Genetic basis of biomarkers of aging

Abstract

Aging is a gradual and irreversible process that substantially increases the risk of numerous diseases. Elucidating the genetic basis of biomarkers of age-related traits and diseases could facilitate the understanding of their underlying biological pathways, which is crucial for their prevention, early diagnosis and/or treatment. Therefore, in my dissertation research, I aimed to (1) identify the genetic basis of different well-established biomarkers of age-related diseases, including blood-based, sensory and lipid biomarkers, through genome-wide association studies (GWASs), (2) assess the association of polygenic risk scores (PRS) of Alzheimer’s disease (AD) with cognitive performance, and (3) examine the potentially causal association of microRNAs and cognition using the Mendelian randomization framework. Using aggregated data from different population-based studies, I conducted a GWAS meta-analysis of plasma levels of neurofilament light chain (NfL), an ultrasensitive biomarker of neurodegeneration, in individuals from European and African-American ancestry. This analysis identified several novel genetic loci associated with an increased risk of neurodegeneration. I also conducted a GWAS on olfactory dysfunction and identified a genetic locus enriched for olfactory receptor genes to be associated with performance on a smell discrimination task. Through a two-sample Mendelian randomization approach, I found evidence for a potentially causal detrimental effect of olfactory dysfunction on various health outcomes. Furthermore, I conducted GWASs on both the levels and composition of ~1000 complex lipid species, which revealed numerous novel genetic determinants of circulating lipid species, some of which were also related to cardiometabolic traits and diseases. Moreover, I generated PRS scores for AD and identified significant associations of these PRS scores with specific measures of cognitive performance, including working memory and measures derived from detailed eye movement assessments (e.g., anti-saccade error rate). Finally, I conducted a two-sample Mendelian randomization study to examine the causal association of circulating microRNA levels with cognition, which did not yield evidence for a causal association. This could be either due to the relatively small sample size available for the Mendelian randomization analysis, or indicate that although circulating microRNAs could be useful as markers of cognition, they may not be caudally involved in the pathogenesis of cognitive impairment. In conclusion, I systematically explored the genetic basis of several important age-related biomarkers and traits by leveraging a combination of GWAS, in silico functional analysis, PRS and Mendelian randomization approaches. These analyses not only revealed numerous novel genetic determinants of age-related traits and diseases, but also yielded crucial biological insights into the mechanisms underlying aging and age-related diseases that warrant further investigation in future studies.