The consequences of a year of the COVID-19 pandemic for the mental health of young adult twins in England and Wales.

BACKGROUND: The COVID-19 pandemic has affected all our lives, not only through the infection itself but also through the measures taken to control the spread of the virus (e.g. lockdown). AIMS: Here, we investigated how the COVID-19 pandemic and unprecedented lockdown affected the mental health of young adults in England and Wales. METHOD: We compared the mental health symptoms of up to 4773 twins in their mid-20s in 2018 prior to the COVID-19 pandemic (T1) and during four-wave longitudinal data collection during the pandemic in April, July and October 2020, and in March 2021 (T2-T5) using phenotypic and genetic longitudinal designs. RESULTS: The average changes in mental health were small to medium and mainly occurred from T1 to T2 (average Cohen d = 0.14). Despite the expectation of catastrophic effects of the pandemic on mental health, we did not observe trends in worsening mental health during the pandemic (T3-T5). Young people with pre-existing mental health problems were disproportionately affected at the beginning of the pandemic, but their increased problems largely subsided as the pandemic persisted. Twin analyses indicated that the aetiology of individual differences in mental health symptoms did not change during the lockdown (average heritability 33%); the average genetic correlation between T1 and T2-T5 was 0.95, indicating that genetic effects before the pandemic were substantially correlated with genetic effects up to a year later. CONCLUSIONS: We conclude that on average the mental health of young adults in England and Wales has been remarkably resilient to the effects of the pandemic and associated lockdown.

Pathfinder: a gamified measure to integrate general cognitive ability into the biological, medical, and behavioural sciences.

Genome-wide association (GWA) studies have uncovered DNA variants associated with individual differences in general cognitive ability (g), but these are far from capturing heritability estimates obtained from twin studies. A major barrier to finding more of this 'missing heritability' is assessment--the use of diverse measures across GWA studies as well as time and the cost of assessment. In a series of four studies, we created a 15-min (40-item), online, gamified measure of g that is highly reliable (alpha = 0.78; two-week test-retest reliability = 0.88), psychometrically valid and scalable; we called this new measure Pathfinder. In a fifth study, we administered this measure to 4,751 young adults from the Twins Early Development Study. This novel g measure, which also yields reliable verbal and nonverbal scores, correlated substantially with standard measures of g collected at previous ages (r ranging from 0.42 at age 7 to 0.57 at age 16). Pathfinder showed substantial twin heritability (0.57, 95% CIs = 0.43, 0.68) and SNP heritability (0.37, 95% CIs = 0.04, 0.70). A polygenic score computed from GWA studies of five cognitive and educational traits accounted for 12% of the variation in g, the strongest DNA-based prediction of g to date. Widespread use of this engaging new measure will advance research not only in genomics but throughout the biological, medical, and behavioural sciences.

The consequences of a year of the COVID-19 pandemic for the mental health of young adult twins in England and Wales.

The COVID-19 pandemic has impacted all our lives, not only through the infection itself, but also through the measures taken to control the virus’s spread (e.g., lockdown). Here we investigated how the COVID-19 pandemic and unprecedented lockdown affected the mental health of young adults in England and Wales. We compared the mental health symptoms of up to 4,000 twins in their mid-twenties in 2018 prior to the COVID-19 pandemic (T1) to those in a four-wave longitudinal data collection during the pandemic in April, July, and October 2020, and in March 2021 (T2-T5). The average changes in mental health were small-to-medium and mainly occurred from 2018 (T1) to March 2020 (T2, one month following the start of lockdown; average Cohen d=0.14). Despite the expectation of catastrophic effects on the pandemic on mental health of our young adults, we did not observe trends in worsening mental health during the pandemic (T3-T5). Young people with pre-existing mental health problems were adversely affected at the beginning of the pandemic, but their increased problems largely subsided as the pandemic persisted. Twin analyses indicated that the aetiology of individual differences did not change during the lockdown. The average heritability of mental health symptoms was 33% across 5 waves of assessment, and the average genetic correlation between T1 and T2-T5 was .95, indicating that genetic effects before the pandemic (T1) are substantially correlated with genetic effects up to a year later (T2-T5). We conclude that on average the mental health of young adults in England and Wales has been remarkably resilient to the effects of the pandemic and associated lockdown.

Genetic Correlates of Psychological Responses to the COVID-19 Crisis in Young Adult Twins in Great Britain.

We investigated how the COVID-19 crisis and the extraordinary experience of lockdown affected young adults in England and Wales psychologically. One month after lockdown commenced (T2), we assessed 30 psychological and behavioural traits in more than 4000 twins in their mid-twenties and compared their responses to the same traits assessed in 2018 (T1). Mean changes from T1 to T2 were modest and inconsistent. Contrary to the hypothesis that major environmental changes related to COVID-19 would result in increased variance in psychological and behavioural traits, we found that the magnitude of individual differences did not change from T1 to T2. Twin analyses revealed that while genetic factors accounted for about half of the reliable variance at T1 and T2, they only accounted for ~ 15% of individual differences in change from T1 to T2, and that nonshared environmental factors played a major role in psychological and behavioural changes. Shared environmental influences had negligible impact on T1, T2 or T2 change. Genetic factors correlated on average .86 between T1 and T2 and accounted for over half of the phenotypic stability, as would be expected for a 2-year interval even without the major disruption of lockdown. We conclude that the first month of lockdown has not resulted in major psychological or attitudinal shifts in young adults, nor in major changes in the genetic and environmental origins of these traits. Genetic influences on the modest psychological and behavioural changes are likely to be the result of gene-environment correlation not interaction.

The winding roads to adulthood: A twin study.

Aims: Here we report the results of the first systematic investigation of genetic and environmental influences on 57 psychological traits covering major issues in emerging adulthood such as aspirations, thoughts and attitudes, relationships and personality. We also investigate how these traits relate to physical and mental health, educational attainment and wellbeing. Materials & Methods: We use a sample of nearly 5000 pairs of UK twins aged 21-25 from the Twins Early Development Study. We included 57 measures of traits selected to represent issues in emerging adulthood (EA) such as aspirations, thoughts and attitudes, life events, relationships, sexual and health behaviour and personality. We also included measures related to what are often considered to be the core functional outcomes even though here we refer to the data collected at the same time: adverse physical health, adverse mental health, wellbeing, and education. Results: All 57 traits showed significant genetic influence, with an average heritability of 34% (SNP heritability ~10%). Most of the variance (59% on average) was explained by non-shared environmental influences. These diverse traits were associated with mental health (average correlation 0.20), wellbeing (0.16), physical health (0.12) and educational attainment (0.06). Shared genetic factors explained the majority of these correlations (~50%). Together, these emerging adulthood traits explained on average 30% of variance in the outcomes (range = 8% to 69%), suggesting that these traits relate to the outcomes additively. Discussion & Conclusions: We conclude that even as the majority of individual differences in EA traits is explained by non-shared environmental factors, genetic influence on these traits is still substantial; the environmental uncertainties of emerging adulthood in the 21st century do not diminish the importance of genetics. As adolescents travel down long and winding roads to adulthood, their trip is substantially influenced by genetic proclivities that nudge them down different paths leading to different destinations.

Genetic correlates of psychological responses to the COVID-19 crisis in young adult twins in Great Britain.

We investigated how the COVID-19 crisis and the extraordinary experience of lockdown affected young adults in England and Wales psychologically. One month after lockdown commenced (T2), we assessed 30 psychological and behavioural traits in 4,000 twins in their mid-twenties and compared their responses to the same traits assessed in 2018 (T1). Mean changes from T1 to T2 were modest and inconsistent: just as many changes were in a positive as negative direction. Twin analyses revealed that genetics accounted for about half of the reliable variance at T1 and T2. Genetic factors correlated on average .86 between T1 and T2 and accounted for over half of the phenotypic stability. Systematic environmental influences had negligible impact on T1, T2 or T2 change. Rather than the crisis fundamentally changing people psychologically, our results suggest that genetic differences between individuals play a fundamental role in shaping psychological and behavioural responses to the COVID-19 crisis.

Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood--brain barrier disruption in multiple sclerosis.

Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.

Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis.

BACKGROUND: Several questions arise concerning the use of the anti-CD25 antibody daclizumab to treat multiple sclerosis (MS). OBJECTIVES: To answer the following 3 questions related to the efficacy of daclizumab therapy in patients with MS: Is the therapeutic effect of daclizumab dependent on combination with interferon beta? Is a higher dosage of daclizumab more efficacious in patients with persistent disease activity? Can biomarkers predict full vs partial therapeutic response to daclizumab? DESIGN: An open-label baseline vs treatment phase II clinical trial of daclizumab in patients having MS with inadequate response to interferon beta. Three months of interferon beta treatment at baseline were followed by 5.5 months of interferon beta-daclizumab combination therapy. If patients experienced more than 75% reduction of contrast-enhancing lesions (CELs) on brain magnetic resonance imaging at month 5.5 compared with baseline, daclizumab was continued as monotherapy for 10 months. Otherwise, the dosage of daclizumab was doubled. SETTING: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. PATIENTS: Fifteen patients with MS receiving standard preparations of interferon beta who experienced more than 1 MS exacerbation or whose clinical disability increased in the preceding 12 months and who had at least 2 CELs on baseline brain magnetic resonance images. INTERVENTION: Daclizumab (1 mg/kg) as an intravenous infusion every 4 weeks in combination with interferon beta (months 0-5.5) and as monotherapy (months 6.5-15.5). MAIN OUTCOME MEASURES: The primary outcome was the reduction of CELs among interferon beta monotherapy, interferon beta-daclizumab combination therapy, and daclizumab monotherapy. The secondary outcomes included immunologic biomarkers and changes in clinical disability. RESULTS: Overall, 5 of 15 patients (33%) experienced adverse effects of therapy. Two patients developed systemic adverse effects, and daclizumab therapy was discontinued. Although daclizumab monotherapy was efficacious in 9 of 13 patients with MS, interferon beta-daclizumab combination therapy was necessary to stabilize disease activity in the other 4 patients. Daclizumab therapy led to 72% inhibition of new CELs and significant improvement in clinical disability. Pilot biomarkers (increase in CD56bright natural killer cells and decrease in CD8+ T cells) were identified that can differentiate between full and partial daclizumab responders. CONCLUSIONS: Daclizumab monotherapy is effective in most patients who experienced persistent MS disease activity with interferon beta therapy. Interferon beta-daclizumab combination therapy or higher dosages of daclizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to daclizumab monotherapy. Administration among a large patient sample during a longer period is needed to fully define the safety and long-term efficacy of daclizumab as treatment for high-inflammatory MS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00001934.

The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease.

The transcription factor REST silences neuronal gene expression in non-neuronal cells. In neurons, the protein is sequestered in the cytoplasm in part through binding to huntingtin. Polyglutamine expansions in huntingtin, which causes Huntington's disease (HD), abrogates REST-huntingtin binding. Consequently, REST translocates to the nucleus, occupies RE1 repressor sequences and decreases neuronal gene expression. In this work, we found that levels of several microRNAs (miRNAs) with upstream RE1 sites are decreased in HD patient cortices relative to healthy controls. Interestingly, one of these, the bifunctional brain enriched miR-9/miR-9*, targets two components of the REST complex: miR-9 targets REST and miR-9* targets CoREST. These data provide evidence for a double negative feedback loop between the REST silencing complex and the miRNAs it regulates.

Optimized clonotypic analysis of T-cell receptor repertoire in immune reconstitution.

OBJECTIVE: In recent years, T-cell receptor (TCR) sequencing analysis has proven an effective technique for the identification of T-cell populations of interest in cancer and autoimmunity, as well as for the characterization of peripheral immune repertoire reconstitution after hematopoietic stem cell transplantation (HSCT). However, despite its increased utilization, to our knowledge no group has investigated the minimum number of sequences necessary to accurately and efficiently describe the composition of TCR repertoire. The primary aim of this study was to optimize a procedure for clonotypic analysis of the TCR repertoire in patients undergoing autologous HSCT. MATERIALS AND METHODS: TCR beta-chain diversity was analyzed by DNA sequencing and CDR3 spectratyping CD8(+) T cells isolated from three patients with multiple sclerosis undergoing autologous HSCT. Samples were collected at baseline and 1 or 2 years post-HSCT. RESULTS: Using DNA cloning and high throughput sequencing, we analyzed over 1500 in-frame TCR sequences, allowing us to evaluate how our measures of TCR repertoire diversity change with increasing numbers of sequences included in the analysis. Our findings show that by analyzing 75 to 100 in-frame sequences, we are able to estimate TCR diversity within 5.0% to 7.4% of the values obtained at endpoint analysis (213-312 sequences per sample). CONCLUSIONS: This study confirms the use of TCR sequencing as an effective technique for the characterization of immune renewal after autologous HSCT. In addition, we demonstrate for the first time convincing evidence to support the use of moderate sample sizes to accurately and efficiently evaluate TCR repertoire diversity.

Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis.

Administration of daclizumab, a humanized mAb directed against the IL-2Ralpha chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4(+) T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4(+) and CD8(+) T cells and significant expansion of CD56(bright) natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56(bright) NK cells and contraction of CD4(+) and CD8(+) T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56(bright) NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.

Clonotypic analysis of cerebrospinal fluid T cells during disease exacerbation and remission in a patient with multiple sclerosis.

Migration of autoreactive T cells into the central nervous system (CNS) compartment is thought to be an important step in the pathogenesis of multiple sclerosis (MS). To follow the evolution of T cell repertoire in the CNS of a patient with relapsing-remitting MS, we analyzed cerebrospinal fluid (CSF) cells obtained during an acute clinical exacerbation, and subsequent disease remission after 13 months of immunomodulatory therapy. T cell receptor CDR3 region length distribution was significantly altered during the relapse, demonstrating the presence of clonally expanded T cells in the CSF. CDR3 spectratyping is a valuable approach to identify disease-associated T cells in the CNS.

Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients.

Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4(+) T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.