title: Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.
abstract: Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 inSEMA5B, rs460976 on 21q22.3 (1 kb fromTMPRSS2) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 inITPK1associated with stroke and heart failure, rs7081476 on 10p12.1 inANKRD26associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on the expression of nearby genes. Our mediation analyses suggest that the effects of some SNPs are mediated by specific endophenotypes. In conclusion, these findings indicate that loci with pleiotropic effects on age-related disorders tend to be enriched in genes involved in underlying mechanisms potentially related to nervous, cardiovascular and immune system functions, stress resistance, inflammation, ion channels and hematopoiesis, supporting the hypothesis of shared pathological role of infection, and inflammation in chronic age-related diseases.
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Liang
authors: L
authors: He
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Yelena
authors: Y
authors: Kernogitski
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Irina
authors: I
authors: Kulminskaya
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Yury
authors: Y
authors: Loika
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Konstantin G
authors: KG
authors: Arbeev
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Elena
authors: E
authors: Loiko
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Olivia
authors: O
authors: Bagley
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Matt
authors: M
authors: Duan
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Arseniy
authors: A
authors: Yashkin
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Svetlana V
authors: SV
authors: Ukraintseva
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Mikhail
authors: M
authors: Kovtun
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Anatoliy I
authors: AI
authors: Yashin
authors: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University Durham, NC, USA.
authors: Alexander M
authors: AM
authors: Kulminski
keywords: CVDs; age-dependent effects; age-related traits; genetic association study; mediation analysis; pleiotropic analysis