Discovery and Replication Case:Control Sample Sets.

<p>Contributing project totals in discovery and replication phases. The totals represent the number of high quality datasets derived from samples.</p

CNVs Enriched in Geriatric Individuals.

<p>CNVs Enriched in Geriatric Individuals.</p

Principle Components Analysis of Pediatric and Geriatric Cohorts.

<p>Discovery U.S. Pediatric vs. Icelandic Geriatric A) Principle components (PC) 1 vs. 2 shows distinct clusters likely due to sporadic differential profiles of a specific subset of SNPs between arrays. Since CNV calling is based on multiple neighboring SNPs and differential clustering SNPs are randomly distributed, CNV discovery should not experience significant bias. B) PC2 vs. 3 representing population structure showing some overlap of pediatric and geriatric cohorts C) SNP genotype allele frequency differences genome wide showing close correlation. Replication U.S. Pediatric vs. U.S. Geriatric D) Replication of U.S. pediatric and U.S. geriatric PC1 vs. PC2 showing high overlap unlike panel A U.S. pediatric and Icelandic geriatric E) Geriatric replication cohort in isolation for clarity F) Population structure of pediatric subjects with significantly associated risk CNVs for short lifespan showing broad normal distribution minimizing test statistic inflation for rare variants opposed to tight clustering(37) G) Pediatric replication cohort in isolation for clarity.</p

Manhattan Plot of SNP based CNV Statistics. (A)Deletions and (B)Duplications.

<p>Manhattan Plot of SNP based CNV Statistics. (A)Deletions and (B)Duplications.</p

Representative Interactions of the Lifespan Longevity Associated Genes Identified.

<p>Gene-gene interactions of independently significant loci. Additional genes implicated by interacting with genes in significantly associated longevity loci. Alternative splicing gene function annotation enrichment of significant loci suggests diverse genetic perturbation with a common biological role. Extension of this functional category to other genes annotated by functional studies with interactions to associated genes implicates potential for screening diverse etiology.</p

CNVs Enriched in Pediatric Individuals.

*<p>Gene not overlapped so closest proximal gene annotated. Gene delimiters were defined based on UCSC genes table reference including exons and introns. Any direct overlap of any segment of the gene delimiters is considered a hit such that complete overlap of the gene is not required. Combined p-values were calculated using Fisher’s method.</p

Independent Technology Validation of Presence of CNV Events to Confirm CNVs Detected by Illumina Array.

<p>Error bars denote the standard deviation of quadruplicate runs.</p

Comparison of observed and expected association results for rs2794520 and CRVE in A) SP2, B) SiMES and C) SINDI datasets.

<p>Observed regression values presented in black and estimated values presented in gray. Regression models were adjusted for age and sex in SP2 and age, sex and population stratification (first 2 principal components in SiMES and first 3 principal components in SINDI only).</p

Clinical measures in SiMES, SP2 and SINDI datasets used in study.

*<p>Excluding 242 samples from SINDI, 190 samples from SiMES and 48 samples from SP2, respectively who had CRP values >10 mg/L.</p>†<p>hypertension defined as history of hypertension or SBP>140 mmHg or DBP>90 mmHg.</p>‡<p>diabetes defined as participants with a history of diabetes mellitus or fasting glucose levels ≥7.0 mmol/L in SP2 and HbA1c levels ≥6.5% in non-fasting blood samples and/or those with previous history in SiMES and SINDI.</p

Linear regression of rs2794520 with CRVE and CRAE traits in datasets used in the study.

<p>The test allele for rs2794520 was the G allele.</p><p>Estimated power: based on average predicted effect estimate (0.45 µm CRVE) from SiMES, SP2 and SINDI datasets (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067650#pone-0067650-g001" target="_blank">Figure 1</a>) and a minor allele frequency of 0.40, at α = 0.05.</p