Circulating Polyunsaturated Fatty Acids and COVID-19: A Prospective Cohort Study and Mendelian Randomization Analysis

Higher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 fatty acids, have been linked to a better prognosis in patients of coronavirus disease 2019 (COVID-19). However, the effects and causality of pre-infection PUFA levels remain unclear. This study aimed to investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity. We first performed a prospective cohort study in UK Biobank, with 20,626 controls who were tested negative and 4,101 COVID-19 patients, including 970 hospitalized ones. Plasma PUFAs at baseline (blood samples collected from 2007 to 2010) were measured by nuclear magnetic resonance, including total PUFAs, omega-3 PUFAs, omega-6 PUFAs, docosahexaenoic acid (DHA), linoleic acid (LA), and the omega-6/omega-3 ratio. Moreover, going beyond UK Biobank, we leveraged summary statistics from existing genome-wide association studies to perform bidirectional two-sample Mendelian randomization (MR) analyses to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity. In the observational association analysis of each PUFA measure separately, total, omega-3, and omega-6 PUFAs, DHA, and LA were associated with a lower risk of severe COVID-19. Omega-3 PUFAs and DHA were also associated with a lower risk of testing positive for COVID-19. The omega-6/omega-3 ratio was positively associated with risks of both susceptibility and severity. When omega-6, omega-3, and their ratio are jointly analyzed, only omega-3 PUFAs remained significantly and inversely associated with both susceptibility and severity. The forward MR analysis indicated that docosapentaenoic acid (DPA-n3) and arachidonic acid (AA) might be causally associated with a lower risk of severe COVID-19, with OR (95% CI) per one SD increase in the plasma level as 0.89 (0.81, 0.99) and 0.96 (0.94, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs. Our observational analysis supported that higher circulating omega-3 PUFAs, especially DHA, may lower the susceptibility to and alleviate the severity of COVID-19. Our MR analysis further supported causal associations of DPA-n3 and AA with a lower risk of severe COVID-19

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations

Each human genome carries tens of thousands of coding variants. The extent to which this variation is functional and the mechanisms by which they exert their influence remains largely unexplored. To address this gap, we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, of which 421 SNVs segregate at > 1% allele frequency in human populations. We find that interaction-disruptive SNVs are prevalent at both rare and common allele frequencies. Furthermore, these results suggest that 10.5% of missense variants carried per individual are disruptive, a higher proportion than previously reported; this indicates that each individual’s genetic makeup may be significantly more complex than expected. Finally, we demonstrate that candidate disease-associated mutations can be identified through shared interaction perturbations between variants of interest and known disease mutations

Independent impacts of aging on mitochondrial DNA quantity and quality in humans

Background The accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes. However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes. In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts. Results We report a high prevalence of pathogenic mtDNA heteroplasmies in this population. We also find an increase in mtDNA heteroplasmies with age (β = 0.011, P = 5.77e-6), and showed that, on average, individuals aged 70-years or older had 58.5% more mtDNA heteroplasmies than those under 40-years old. Conversely, mtDNA copy number decreased by an average of 0.4 copies per year (β = −0.395, P = 0.0097). Multiple regression analyses also showed that age had independent effects on mtDNA copy number decrease and heteroplasmy accumulation. Finally, mtDNA copy number was positively associated with serum bicarbonate level (P = 4.46e-5), and inversely correlated with white blood cell count (P = 0.0006). Moreover, the aggregated heteroplasmy load was associated with blood apolipoprotein B level (P = 1.33e-5), linking the accumulation of mtDNA mutations to age-related physiological markers. Conclusions Our population-based study indicates that both mtDNA quality and quantity are influenced by age. An open question for the future is whether interventions that would contribute to maintain optimal mtDNA copy number and prevent the expansion of heteroplasmy could promote healthy aging

The Evolutionary And Clinical Significance Of Regulatory And Mitochondrial Genetic Variants

Genetic adaptations to local environment during evolution shaped the human genome. Identifying evolutionarily important genetic variants is clinically significant because the mismatch between our slow-evolving genome and the cultural upheaval underlies many diseases of civilization. Recent sequencing technology advances start a Genomic era and promise to elucidate the genetic basis of human health and disease. While most attention had been drawn to protein-coding genes in the nuclear genome, regulatory regions and mitochondrial genome were much less studied. My research aims to investigate the evolutionary and clinical significance of these two categories. Starting my research, I summarized the latest advances in understanding the role of nutrition in human genome evolution and introduced to the Nutrition field population genomics approaches to identify dietary adaptions. My first research project examined the adaptation of regulatory variants to 42 environmental factors. With a newly developed environmental correlation method, I found that expression QTLs are enriched in signals of environmental adaptation and regulatory adaptation are especially important for some environmental factors, like climate, and for some biological pathways, including immune and metabolic pathways. My second project was a case study to test a hypothesis that an Asian-common haplotype was adaptive to the plant-based diet in Asia by enhancing non-heme iron absorption. With an iron absorption study involving 57 Asian women volunteers, I found that consistent to our hypothesis homozygous carriers of the adaptive haplotype absorbed 22% more non-heme iron than non-carriers. Intriguingly, I also observed that compared to Caucasian women, Asian women absorbed more non-heme iron even in face of higher iron store. My third project utilized the next-generation sequencing data from the 1000 Genomes Project and investigated the prevalence and clinical relevance of mitochondrial DNA (mtDNA) heteroplasmy, the presence of multiple versions of mtDNA in a cell. I found that about 90% healthy individuals carry at least one heteroplasmies and at least 20% individuals harbor disease-associated heteroplasmies. I demonstrated that heteroplasmic mutations are highly pathogenic and subject to weak negative selection. My research suggests that heteroplasmic mutations may drift to high frequency across life-span and contribute to age-related diseases

Gene-vegetarianism interactions detected in genome-wide analyses across 30 serum biomarkers: a population-based cohort study in UK Biobank (Supplementary Tables)

   Objectives: To determine the associations of vegetarianism with 30 serum biomarkers, and to identify genetic variants that modify these associations. Design: A population-based cohort study. Setting: United Kingdom.  Participants: A total of 155,375 UK Biobank participants with biomarker measurements, genetic data, dietary information, and relevant covariates were included. A rigorous sample of vegetarians was defined based on consistent responses to four questions in two dietary surveys. Main outcome measures: Effects of vegetarianism and gene-vegetarianism interactions on 30 serum biomarkers for diabetes, cancer, cardiovascular, skeletal, renal, and liver diseases. Results: Compared to a matched sample of non-vegetarians, vegetarians had significantly lower levels of all cholesterol measures and vitamin D, and a higher level of triglycerides, while no significant differences were observed for sex hormones. We found a genetic variant, rs72952628 (C/T), that modified the association between vegetarianism and serum calcium (P for interaction = 4.47e-08). Vegetarianism was associated with a 0.13 units decrease (95% confidence interval -0.09 to -0.18) in calcium in CC individuals, but with 0.30 units increase (0.14 to 0.46) in CT individuals. This variant is located in the gene MMAA, which is part of the vitamin B12 metabolism pathway; B12 has a high nutrient deficiency potential in vegetarians. Gene-based interaction analysis revealed two additional significant genic regions, RNF168 in testosterone (P = 1.45e-06) and ZNF277 in eGFR (P = 6.76e-07), which have previously been associated with testicular and renal traits, respectively.  Conclusions: Vegetarianism was associated with 15 of the 30 serum biomarkers examined, and evidence of genetic modifications was found for three biomarkers: calcium, testosterone, and eGFR.   </p