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Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.
Thursday,2020-11-19 11:10 America/Los_Angeles — ecterry
| Title | Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases. |
| Publication Type | Journal Article |
| Year of Publication | 2016 |
| Authors | He, L, Kernogitski, Y, Kulminskaya, I, Loika, Y, Arbeev, KG, Loiko, E, Bagley, O, Duan, M, Yashkin, A, Ukraintseva, SV, Kovtun, M, Yashin, AI, Kulminski, AM |
| Journal | Front Genet |
| Volume | 7 |
| Pagination | 179 |
| Date Published | 2016 |
| ISSN | 1664-8021 |
| Abstract | <p>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 in , rs460976 on 21q22.3 (1 kb from ) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in associated with stroke and heart failure, rs7081476 on 10p12.1 in associated 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.</p> |
| DOI | 10.3389/fgene.2016.00179 |
| Alternate Journal | Front Genet |
| PubMed ID | 27790247 |
| PubMed Central ID | PMC5061751 |
| Grant List | HHSN268201100012C / HL / NHLBI NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States N01HC95163 / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States HHSN268201100005G / HL / NHLBI NIH HHS / United States HHSN268201100008I / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States N01HC95169 / HL / NHLBI NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States UL1 RR024156 / RR / NCRR NIH HHS / United States N01 HC085085 / HC / NHLBI NIH HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States N01HC95164 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States P30 AG034424 / AG / NIA NIH HHS / United States N02HL64278 / HL / NHLBI NIH HHS / United States N01HC95162 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States N01HC95168 / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States N01HC95165 / HL / NHLBI NIH HHS / United States N01HC95159 / HL / NHLBI NIH HHS / United States N01HC95161 / HL / NHLBI NIH HHS / United States N01HC65226 / HL / NHLBI NIH HHS / United States P01 AG043352 / AG / NIA NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States N01HC95167 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States R01 AG047310 / AG / NIA NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC95166 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States N01 HC045133 / HC / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States |
ePub date:
16/10