title: Copy number variations in alternative splicing gene networks impact lifespan.
abstract: Longevity has a strong genetic component evidenced by family-based studies. Lipoprotein metabolism, FOXO proteins, and insulin/IGF-1 signaling pathways in model systems have shown polygenic variations predisposing to shorter lifespan. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry genotyped with 302,108 SNP probes. Positive findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group (P=3.33×10(-8)-1.6×10(-2) unadjusted), while only one duplication was enriched in the geriatric cohort (P=6.3×10(-4)). Population stratification correction resulted in 5 deletions and 3 duplications remaining significant (P=5.16×10(-5)-4.26×10(-2)) in the replication cohort. Three deletions and four duplications were significant combined (combined P=3.7×10(-4)-3.9×10(-2)). All associated loci were experimentally validated using qPCR. Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing (P=0.0077 Benjamini and Hochberg corrected). We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan.
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors: Joseph T
authors: JT
authors: Glessner
authors: Albert Vernon
authors: AV
authors: Smith
authors: Saarene
authors: S
authors: Panossian
authors: Cecilia E
authors: CE
authors: Kim
authors: Nagahide
authors: N
authors: Takahashi
authors: Kelly A
authors: KA
authors: Thomas
authors: Fengxiang
authors: F
authors: Wang
authors: Kallyn
authors: K
authors: Seidler
authors: Tamara B
authors: TB
authors: Harris
authors: Lenore J
authors: LJ
authors: Launer
authors: Brendan
authors: B
authors: Keating
authors: John
authors: J
authors: Connolly
authors: Patrick M A
authors: PM
authors: Sleiman
authors: Joseph D
authors: JD
authors: Buxbaum
authors: Struan F A
authors: SF
authors: Grant
authors: Vilmundur
authors: V
authors: Gudnason
authors: Hakon
authors: H
authors: Hakonarson
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics*; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008074:Lipoproteins / Q000235:genetics; D008136:Longevity / Q000235:genetics*; D008297:Male; D044465:White People
chemical_list: D051858:Forkhead Transcription Factors; D008074:Lipoproteins; D007334:Insulin-Like Growth Factor I
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