ABSTRACT
Apolipoprotein E ε4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.
Subject(s)
Apolipoprotein E4/genetics , COVID-19/complications , COVID-19/genetics , Cerebral Hemorrhage/genetics , Mental Fatigue/genetics , Patient Acuity , Adult , Aged , Autopsy , Biological Specimen Banks , COVID-19/diagnosis , COVID-19/epidemiology , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/epidemiology , Cohort Studies , Female , Finland/epidemiology , Genetic Association Studies/methods , Heterozygote , Humans , Male , Mental Fatigue/diagnosis , Mental Fatigue/epidemiology , Microvessels/pathology , Middle Aged , Prospective Studies , Risk Factors , Young Adult , Post-Acute COVID-19 SyndromeABSTRACT
Individuals are not perfectly consistent, and interindividual variability is a common feature in all varieties of human behavior. Some individuals respond more variably than others, however, and this difference may be important to understanding how the brain works. In this paper, we explore genetic contributions to response time (RT) slope variability on a reflexive attention task. We are interested in such variability because we believe it is an important part of the overall picture of attention that, if understood, has the potential to improve intervention for those with attentional deficits. Genetic association studies are valuable in discovering biological pathways of variability and several studies have found such associations with a sustained attention task. Here, we expand our knowledge to include a reflexive attention task. We ask whether specific candidate genes are associated with interindividual variability on a childhood reflexive attention task in 9-16 year olds. The genetic makers considered are on 11 genes: APOE, BDNF, CHRNA4, COMT, DRD4, HTR4, IGF2, MAOA, SLC5A7, SLC6A3, and SNAP25. We find significant associations with variability with markers on nine and we discuss the results in terms of neurotransmitters associated with each gene and the characteristics of the associated measures from the reflexive attention task.
Subject(s)
Attention/physiology , Individuality , Reaction Time/genetics , Adolescent , Child , Contrast Sensitivity , Cues , Female , Follow-Up Studies , Games, Experimental , Gene Regulatory Networks , Genetic Association Studies , Genotype , Humans , Male , Mental Fatigue/genetics , Minisatellite Repeats , Models, Psychological , Neurotransmitter Agents/metabolism , Polymorphism, Single Nucleotide , Psychomotor Performance , Surveys and Questionnaires , Video GamesABSTRACT
Prolonged demands on the attention system can cause a decay in performance over time known as the time-on-task effect. The inter-subject differences in the rate of this decline are large, and recent efforts have been made to understand the biological bases of these individual differences. In this study, we investigate the genetic correlates of the time-on-task effect, as well as its accompanying changes in subjective fatigue and mood. N = 332 subjects performed a 20-minute test of sustained attention (the Psychomotor Vigilance Test) and rated their subjective states before and after the test. We observed substantial time-on-task effects on average, and large inter-individual differences in the rate of these declines. The 10-repeat allele of the variable number of tandem repeats marker (VNTR) in the dopamine transporter gene and the Met allele of the catechol-o-methyl transferase (COMT) Val158Met polymorphism were associated with greater vulnerability to time-on-task. Separately, the exon III DRD4 48 bp VNTR of the dopamine receptor gene DRD4 was associated with subjective decreases in energy. No polymorphisms were associated with task-induced changes in mood. We posit that the dopamine transporter and COMT genes exert their effects by increasing dopaminergic tone, which may induce long-term changes in the prefrontal cortex, an important mediator of sustained attention. Thus, these alleles may affect performance particularly when sustained dopamine release is necessary.
Subject(s)
Arousal/genetics , Catechol O-Methyltransferase/genetics , Dopamine Plasma Membrane Transport Proteins/genetics , Mental Fatigue/genetics , Polymorphism, Genetic , Receptors, Dopamine D4/genetics , Adolescent , Adult , Arousal/physiology , Base Sequence , Catechol O-Methyltransferase/physiology , DNA Primers/genetics , Dopamine Plasma Membrane Transport Proteins/physiology , Female , Gene Frequency , Humans , Male , Mental Fatigue/physiopathology , Minisatellite Repeats , Polymorphism, Single Nucleotide , Psychomotor Performance/physiology , Receptors, Dopamine D4/physiology , Task Performance and Analysis , Young AdultABSTRACT
Changes in the functional status under the effect of intense mental exercise were studied in carriers of different variants of DAT1, DRD2, and COMT genes. The volunteers (n=140) performed 3-h monotonous mental work (information processing and logical problem solving). The degree of fatigue was evaluated before and after exercise by the HAM (Health status-Activity-Moods) and AMF (Acute Mental Fatigue) questionnaires. A significant relationship between the DAT1, DRD2, and COMT gene polymorphism and changes in the mental sphere status were revealed. The effects of these polymorphisms were the most pronounced in girls. The results are discussed within the framework of hypothesis on the effects of changes in the phasic/tonic dopamine proportion on the studied functions.
