Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence forPAPSS2as 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 ~80 kb 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. Keywords: Longevity genetics-Gene expression-PAPSS2Life span is the result of a complicated interplay between genetic and environmental factors. Although much of the genetic research on aging has focused on predisposition of age-related diseases such as cardiovascular and Alzheimer's disease, compelling evidence from animal models and human studies supports the existence of genetic factors that enhance life span itself by influencing cellular aging (1-3).Studies of twins reared together and twins reared apart suggest that genetic factors explained ~30% of the variance in longevity (4,5), and heritability of life span in the Old Order Amish was previously estimated as ~25% (6). A stronger genetic influence on longevity has been reported for more extreme life-span phenotypes (eg, premature death or exceptional survival) than for life span in general (7,8). A study by Perls and colleagues demonstrated that the siblings of centenarians are 8-17 times more likely to survive to age 100 compared with other individuals from their birth cohorts (9). Ashkenazi parents of centenarians were approximately seven times more likely to live to age 90 (10), and the Leiden Longevity Study found that mortality rates in first-degree relatives of long-lived individuals were 30% lower compared with the general population (11). These studies support the concept that longevity is a familial trait likely to be inherited and demonstrate the potential utility of using family studies in identifying longevity assurance genes.

Genetic Determinants for Leisure-Time Physical Activity

“…This speculation has been partly supported by previous genetic studies. Among previously reported genes, the GABRG3 gene could influence the reward or aversive experience of physical activity through dopaminergic actions directly(3, 12, 13, 26); the CYP19A1 gene has been associated to insulin resistance and obesity(27); PAPSS2 has been reported to be involved in initial skeletal development, which may influence the capacity to perform physical activity later in life, and interestingly it has also been related to longevity in a recent study(28, 29).…”

A metabolism-related gene signature for predicting the prognosis in thyroid carcinoma

“…Nevertheless, the enhanced PAPSS2 is vital to push migration and metastasis of breast cancer cells ( Zhang et al, 2019 ) and shows shorter relapse-free survival periods in cancer of the breast ( Jung et al, 2016 ). Furthermore, we discovered an intriguing report that identified PAPSS2 as a candidate gene for extending life span through a meta-analysis GWAS of survival to age 90 ( Yerges-Armstrong et al, 2016 ). This may be connected with PAPSS2 -mediated premature senescence ( Jung et al, 2016 ).…”

Novel DNA methylation marker discovery by assumption‐free genome‐wide association analysis of cognitive function in twins

“…In Table 1, KLHDC4 mapped to the top significant CpG has been reported to be associated with Huntington Disease‐Like 2 (https://www.genecards.org/cgi-bin/carddisp.pl?gene=KLHDC4), a disorder characterized partially by cognitive abnormalities. The second top significant PAPSS2 gene is shown to be a novel longevity gene by expression profiling of genes within regions identified by a meta‐analysis GWAS of survival to age 90 (Yerges‐Armstrong et al, 2016). The third top significant MRPS18B gene is a mitochondrial gene.…”