Publications by authors named "Ian J Deary"

933 Publications

The Edinburgh Lifetime Musical Experience Questionnaire (ELMEQ): Responses and non-musical correlates in the Lothian Birth Cohort 1936.

PLoS One 2021 15;16(7):e0254176. Epub 2021 Jul 15.

Reid School of Music, Edinburgh College of Art, University of Edinburgh, Edinburgh, United Kingdom.

There is growing evidence of the potential effects of musical training on the human brain, as well as increasing interest in the potential contribution of musical experience to healthy ageing. Conducting research on these topics with older adults requires a comprehensive assessment of musical experience across the lifespan, as well as an understanding of which variables might correlate with musical training and experience (such as personality traits or years of education). The present study introduces a short questionnaire for assessing lifetime musical training and experience in older populations: the Edinburgh Lifetime Musical Experience Questionnaire (ELMEQ). 420 participants from the Lothian Birth Cohort 1936 completed the ELMEQ at a mean age of 82 years. We used their responses to the ELMEQ to address three objectives: 1) to report the prevalence of lifetime musical experience in a sample of older adults; 2) to demonstrate how certain item-level responses can be used to model latent variables quantifying experience in different musical domains (playing a musical instrument, singing, self-reported musical ability, and music listening); and 3) to examine non-musical (lifespan) correlates of these domains. In this cohort, 420 of 431 participants (97%) completed the questionnaire. 40% of participants reported some lifetime experience of playing a musical instrument, starting at a median age of 10 years and playing for a median of 5 years. 38% of participants reported some lifetime experience of singing in a group. Non-musical variables of childhood environment, years of education, childhood cognitive ability, female sex, extraversion, history of arthritis and fewer constraints on activities of daily living were found to be associated, variously, with the domains of playing a musical instrument, singing, self-reported musical ability, and music listening. The ELMEQ was found to be an effective research tool with older adults and is made freely available for future research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254176PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282069PMC
July 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 Jun 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 May 25. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
May 2021

Pre-pandemic cognitive function and COVID-19 vaccine hesitancy: cohort study.

Brain Behav Immun 2021 08 20;96:100-105. Epub 2021 May 20.

Department of Psychology, University of Edinburgh, UK.

Background: Whereas several predictors of COVID-19 vaccine hesitancy have been reported, the role of cognitive function is largely unknown. Accordingly, our objective was to evaluate the association between scores from an array of cognitive function tests and self-reported vaccine hesitancy after the announcement of the successful testing of the first COVID-19 vaccine (Oxford University/AstraZeneca).

Methods: We used individual-level data from a pandemic-focused study ('COVID Survey'), a prospective cohort study nested within United Kingdom Understanding Society ('Main Survey'). In the week immediately following the announcement of successful testing of the first efficacious inoculation (November/December 2020), data on vaccine intentionality were collected in 11,740 individuals (6702 women) aged 16-95 years. Pre-pandemic scores on general cognitive function, ascertained from a battery of six tests, were captured in 2011/12 wave of the Main Survey. Study members self-reported their intention to take up a vaccination in the COVID-19 Survey.

Results: Of the study sample, 17.2% (N = 1842) indicated they were hesitant about having the vaccine. After adjustment for age, sex, and ethnicity, study members with a lower baseline cognition score were markedly more likely to be vaccine hesitant (odds ratio per standard deviation lower score in cognition; 95% confidence interval: 1.76; 1.62, 1.90). Adjustment for mental and physical health plus household shielding status had no impact on these results, whereas controlling for educational attainment led to partial attenuation but the probability of hesitancy was still elevated (1.52; 1.37, 1.67). There was a linear association for vaccine hesitancy across the full range of cognition scores (p for trend: p < 0.0001).

Conclusions: Erroneous social media reports might have complicated personal decision-making, leading to people with lower cognitive ability being vaccine-hesitant. With individuals with lower cognition also experiencing higher rates of COVID-19 in studies conducted prior to vaccine distribution, these new findings are suggestive of a potential additional disease burden.
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http://dx.doi.org/10.1016/j.bbi.2021.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133799PMC
August 2021

Pre-pandemic mental and physical health as predictors of COVID-19 vaccine hesitancy: evidence from a UK-wide cohort study.

medRxiv 2021 Apr 30. Epub 2021 Apr 30.

Importance: Although several predictors of COVID-19 vaccine hesitancy have been identified, the role of physical health has not been well-examined, and the association with mental health is unknown.

Objective: To examine the association of pre-pandemic mental health, physical health, and shielding with vaccine hesitancy after the announcement of the successful testing of the Oxford University/AstraZeneca vaccine.

Design Setting And Participants: We used individual-level data from a pandemic-focused investigation (COVID Survey), a prospective cohort study nested within the UK Understanding Society (Main Survey) project. In the week immediately following the announcement of successful testing of the first efficacious inoculation (November/December 2020), data on vaccine intentionality were collected in 12,035 individuals aged 16-95 years. Pre-pandemic, study members had responded to enquiries about diagnoses of mental and physical health, completed the 12-item General Health Questionnaire for symptoms of psychological distress (anxiety and depression), and indicated whether they or someone in their household was shielding.

Main Outcome Measures: Self-reported intention to take up a vaccination for COVID-19. To summarise our results, we computed odds ratios with accompanying 95% confidence intervals for indices of health and shielding adjusted for selected covariates.

Results: In an analytical sample of 11,955 people (6741 women), 15.4% indicated that they were vaccine hesitant. Relative to their disease-free counterparts, shielding was associated with a 24% lower risk of being hesitant (odds ratio; 95% confidence interval: 0.76; 0.59, 0.96), after adjustment for a range of covariates which included age, education, and ethnicity. Corresponding results for cardiometabolic disease were 22% (0.78; 0.64, 0.95), and for respiratory disease were 26% (0.74; 0.59, 0.93). Having a pre-pandemic diagnosis of anxiety or depression, or a high score on the distress symptom scale, were all unrelated to the willingness to take up a vaccine.

Conclusions And Relevance: People who have been prioritised for COVID-19 vaccination owing to a physical condition are more likely to take it up. These effects were not apparent for indices of mental health.
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http://dx.doi.org/10.1101/2021.04.27.21256185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132272PMC
April 2021

Comparison of structural MRI brain measures between 1.5 and 3 T: Data from the Lothian Birth Cohort 1936.

Hum Brain Mapp 2021 Aug 19;42(12):3905-3921. Epub 2021 May 19.

Lothian Birth Cohorts Group, The University of Edinburgh, Edinburgh, UK.

Multi-scanner MRI studies are reliant on understanding the apparent differences in imaging measures between different scanners. We provide a comprehensive analysis of T -weighted and diffusion MRI (dMRI) structural brain measures between a 1.5 T GE Signa Horizon HDx and a 3 T Siemens Magnetom Prisma using 91 community-dwelling older participants (aged 82 years). Although we found considerable differences in absolute measurements (global tissue volumes were measured as ~6-11% higher and fractional anisotropy [FA] was 33% higher at 3 T than at 1.5 T), between-scanner consistency was good to excellent for global volumetric and dMRI measures (intraclass correlation coefficient [ICC] range: .612-.993) and fair to good for 68 cortical regions (FreeSurfer) and cortical surface measures (mean ICC: .504-.763). Between-scanner consistency was fair for dMRI measures of 12 major white matter tracts (mean ICC: .475-.564), and the general factors of these tracts provided excellent consistency (ICC ≥ .769). Whole-brain structural networks provided good to excellent consistency for global metrics (ICC ≥ .612). Although consistency was poor for individual network connections (mean ICCs: .275-.280), this was driven by a large difference in network sparsity (.599 vs. .334), and consistency was improved when comparing only the connections present in every participant (mean ICCs: .533-.647). Regression-based k-fold cross-validation showed that, particularly for global volumes, between-scanner differences could be largely eliminated (R range .615-.991). We conclude that low granularity measures of brain structure can be reliably matched between the scanners tested, but caution is warranted when combining high granularity information from different scanners.
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http://dx.doi.org/10.1002/hbm.25473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288101PMC
August 2021

Pre-pandemic cognitive function and COVID-19 mortality: prospective cohort study.

Eur J Epidemiol 2021 May 24;36(5):559-564. Epub 2021 Apr 24.

Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.

Poorer performance on standard tests of pre-morbid cognitive function is related to an elevated risk of death from lower respiratory tract infections but the link with coronavirus (COVID‑19) mortality is untested. Participants in UK Biobank, aged 40 to 69 years at study induction (2006-10), were administered a reaction time test, an indicator of information processing speed, and also had their verbal-numeric reasoning assessed. Between April 1st and September 23rd 2020 there were 388 registry-confirmed deaths (138 women) ascribed to COVID-19 in 494,932 individuals (269,602 women) with a reaction time test result, and 125 such deaths (38 women) in the subgroup of 180,198 people (97,794 women) with data on verbal-numeric reasoning. In analyses adjusted for age, sex, and ethnicity, a one standard deviation slower reaction time was related to a higher rate of death from COVID-19 (hazard ratio; 95% confidence interval: 1.18; 1.09, 1.28), as was a one standard deviation disadvantage on the verbal-numeric reasoning test (1.32; 1.09, 1.59). While there was some attenuation in these relationships after adjustment for additional covariates which included socio-economic status and lifestyle factors, the two pre-pandemic indicators of cognitive function continued to be related to COVID-19 mortality.
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http://dx.doi.org/10.1007/s10654-021-00743-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065311PMC
May 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Intelligence, health and death.

Nat Hum Behav 2021 04 1;5(4):416-430. Epub 2021 Apr 1.

Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.

The field of cognitive epidemiology studies the prospective associations between cognitive abilities and health outcomes. We review research in this field over the past decade and describe how our understanding of the association between intelligence and all-cause mortality has consolidated with the appearance of new, population-scale data. To try to understand the association better, we discuss how intelligence relates to specific causes of death, diseases/diagnoses and biomarkers of health through the adult life course. We examine the extent to which mortality and health associations with intelligence might be attributable to people's differences in education, other indicators of socioeconomic status, health literacy and adult environments and behaviours. Finally, we discuss whether genetic data provide new tools to understand parts of the intelligence-health associations. Social epidemiologists, differential psychologists and behavioural and statistical geneticists, among others, contribute to cognitive epidemiology; advances will occur by building on a common cross-disciplinary knowledge base.
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http://dx.doi.org/10.1038/s41562-021-01078-9DOI Listing
April 2021

Pre-pandemic Cognitive Function and COVID-19 Vaccine Hesitancy: Cohort Study.

medRxiv 2021 Mar 25. Epub 2021 Mar 25.

Department of Psychology, University of Edinburgh, UK.

Background: Whereas several predictors of COVID-19 vaccine hesitancy have been examined, the role of cognitive function following the widely publicised development of an inoculation is unknown.

Objective: To test the association between scores from an array of cognitive function tests and self-reported vaccine hesitancy after the announcement of the successful testing of the Oxford University/AstraZeneca vaccine.

Design Setting And Participants: We used individual-level data from a pandemic-focused study (COVID Survey), a prospective cohort study nested within Understanding Society (Main Survey). In the week immediately following the announcement of successful testing of the first efficacious inoculation (November/December 2020), data on vaccine intentionality were collected in 11740 individuals (6702 women) aged 16-95. Pre-pandemic scores on general cognitive function, ascertained from a battery of six tests, were captured in 2011/12 wave of the Main Survey.

Measurements: Self-reported intention to take up a vaccination for COVID-19. To summarise our results, we computed odds ratios with accompanying 95% confidence intervals for general cognitive function adjusted for selected covariates.

Results: Of the study sample, 17.2% (N=1842) indicated they were hesitant about having the vaccine. After adjustment for age, sex, and ethnicity, study members with a lower baseline cognition score were markedly more likely to be vaccine hesitant (odds ratio per standard deviation lower score in cognition; 95% confidence interval: 1.76; 1.62, 1.90). Adjustment for mental and physical health plus household shielding status had no impact on these results, whereas controlling for educational attainment led to partial attenuation but the probability of hesitancy was still elevated (1.52; 1.37, 1.67). There was a linear association for vaccine hesitancy across the full range of cognition scores (p for trend: p<0.0001).

Limitations: Our outcome was based on intention rather than behaviour.

Conclusions: Erroneous social media reports might have complicated personal decision-making, leading to people with lower cognitive ability test scores being vaccine-hesitant. With people with lower cognition also experiencing higher rates of COVID-19 in studies conducted prior to vaccine distribution, these new findings are suggestive of a potential additional disease burden.
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http://dx.doi.org/10.1101/2021.03.16.21253634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010758PMC
March 2021

Predicting COVID-19 vaccine take-up: Moving beyond demographics.

Brain Behav Immun 2021 07 27;95:17-18. Epub 2021 Mar 27.

Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, UK. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2021.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997898PMC
July 2021

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 Mar 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

Apolipoprotein E e4 allele status and later-life depression in the Lothian Birth Cohort 1936.

Psychol Med 2021 Mar 2:1-9. Epub 2021 Mar 2.

Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.

Background: Previous results have been mixed regarding the role of the apolipoprotein E e4 (APOE e4) allele in later-life depression: some studies note that carriers experience greater symptoms and increased risk while others find no such association. However, there are few prospective, population-based studies of the APOE e4-depression association and fewer that examine depressive symptom trajectory and depression risk longitudinally. We examined the association between APOE e4 allele status and longitudinal change in depressive symptoms and depression risk in later-life, over a 12-year follow-up period.

Methods: We used data from 690 participants of the Lothian Birth Cohort 1936 who took part in the Scottish Mental Survey 1947 (aged 11) and were followed-up in later-life over five waves from 2004 to 2019 (aged 70-82). We used APOE e4 allele status to predict longitudinal change in depressive symptom scores and risk of depression (defined by a symptom score threshold or use of depression-related medication). Models were adjusted for sex, childhood cognitive ability, childhood social class, education, adult social class, smoking status and functional limitations at baseline.

Results: Depressive symptom scores increased with age. Once adjusted for covariates, APOE e4 allele status did not significantly predict symptom score trajectories or depression risk. Greater functional limitations at baseline significantly predicted poorer symptom score trajectories and increased depression risk (defined by medications). APOE e4 allele status did not significantly moderate the contribution of sex, education or functional limitations.

Conclusions: There was no evidence that APOE e4 carriers experience an increased risk for later-life depression.
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http://dx.doi.org/10.1017/S0033291721000623DOI Listing
March 2021

DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts.

Clin Epigenetics 2021 02 23;13(1):40. Epub 2021 Feb 23.

MRC Integrative Epidemiology, Bristol Medical School, Bristol, BS8 2BN, UK.

Background: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones.

Results: We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R = 10.6%).

Conclusions: This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.
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http://dx.doi.org/10.1186/s13148-021-01027-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903628PMC
February 2021

Creating and validating a DNA methylation-based proxy for interleukin-6.

J Gerontol A Biol Sci Med Sci 2021 Feb 17. Epub 2021 Feb 17.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Background: Studies evaluating the relationship between chronic inflammation and cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals' persisting levels of inflammation. DNA methylation has shown utility in indexing environmental exposures and could be leveraged to provide proxy signatures of chronic inflammation.

Methods: We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 875 older adults (Lothian Birth Cohort 1936; mean age: 70 years) to develop a DNA methylation-based predictor. The predictor was tested in an independent cohort (Generation Scotland; n=7,028 [417 with measured IL-6], mean age: 51 years).

Results: A weighted score from 35 CpG sites optimally predicted IL-6 in the independent test set (Generation Scotland; R 2=4.4%, p=2.1x10 -5). In the independent test cohort, both measured IL-6 and the DNA methylation proxy increased with age (serum IL-6: n=417, β=0.02, SE=0.004 p=1.3x10 -7; DNAm IL-6 score: n=7,028, β=0.02, SE=0.0009, p<2x10 -16). Serum IL-6 did not associate with cognitive ability (n=417, β=-0.06, SE=0.05, p=0.19); however, an inverse association was identified between the DNA methylation score and cognitive functioning (n=7,028, β=-0.16, SE=0.02, pFDR<2x10 -16).

Conclusions: These results suggest methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for further insight into the relationship between inflammation and pertinent health outcomes.
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http://dx.doi.org/10.1093/gerona/glab046DOI Listing
February 2021

Pre-pandemic cognitive function and COVID-19 mortality: prospective cohort study.

medRxiv 2021 Feb 8. Epub 2021 Feb 8.

Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, UK; Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, UK.

Background: Poorer performance on standard tests of cognitive function is related to an elevated risk of death from lower respiratory tract infections. Whether pre-pandemic measures of cognition are related to COVID-19 mortality is untested.

Methods: UK Biobank, a prospective cohort study, comprises around half a million people who were aged 40 to 69 years at study induction between 2006 and 2010 when a reaction time test was administered to the full sample, and verbal-numeric reasoning assessed in a subgroup. Death from COVID-19 was ascertained from participant linkage to a UK-wide national registry.

Results: Between April 1st and September 23rd 2020, there were 388 deaths (138 women) ascribed to COVID-19 in the 494,932 individuals (269,602 women) with a reaction time test result, and 125 such deaths (38 women) in the 180,198 (97,794 women) for whom there were data on verbal-numeric reasoning. In analyses adjusted for age, sex, and ethnicity, a one standard deviation (118.2 msec) slower reaction time was related to a higher rate of death from COVID-19 (hazard ratio; 95% confidence interval: 1.18; 1.09, 1.28). A one standard deviation disadvantage (2.16 point) on the verbal-numeric reasoning test was also associated with an elevated risk of death (1.32; 1.09, 1.59). Attenuation after adjustment for additional covariates followed a similar pattern for both measures of cognition. For verbal-numeric reasoning, for instance, the hazard ratios were 1.22 (0.98, 1.51) after control for socioeconomic status, 1.16 (0.96, 1.41) after lifestyle factors, 1.25 (1.04, 1.52) after co-morbidity, and 1.29 (1.01, 1.64) after physiological indices.

Conclusions: In the present study, poorer performance on two pre-pandemic indicators of cognitive function, including reaction time, a knowledge-reduced measure, was related to death ascribed to COVID-19.
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http://dx.doi.org/10.1101/2021.02.07.21251082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872381PMC
February 2021

Trajectories of Big Five Personality Traits: A Coordinated Analysis of 16 Longitudinal Samples.

Eur J Pers 2020 May 1;34(3):301-321. Epub 2020 May 1.

Northwestern University, Chicago, IL USA.

This study assessed change in self-reported Big Five personality traits. We conducted a coordinated integrative data analysis using data from 16 longitudinal samples, comprising a total sample of over 60 000 participants. We coordinated models across multiple datasets and fit identical multi-level growth models to assess and compare the extent of trait change over time. Quadratic change was assessed in a subset of samples with four or more measurement occasions. Across studies, the linear trajectory models revealed declines in conscientiousness, extraversion, and openness. Non-linear models suggested late-life increases in neuroticism. Meta-analytic summaries indicated that the fixed effects of personality change are somewhat heterogeneous and that the variability in trait change is partially explained by sample age, country of origin, and personality measurement method. We also found mixed evidence for predictors of change, specifically for sex and baseline age. This study demonstrates the importance of coordinated conceptual replications for accelerating the accumulation of robust and reliable findings in the lifespan developmental psychological sciences.
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http://dx.doi.org/10.1002/per.2259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869960PMC
May 2020

Genetic variation, brain, and intelligence differences.

Mol Psychiatry 2021 Feb 2. Epub 2021 Feb 2.

Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.

Individual differences in human intelligence, as assessed using cognitive test scores, have a well-replicated, hierarchical phenotypic covariance structure. They are substantially stable across the life course, and are predictive of educational, social, and health outcomes. From this solid phenotypic foundation and importance for life, comes an interest in the environmental, social, and genetic aetiologies of intelligence, and in the foundations of intelligence differences in brain structure and functioning. Here, we summarise and critique the last 10 years or so of molecular genetic (DNA-based) research on intelligence, including the discovery of genetic loci associated with intelligence, DNA-based heritability, and intelligence's genetic correlations with other traits. We summarise new brain imaging-intelligence findings, including whole-brain associations and grey and white matter associations. We summarise regional brain imaging associations with intelligence and interpret these with respect to theoretical accounts. We address research that combines genetics and brain imaging in studying intelligence differences. There are new, though modest, associations in all these areas, and mechanistic accounts are lacking. We attempt to identify growing points that might contribute toward a more integrated 'systems biology' account of some of the between-individual differences in intelligence.
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http://dx.doi.org/10.1038/s41380-021-01027-yDOI Listing
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 Apr;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Quantitative measurements of enlarged perivascular spaces in the brain are associated with retinal microvascular parameters in older community-dwelling subjects.

Cereb Circ Cogn Behav 2020 ;1:100002

Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, and VAMPIRE Project, University of Edinburgh, Edinburgh, EH16 4SB, UK.

Background: Perivascular Spaces (PVS) become increasingly visible with advancing age on brain MRI, yet their relationship to morphological changes in the underlying microvessels remains poorly understood. Retinal and cerebral microvessels share morphological and physiological properties. We compared computationally-derived PVS morphologies with retinal vessel morphologies in older people.

Methods: We analysed data from community-dwelling individuals who underwent multimodal brain MRI and retinal fundus camera imaging at mean age 72.55 years (SD=0.71). We assessed centrum semiovale PVS computationally to determine PVS total volume and count, and mean per-subject individual PVS length, width and size. We analysed retinal images using the VAMPIRE software suite, obtaining the Central Retinal Artery and Vein Equivalents (CRVE and CRAE), Arteriole-to-Venule ratio (AVR), and fractal dimension (FD) of both eyes. We investigated associations using general linear models, adjusted for age, gender, and major vascular risk factors.

Results: In 381 subjects with all measures, increasing total PVS volume and count were associated with decreased CRAE in the left eye (volume =-0.170, count =-0.184, <0.001). No associations of PVS with CRVE were found. The PVS total volume, individual width and size increased with decreasing FD of the arterioles (a) and venules (v) of the left eye (total volume: FDa =-0.137, FDv =-0.139, <0.01; width: FDa =-0.144, FDv =-0.158, <0.01; size: FDa =-0.157, FDv =-0.162, <0.01).

Conclusions: Increase in PVS number and size visible on MRI reflect arteriolar narrowing and lower retinal arteriole and venule branching complexity, both markers of impaired microvascular health. Computationally-derived PVS metrics may be an early indicator of failing vascular health and should be tested in longitudinal studies.
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http://dx.doi.org/10.1016/j.cccb.2020.100002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792660PMC
January 2020

Assessing individual-level change in dementia research: a review of methodologies.

Alzheimers Res Ther 2021 01 15;13(1):26. Epub 2021 Jan 15.

Department of Psychology, University of Edinburgh, F17, 7 George Square, Edinburgh, EH8 9JZ, UK.

Background: Whether in the context of monitoring disease progression or in assessing the effects of interventions, a major challenge in dementia research is determining when an individual has undergone meaningful change in symptoms and other relevant outcomes such as cognitive test performance. The challenge lies in differentiating genuine improvement or deterioration from change in scores due to random and systematic error. BODY: In this review, we discuss the advantages and limitations of available methods for assessing individual-level change in the context of key challenges, including imperfect and differential reliability of scores, and practice effects. We discuss indices of reliable change and the use of composite and item response theory (IRT) scores.

Conclusion: We conclude that IRT-based approaches hold particular promise because they have the flexibility to accommodate solutions to a wide range of issues that influence the accuracy of judgements of meaningful change. We close by discussing the practical implications of adopting IRT-based approaches.
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http://dx.doi.org/10.1186/s13195-021-00768-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811223PMC
January 2021

Life Course Air Pollution Exposure and Cognitive Decline: Modelled Historical Air Pollution Data and the Lothian Birth Cohort 1936.

J Alzheimers Dis 2021 ;79(3):1063-1074

Centre for Research on Environment, Society and Health, School of GeoSciences, University of Edinburgh, Edinburgh, UK.

Background: Air pollution has been consistently linked with dementia and cognitive decline. However, it is unclear whether risk is accumulated through long-term exposure or whether there are sensitive/critical periods. A key barrier to clarifying this relationship is the dearth of historical air pollution data.

Objective: To demonstrate the feasibility of modelling historical air pollution data and using them in epidemiologicalmodels.

Methods: Using the EMEP4UK atmospheric chemistry transport model, we modelled historical fine particulate matter (PM2.5) concentrations for the years 1935, 1950, 1970, 1980, and 1990 and combined these with contemporary modelled data from 2001 to estimate life course exposure in 572 participants in the Lothian Birth Cohort 1936 with lifetime residential history recorded. Linear regression and latent growth models were constructed using cognitive ability (IQ) measured by the Moray House Test at the ages of 11, 70, 76, and 79 years to explore the effects of historical air pollution exposure. Covariates included sex, IQ at age 11 years, social class, and smoking.

Results: Higher air pollution modelled for 1935 (when participants would have been in utero) was associated with worse change in IQ from age 11-70 years (β = -0.006, SE = 0.002, p = 0.03) but not cognitive trajectories from age 70-79 years (p > 0.05). There was no support for other critical/sensitive periods of exposure or an accumulation of risk (all p > 0.05).

Conclusion: The life course paradigm is essential in understanding cognitive decline and this is the first study to examine life course air pollution exposure in relation to cognitive health.
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http://dx.doi.org/10.3233/JAD-200910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990442PMC
January 2021

Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability.

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Genomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.
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http://dx.doi.org/10.1038/s41380-020-00985-zDOI Listing
January 2021

Dietary patterns and trajectories of global- and domain-specific cognitive decline in the Lothian Birth Cohort 1936.

Br J Nutr 2020 Dec 23:1-10. Epub 2020 Dec 23.

Lothian Birth Cohorts Group, Department of Psychology, University of Edinburgh, Edinburgh, UK.

Healthy dietary patterns may protect against age-related cognitive decline, but results of studies have been inconsistent and few have had extensive longitudinal follow-up with comprehensive cognitive testing. The aim of the present study was to determine associations of dietary patterns with trajectories of global- and domain-specific cognitive change over a 12-year period. Data from 863 community-dwelling, dementia-free participants from the Lothian Birth Cohort 1936 study of ageing completed a FFQ at baseline (aged 70 years) and underwent cognitive testing at baseline, and at the ages of 73, 76, 79 and 82 years. Composite cognitive scores were constructed for four cognitive domains (visuospatial ability, processing speed, memory and verbal ability) and global cognitive function. A Mediterranean-style pattern and a traditional pattern were derived using principal component analysis of self-reported dietary intakes. In fully adjusted latent growth curve models, higher baseline adherence to the Mediterranean-style dietary pattern (β = 0·056, P = 0·009) and lower baseline adherence to the traditional dietary pattern (β  =  -0·087, P < 0·001) were cross-sectionally associated with better verbal ability. A slightly steeper decline in verbal ability over 12 years was observed in those with higher Mediterranean-style diet scores at baseline (β = -0·003, P = 0·008). All other associations were non-significant. Our findings in this well-characterised Scottish cohort indicate that adherence to a healthy Mediterranean-style diet is associated cross-sectionally with better verbal (crystallised) ability, with the converse being true for the traditional diet. A healthier baseline diet did not predict a reduced risk of global- or domain-specific cognitive decline.
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http://dx.doi.org/10.1017/S0007114520005139DOI Listing
December 2020

Is Healthy Neuroticism Associated with Health Behaviors? A Coordinated Integrative Data Analysis.

Collabra Psychol 2020 21;6(1). Epub 2020 Jul 21.

Humboldt University, Berlin Germany, Department of Psychology.

Current literature suggests that neuroticism is positively associated with maladaptive life choices, likelihood of disease, and mortality. However, recent research has identified circumstances under which neuroticism is associated with positive outcomes. The current project examined whether "healthy neuroticism", defined as the interaction of neuroticism and conscientiousness, was associated with the following health behaviors: smoking, alcohol consumption, and physical activity. Using a pre-registered multi-study coordinated integrative data analysis (IDA) approach, we investigated whether "healthy neuroticism" predicted the odds of engaging in each of the aforementioned activities. Each study estimated identical models, using the same covariates and data transformations, enabling optimal comparability of results. These results were then meta-analyzed in order to estimate an average (N-weighted) effect and to ascertain the extent of heterogeneity in the effects. Overall, these results suggest that neuroticism alone was not related to health behaviors, while individuals higher in conscientiousness were less likely to be smokers or drinkers, and more likely to engage in physical activity. In terms of the healthy neuroticism interaction of neuroticism and conscientiousness, significant interactions for smoking and physical activity suggest that the association between neuroticism and health behaviors was smaller among those high in conscientiousness. These findings lend credence to the idea that healthy neuroticism may be linked to certain health behaviors and that these effects are generalizable across several heterogeneous samples.
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http://dx.doi.org/10.1525/collabra.266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751766PMC
July 2020

Is Healthy Neuroticism Associated with Longevity? A Coordinated Integrative Data Analysis.

Collabra Psychol 2020 21;6(1). Epub 2020 Jul 21.

Northwestern University, Department of Medical Social Sciences, Chicago, IL, USA.

Individual differences in the Big Five personality traits have emerged as predictors of health and longevity. Although there are robust protective effects for higher levels of conscientiousness, results are mixed for other personality traits. In particular, higher levels of neuroticism have significantly predicted an increased risk of mortality, no-risk at all, and even a reduced risk of dying. The current study hypothesizes that one potential reason for the discrepancy in these findings for neuroticism is that interactions among neuroticism and other key personality traits have largely been ignored. Thus, in the current study we focus on testing whether the personality traits neuroticism and conscientiousness interact to predict mortality. Specifically, we borrow from recent evidence of "healthy neuroticism" to explore whether higher levels of neuroticism are only a risk factor for increased mortality risk when conscientiousness levels are low. We conducted a pre-registered integrative data analysis using 12 different cohort studies (total = 44,702). Although a consistent pattern emerged of higher levels of conscientiousness predicting a reduced hazard of dying, neuroticism did not show a consistent pattern of prediction. Moreover, no study provided statistical evidence of a neuroticism by conscientiousness interaction. The current findings do not support the idea that the combination of high conscientiousness and high neuroticism can be protective for longevity. Future work is needed to explore different protective factors that may buffer the negative effects of higher levels of neuroticism on health, as well as other behaviors and outcomes that may support the construct of healthy neuroticism.
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http://dx.doi.org/10.1525/collabra.268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751763PMC
July 2020
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