Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity
Kristen Fortney, Edgar Dobriban, Paolo Garagnani, Chiara Pirazzini, Daniela Monti, Daniela Mari, Gil Atzmon, Nir Barzilai et al.. PLoS Genetics, 2015-12-17
Topic: Genetics and APOE
We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR < 10%. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated (FDR < 5%) included APOE/TOMM40 (associated with Alzheimer's disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease). Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer's disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes.
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APA 7th
Fortney, K., Dobriban, E., Garagnani, P., Pirazzini, C., Monti, D., Mari, D., et al. (2015). Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1005728
Vancouver
Fortney K, Dobriban E, Garagnani P, Pirazzini C, Monti D, Mari D, et al. Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity. PLoS Genetics. 2015. doi:10.1371/journal.pgen.1005728. PMID: 26677855.
BibTeX
@article{fortney2015-26677855,
author = {Fortney, Kristen and Dobriban, Edgar and Garagnani, Paolo and Pirazzini, Chiara and Monti, Daniela and Mari, Daniela and Atzmon, Gil and Barzilai, Nir and others},
title = {{Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity}},
journal = {PLoS Genetics},
year = {2015},
doi = {10.1371/journal.pgen.1005728},
pmid = {26677855},
url = {https://doi.org/10.1371/journal.pgen.1005728}
}
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Key findings
- We developed a new statistical framework to find genetic variants associated with extreme longevity.
- The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity.
- To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity.
- These results indicate that several disease variants may be depleted in centenarians versus the general population.
- In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%.
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 67/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 39 of the 58 points we could judge it on, which is 67 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (PLoS Genetics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2015 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | A review of other studies — randomization is not credited here |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26677855) |
| Free to read | 2 / 2 | Free to read |
| Points | 39 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 39 of the 58 points we could judge it on is 67 out of 100. |
| Total | 67 / 100 | — |
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