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Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity - PubMed

  • ️Thu Jan 01 2015

Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

Kristen Fortney et al. PLoS Genet. 2015.

Abstract

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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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Disease GWAS show substantial genetic overlap with longevity.

Shown are results for coronary artery disease and Alzheimer’s disease. The y axis is the observed P values for longevity[3], and the x axis is the expected P values under the null hypothesis that the disease is independent of longevity. The cyan, blue and purple lines show the P values for longevity of the top 100, 250, and 500 disease SNPs from independent genetic loci, respectively. Red lines show the background distribution of longevity P values for all independent genetic loci tested in both the longevity and disease GWAS. The grey horizontal line corresponds to the threshold for nominal significance (P< = 0.05) for longevity. Significance of enrichment was determined with the hypergeometric test. (*) P < 0.05, (**) P < 0.005. Q-Q plots for other diseases and traits are shown in S1 and S2 Figs.

Fig 2
Fig 2. Informed GWAS implicates 8 loci in longevity.

A. Shown is a basic schematic of our method for deriving weights. First, we perform a cross-disease analysis across all meta-analyses of disease GWA studies. Next, we use the results of the cross-disease analysis to derive weights for the longevity GWAS. Finally, we weight the P values from the longevity studies, and identify significant SNPs. B. Weighting boosts new loci to significance. Shown are Manhattan plots of all SNPs before (in black) and after (green) adjusting their P values with disease-informed weights. The black and green lines show the FDR < 10% cutoff in the unweighted and weighted GWAS, respectively. Without weights, only the APOE locus is significant in NECS and 90PLUS; after weighting, 7 more loci become statistically significant at FDR < 10%. The x axis shows SNPs according to their chromosomal positions.

Fig 3
Fig 3. Nominal associations with multiple diseases for longevity loci.

Shown are raw P values for each lead longevity SNP in each of the 14 meta-analyses of disease GWA studies that contributed to the cross-disease analysis used by iGWAS. Colors of blue indicate P values in the disease GWAS. The darkest blue corresponds to genome-wide significance. ADIP, adiponectin levels; LOAD, late-onset Alzheimer's disease; AMD, age-related macular degeneration; ART, rheumatoid arthritis; BMD, bone mineral density; BMI, body mass index; DBP, diastolic blood pressure; DIA, type 2 diabetes; CAD, coronary artery disease; INS, fasting insulin levels; CKD, chronic kidney disease; CAN_LUNG, lung cancer; CAN_PANC, pancreatic cancer; TCHO, total cholesterol.

Fig 4
Fig 4. Regional plots for four longevity-associated SNPs.

The y axis shows weighted P values and the x axis indicates position of the SNPs. Color of the SNP indicates linkage to the lead SNP (purple). Green boxes indicate genes harboring missense SNPs in LD with candidate longevity SNPs, and magenta boxes indicate genes whose expression is associated with a candidate longevity SNP (eQTL). A. Data for rs4420638 in APE/TOMM40. B. Data for rs497756 in CDKN2B. C. Data for rs514659 in ABO. D. Data for rs3184504 in SH2B3.

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