Strong impact of natural-selection–free heterogeneity in genetics of age-related phenotypes

Abstract

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.

Mendelian pathway analysis of laboratory traits reveals distinct roles for ciliary subcompartments in common disease pathogenesis

“…51,52 That being said, the EHBP1 gene has not been implicated in any Mendelian genetic disorders, whereas bi-allelic pathogenic variants in WDPCP have been shown to cause Bardet-Biedl syndrome, a disorder characterized, in part, by hepatic fibrosis and dyslipidemia, both phenotypes characterized by perturbed GGT and LDL cholesterol levels. 8,35 Replication of known associations Of the 27 significant gene-trait associations we identified that replicate previously-known associations from the literature, 11 have been reported as mapping to the ciliary candidate genes that we set out to study: CENPF with Creatinine, 53,54 CEP164 with HDL, 44,55 POC5 with Cholesterol LDL and HDL, 51,52,56,57 PROSER3 with HDL, 52 RP1 with Cholesterol and LDL, 51,58,59 RP1L1 with Triglycerides, 51,52 SDCCAG8 with Creatinine, 53,55,60 and SPATA7 with Creatinine 54 (Figures 2-3, S5-6, S22-23, S25-28 ). Our study adds further evidence to the hypothesis that these ciliary genes play in important role in affecting these laboratory phenotypes in the general population.…”

Age‐related changes to macrophages are detrimental to fracture healing in mice

“…Heterogenous changes are present across many aspects of the biology of aging with an impact that is not fully understood. Age‐related genetic heterogenicity could result from cumulative effects from the environment or an unknown mechanism (Kulminski et al, ). How to properly analyze the heterogenicity present in large genetic datasets is not clearly defined.…”

Age-related changes to macrophages are detrimental to fracture healing

“…Heterogenous changes are present across many aspects of the biology of aging with an impact that is not fully understood. Age-related genetic heterogenicity could result from cumulative effects from the environment or an unknown mechanism [65]. How to properly analyze the heterogenicity present in large genetic datasets is not clearly defined.…”