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