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Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.
Tuesday,2020-03-17 13:49 America/Los_Angeles — ecterry
| Title | Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | Kulminski, AM, Huang, J, Loika, Y, Arbeev, KG, Bagley, O, Yashkin, A, Duan, M, Culminskaya, I |
| Journal | Aging (Albany NY) |
| Volume | 10 |
| Issue | 3 |
| Pagination | 492-514 |
| Date Published | 2018 03 29 |
| ISSN | 1945-4589 |
| Keywords | Aging, Computational Biology, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide |
| Abstract | <p>A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.</p> |
| DOI | 10.18632/aging.101407 |
| Alternate Journal | Aging (Albany NY) |
| PubMed ID | 29615537 |
| PubMed Central ID | PMC5892700 |
| Grant List | HHSN268201100012C / HL / NHLBI NIH HHS / United States RC4 AG039029 / AG / NIA NIH HHS / United States UL1 RR033176 / RR / NCRR NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States U01 AG009740 / AG / NIA 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 HHSN268201500001C / 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 HHSN268200800007C / HL / NHLBI NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States R01 HL085251 / HL / 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 R01 HL076784 / HL / NHLBI NIH HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States N01HC95164 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States N01HC55222 / HL / NHLBI 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 R01 HL105756 / HL / NHLBI NIH HHS / United States N01HC95168 / HL / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States R01 AG008122 / AG / NIA 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 HHSN268201500001I / HL / NHLBI NIH HHS / United States N01HC95161 / HL / NHLBI NIH HHS / United States N01HC65226 / HL / NHLBI NIH HHS / United States N01 HC085084 / HC / 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 HHSN268201100009C / 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 RC2 AG036495 / AG / NIA 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 AG028321 / AG / NIA 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:
08/03