |
13629-25_3 | Q9Y4P1 | ATG4B | −0.23443 | 0.063475 | −3.6932 | 0.000282 | 0.975495 | 0.854651 |
9749-190_3 | P13796 | LCP1 | 0.181824 | 0.049431 | 3.678319 | 0.000297 | 1.089198 | 0.040104 |
14057-68_3 | O95150 | TNFSF15 | −0.22904 | 0.063327 | −3.61671 | 0.000372 | 0.780793 | 1.10 × 10−9 |
12572-236_3 | O43281 | EFS | −0.08412 | 0.023752 | −3.54161 | 0.000488 | 0.933805 | 5.38 × 10−5 |
12784-10_3 | O95704 | APBB3 | −0.17642 | 0.049996 | −3.52875 | 0.000511 | 0.870573 | 7.23 × 10−6 |
10064-12_3 | O75884 | RBBP9 | −0.10174 | 0.028931 | −3.51656 | 0.000534 | 0.994783 | 0.918297 |
13393-46_3 | Q9BUN8 | DERL1 | −0.1092 | 0.031437 | −3.4736 | 0.000622 | 0.957411 | 0.010074 |
9087-8_3 | Q5JS37 | NHLRC3 | −0.13061 | 0.037984 | −3.4386 | 0.000704 | 0.928668 | 0.018714 |
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Bae, H.; Gurinovich, A.; Karagiannis, T.T.; Song, Z.; Leshchyk, A.; Li, M.; Andersen, S.L.; Arbeev, K.; Yashin, A.; Zmuda, J.; et al. A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants. Int. J. Mol. Sci. 2023, 24, 116. https://doi.org/10.3390/ijms24010116
Bae H, Gurinovich A, Karagiannis TT, Song Z, Leshchyk A, Li M, Andersen SL, Arbeev K, Yashin A, Zmuda J, et al. A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants. International Journal of Molecular Sciences. 2023; 24(1):116. https://doi.org/10.3390/ijms24010116
Chicago/Turabian StyleBae, Harold, Anastasia Gurinovich, Tanya T. Karagiannis, Zeyuan Song, Anastasia Leshchyk, Mengze Li, Stacy L. Andersen, Konstantin Arbeev, Anatoliy Yashin, Joseph Zmuda, and et al. 2023. "A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants" International Journal of Molecular Sciences 24, no. 1: 116. https://doi.org/10.3390/ijms24010116
APA StyleBae, H., Gurinovich, A., Karagiannis, T. T., Song, Z., Leshchyk, A., Li, M., Andersen, S. L., Arbeev, K., Yashin, A., Zmuda, J., An, P., Feitosa, M., Giuliani, C., Franceschi, C., Garagnani, P., Mengel-From, J., Atzmon, G., Barzilai, N., Puca, A., ... Sebastiani, P. (2023). A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants. International Journal of Molecular Sciences, 24(1), 116. https://doi.org/10.3390/ijms24010116