title: Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence for PAPSS2 as a Longevity Gene.
abstract: Although there is compelling evidence for a genetic contribution to longevity, identification of specific genes that robustly associate with longevity has been a challenge. In order to identify longevity-enhancing genes, we measured differential gene expression between offspring of long-lived Amish (older than 90 years; cases, n = 128) and spouses of these offspring (controls, n = 121) and correlated differentially expressed transcripts with locations of longevity-associated variants detected in a prior genome-wide association study (GWAS) of survival to age 90. Expression of one of these transcripts, 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2), was significantly higher in offspring versus controls (4×10(-4)) and this association was replicated using quantitative real-time polymerase chain reaction. PAPSS2, a sulfation enzyme located on chromosome 10, is ~80kb upstream of the PAPSS2 transcription start site. We found evidence of cis-expression for the originally reported GWAS SNP and PAPSS2 Monogenic conditions linked to PAPSS2 include andrenocortical androgen excess resulting in premature pubarche and skeletal dysplasias, both of which have premature aging features. In summary, these findings provide novel evidence for PAPSS2 as a longevity locus and illustrate the value of harnessing multiple "-omic" approaches to identify longevity candidates.
authors.affiliation: Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.affiliation: Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore.
authors.forename: Sumbul
authors.initials: S
authors.lastname: Chai
authors.affiliation: Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore.
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: SouthTexas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: SouthTexas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Maryland.
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.affiliation: Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Maryland.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.affiliation: Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore. cdamcott@medicine.umaryland.edu.
authors.forename: Coleen M
authors.initials: CM
authors.lastname: Damcott
mesh_terms: D000369:Aged, 80 and over; D061365:Amish / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D010414:Pennsylvania; D020641:Polymorphism, Single Nucleotide; D013430:Sulfate Adenylyltransferase / Q000235:genetics*
chemical_list: D009097:Multienzyme Complexes; C022322:PAPS synthetase; D013430:Sulfate Adenylyltransferase
keywords: Gene expression; Longevity genetics; PAPSS2