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"Logue, Mark"
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The King's war : the friendship of George VI and Lionel Logue during World War II
\"The broadcast that George VI made to the British nation on the outbreak of war in September 1939--which formed the climax of the multi-Oscar-winning film The King's Speech--was the product of years of hard work with Lionel Logue, his iconoclastic, Australian-born speech therapist. Yet the relationship between the two men did not end there. Far from it: in the years that followed, Logue was to play an even more important role at the monarch's side. The King's War follows that relationship through the dangerous days of Dunkirk and the drama of D-Day to eventual victory in 1945--and beyond. Like the first book, it is written by Peter Conradi, a London Sunday Times journalist, and Mark Logue (Lionel's grandson), and again draws on exclusive material from the Logue Archive--the collection of diaries, letters, and other documents left by Lionel and his feisty wife, Myrtle. This gripping narrative provides a fascinating portrait of two men and their respective families--the Windsors and the Logues--as they together face the greatest challenge in Britain's history.\"--Dust jacket.
Book
African ancestry GWAS of dementia in a large military cohort identifies significant risk loci
While genome wide association studies (GWASs) of Alzheimer’s Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer’s disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (
n
= 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer’s Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of
APOE
(
p
= 2.48 × 10
−
101
), in
ROBO1
(rs11919682,
p
= 1.63 × 10
−
8
), and RNA RP11-340A13.2 (rs148433063,
p
= 8.56 × 10
−
9
). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes
TREM2
(rs73427293,
p
= 2.95 × 10
−
9
),
CD2AP
(rs7738720,
p
= 1.14 × 10
−9
), and
ABCA7
(rs73505251,
p
= 3.26 × 10
−10
), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (
CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4
, and
TREM2
) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-
APOE
GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.
Journal Article
Genome-wide association study of traumatic brain injury in U.S. military veterans enrolled in the VA million veteran program
Large-scale genetic studies of traumatic brain injury (TBI) are lacking; thus, our understanding of the influence of genetic factors on TBI risk and recovery is incomplete. This study aimed to conduct a genome-wide association study (GWAS) of TBI in VA Million Veteran Program (MVP) enrollees. Participants included a multi-ancestry cohort (European, African, and Hispanic ancestries; N = 304,485; 111,494 TBI cases, 192,991 controls). TBI was assessed using MVP survey data and International Classification of Diseases (ICD) codes from the Veterans Health Administration’s electronic health record. GWAS was performed using logistic regression in PLINK, and meta-analyzed in METAL. FUMA was used for post-GWAS analysis. Genomic structural equation modeling (gSEM) was conducted to investigate underlying genetic associations with TBI, and bivariate MiXeR was used to estimate phenotype specific and shared polygenicity. SNP-based heritability was 0.060 (SE = 0.004,
p
= 7.83×10
-66
). GWAS analysis identified 15 genome-wide significant (GWS) loci at
p
< 5×10
-8
. Gene-based analyses revealed 14 gene-wide significant genes; top genes included
NCAM1, APOE, FTO
, and
FOXP2
. Gene tissue expression analysis identified the brain as significantly enriched, particularly in the frontal cortex, anterior cingulate cortex, and nucleus accumbens. Genetic correlations with TBI were significant for risk-taking behaviors and psychiatric disorders, but generally not significant for the neurocognitive variables investigated. gSEM analysis revealed stronger associations with risk-taking traits than with psychiatric traits. Finally, the genetic architecture of TBI was similar to polygenic psychiatric disorders. Neurodegenerative disorders including Alzheimer’s and Parkinson’s disease showed much less polygenicity, however, the proportion of shared variance with TBI was high. This first well-powered GWAS of TBI identified 15 loci including genes relevant to TBI biology, and showed that TBI is a heritable trait with comparable genetic architecture and high genetic correlation with psychiatric traits. Our findings set the stage for future TBI GWASs that focus on injury severity and diversity and chronicity of symptom sequelae.
Journal Article
Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress
Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.
Journal Article
The correlation of methylation levels measured using Illumina 450K and EPIC BeadChips in blood samples
We examined concordance of methylation levels across the Illumina Infinium HumanMethylation450 BeadChip and the Infinium MethylationEPIC BeadChip.
We computed the correlation for 145 whole blood DNA samples at each of the 422,524 CpG sites measured by both chips.
The correlation at some sites was high (up to r = 0.95), but many sites had low correlation (55% had r < 0.20). The low correspondence between 450K and EPIC measured methylation values at many loci was largely due to the low variability in methylation values for the majority of the CpG sites in blood.
Filtering out probes based on the observed correlation or low variability may increase reproducibility of BeadChip-based epidemiological studies.
Journal Article
Higher ADRD machine learning phenotypic scores are associated with faster conversion to ADRD in Veterans without ICD ADRD diagnoses
Background Alzheimer's Disease and related dementias (ADRD) are under diagnosed and that under diagnosis if detrimental to patients, their families and the VA Health Care System. This crisis of under diagnosis exacerbates existing disparities in healthcare, disproportionately affect Black Americans (BAs) compared to White Americans (WAs). Using a machine learning (ML) model to assign ADRD‐risk scores may help to identify Veterans with undiagnosed ADRD and their risk of developing dementia in the near future. Method We previously developed a ML model based on 850+ variables extracted from structured and unstructured data from the VHA's vast electronic health records, using a training sample of 20,000 BA and 20,000 WA Veterans. Kaplan‐Meier curves were calculated separately for race and ML score quintile group. A Cox‐proportions hazards model was used to obtain an estimate of the hazard ratio (HR) for the risk of developing ADRD. Result The HR comparing the 75th to the 25th percentile of scores is estimated to be 2.20 (95% CI, 1.93‐2.51, p < 0.01). The Kaplan‐Meier plot showed differences in risk for converting to ADRD between races; for BAs, the curves of the highest two quintiles have visibly steeper slopes than those for other quintiles; for WAs, only the highest quintile have visibly steeper slopes than the other quintiles. Conclusion Higher ML scores were associated with higher risk of developing ADRD in the years following the index date. BAs in our sample were at a higher risk for developing ADRD compared to their WA counterparts with the same score.
Journal Article
Genetics of Alzheimer’s Disease in the African American Population
Black/African American (AA) individuals have a higher risk of Alzheimer’s disease (AD) than White non-Hispanic persons of European ancestry (EUR) for reasons that may include economic disparities, cardiovascular health, quality of education, and biases in the methods used to diagnose AD. AD is also heritable, and some of the differences in risk may be due to genetics. Many AD-associated variants have been identified by candidate gene studies, genome-wide association studies (GWAS), and genome-sequencing studies. However, most of these studies have been performed using EUR cohorts. In this paper, we review the genetics of AD and AD-related traits in AA individuals. Importantly, studies of genetic risk factors in AA cohorts can elucidate the molecular mechanisms underlying AD risk in AA and other populations. In fact, such studies are essential to enable reliable precision medicine approaches in persons with considerable African ancestry. Furthermore, genetic studies of AA cohorts allow exploration of the ways the impact of genes can vary by ancestry, culture, and economic and environmental disparities. They have yielded important gains in our knowledge of AD genetics, and increasing AA individual representation within genetic studies should remain a priority for inclusive genetic study design.
Journal Article
The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration
The development of posttraumatic stress disorder (PTSD) is influenced by genetic factors. Although there have been some replicated candidates, the identification of risk variants for PTSD has lagged behind genetic research of other psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Psychiatric genetics has moved beyond examination of specific candidate genes in favor of the genome-wide association study (GWAS) strategy of very large numbers of samples, which allows for the discovery of previously unsuspected genes and molecular pathways. The successes of genetic studies of schizophrenia and bipolar disorder have been aided by the formation of a large-scale GWAS consortium: the Psychiatric Genomics Consortium (PGC). In contrast, only a handful of GWAS of PTSD have appeared in the literature to date. Here we describe the formation of a group dedicated to large-scale study of PTSD genetics: the PGC-PTSD. The PGC-PTSD faces challenges related to the contingency on trauma exposure and the large degree of ancestral genetic diversity within and across participating studies. Using the PGC analysis pipeline supplemented by analyses tailored to address these challenges, we anticipate that our first large-scale GWAS of PTSD will comprise over 10 000 cases and 30 000 trauma-exposed controls. Following in the footsteps of our PGC forerunners, this collaboration-of a scope that is unprecedented in the field of traumatic stress-will lead the search for replicable genetic associations and new insights into the biological underpinnings of PTSD.
Journal Article
Transcriptomic organization of the human brain in post-traumatic stress disorder
Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene
ELFN1
as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.
A transcriptome-wide characterization of the molecular pathology of post-traumatic stress disorder (PTSD) postmortem brains provides a comprehensive resource for mechanistic insight and therapeutic development.
Journal Article
Klotho, PTSD, and advanced epigenetic age in cortical tissue
This study examined the klotho (KL) longevity gene polymorphism rs9315202 and psychopathology, including posttraumatic stress disorder (PTSD), depression, and alcohol-use disorders, in association with advanced epigenetic age in three postmortem cortical tissue regions: dorsolateral and ventromedial prefrontal cortices and motor cortex. Using data from the VA National PTSD Brain Bank (n = 117), we found that rs9315202 interacted with PTSD to predict advanced epigenetic age in motor cortex among the subset of relatively older (>=45 years), white non-Hispanic decedents (corrected p = 0.014, n = 42). An evaluation of 211 additional common KL variants revealed that only variants in linkage disequilibrium with rs9315202 showed similarly high levels of significance. Alcohol abuse was nominally associated with advanced epigenetic age in motor cortex (p = 0.039, n = 114). The rs9315202 SNP interacted with PTSD to predict decreased KL expression via DNAm age residuals in motor cortex among older white non-Hispanics decedents (indirect β = −0.198, p = 0.027). Finally, in dual-luciferase enhancer reporter system experiments, we found that inserting the minor allele of rs9315202 in a human kidney cell line HK-2 genomic DNA resulted in a change in KL transcriptional activities, likely operating via long noncoding RNA in this region. This was the first study to examine multiple forms of psychopathology in association with advanced DNA methylation age across several brain regions, to extend work concerning the association between rs9315202 and advanced epigenetic to brain tissue, and to identify the effects of rs9315202 on KL gene expression. KL augmentation holds promise as a therapeutic intervention to slow the pace of cellular aging, disease onset, and neuropathology, particularly in older, stressed populations.
Journal Article