Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa.

African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multi-generational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within Africa as well as how within-Africa variation can be informative for broader variant interpretation; many variants that are rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity across Africa.

Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations.

Genetic studies in underrepresented populations identify disproportionate numbers of novel associations. However, most genetic studies use genotyping arrays and sequenced reference panels that best capture variation most common in European ancestry populations. To compare data generation strategies best suited for underrepresented populations, we sequenced the whole genomes of 91 individuals to high coverage as part of the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study with participants from Ethiopia, Kenya, South Africa, and Uganda. We used a downsampling approach to evaluate the quality of two cost-effective data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole-genome sequencing data. We show that low-coverage sequencing at a depth of ≥4× captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1×) performed comparably to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation; 4× sequencing detects 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. Low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, effectively identify novel variation particularly in underrepresented populations, and present opportunities to enhance variant discovery at a cost similar to traditional approaches.

Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis.

Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547-560.

Post-traumatic stress disorder symptom remission and cognition in a large cohort of civilian women.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit. METHODS: Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively. RESULTS: Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression. CONCLUSION: Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms.

Adaptive Platform Trials to Transform Amyotrophic Lateral Sclerosis Therapy Development.

Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints. ANN NEUROL 2022;91:165-175.

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection.

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Polygenic risk for autism, attention-deficit hyperactivity disorder, schizophrenia, major depressive disorder, and neuroticism is associated with the experience of childhood abuse.

People who experience childhood abuse are at increased risk of mental illness. Twin studies suggest that inherited genetic risk for mental illness may account for some of these associations. Yet, the hypothesis that individuals who have experienced childhood abuse may carry genetic loading for mental illness has never been tested with genetic data. Using polygenic risk scores for six psychiatric disorders-attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), neuroticism, and schizophrenia-we tested whether genetic risk for mental illness was associated with increased risk of experiencing three types of childhood abuse: physical/emotional abuse, physical assault, and sexual abuse, in a cohort of white non-Hispanic women (n = 11,315). ADHD and MDD genetic risk scores were associated with a higher risk of experiencing each type of childhood abuse, while neuroticism, schizophrenia, BPD, and ASD genetic scores were associated with a higher risk of experiencing physical/emotional abuse and physical assault, but not sexual abuse. Sensitivity analyses examining potential bias from the differential recall of childhood trauma, parental socioeconomic status, and population stratification were consistent with the main findings. A one-standard-deviation increase in genetic risk for mental illness was associated with a modestly elevated risk of experiencing childhood abuse (OR range: 1.05-1.19). Therefore, inherited genetic risk may partly account for the association of childhood abuse with mental illness. In addition, future treatments for mental illness will benefit from taking into consideration the co-occurrence of childhood trauma and genetic loading.

The association of posttraumatic stress disorder, depression, and head injury with mid-life cognitive function in civilian women.

BACKGROUND: Despite evidence linking posttraumatic stress disorder (PTSD), depression, and head injury, separately, with worse cognitive performance, investigations of their combined effects on cognition are limited in civilian women. METHODS: The Cogstate Brief Battery assessment was administered in 10,681 women from the Nurses' Health Study II cohort, mean age 64.9 years (SD = 4.6). Psychological trauma, PTSD, depression, and head injury were assessed using online questionnaires. In this cross-sectional analysis, we used linear regression models to estimate mean differences in cognition by PTSD/depression status and stratified by history of head injury. RESULTS: History of head injury was prevalent (36%), and significantly more prevalent among women with PTSD and depression (57% of women with PTSD and depression, 21% of women with no psychological trauma or depression). Compared to having no psychological trauma or depression, having combined PTSD and depression was associated with worse performance on psychomotor speed/attention ( ß = -.15, p = .001) and learning/working memory ( ß = -.15, p < .001). The joint association of PTSD and depression on worse cognitive function was strongest among women with past head injury, particularly among those with multiple head injuries. CONCLUSIONS: Head injury, like PTSD and depression, was highly prevalent in this sample of civilian women. In combination, these factors were associated with poorer performance on cognitive tasks, a possible marker of future cognitive health. Head injury should be further explored in future studies of PTSD, depression and cognition in women.

Examining the Association Between Childhood Trauma, Brain Injury, and Neurobehavioral Symptoms Among Survivors of Intimate Partner Violence: A Cross-Sectional Analysis.

OBJECTIVE: Understanding factors contributing to neurobehavioral symptom burden among intimate partner violence (IPV) survivors has important implications for prevention, screening, and intervention in this vulnerable population. This study aimed to (1) identify the relationship between childhood trauma and neurobehavioral symptoms among a shelter- and community-based sample of IPV survivors, including investigating the mediating role of posttraumatic stress symptoms and alexithymia in this relationship; (2) assess the association between IPV-related brain injury (BI) severity and neurobehavioral symptoms; and (3) assesses whether physical, emotional, or cognitive domains of neurobehavioral symptom burden show differential associations with childhood trauma or IPV-related BI. SETTING: Community sites serving women who had experienced IPV such as domestic violence shelters and transitional housing sites. PARTICIPANTS: Women survivors of IPV with and without BI (n = 99), aged 18 to 54 years. DESIGN: Retrospective, cross-sectional study design. MEASURES: The following self-reported questionnaires were used: Rivermead Post Concussion Questionnaire (RPQ); Childhood Trauma Questionnaire (CTQ); a modified version of the Conflict Tactics Scale; Brain Injury Severity Assessment (BISA); Clinician-Administered PTSD Scale for DSM IV; and Toronto Alexithymia Scale. The final multivariate regression model assessed the association between childhood abuse, BI severity, and neurobehavioral symptoms (as measured by the RPQ) adjusting for age, educational attainment, and abuse in the past year. We created separate models with total neurobehavioral symptom score as an outcome, as well as somatic, emotional, and cognitive symptom scores. We used structural equation modeling to assess whether posttraumatic stress and alexithymia mediated the effect of childhood trauma and neurobehavioral symptoms. RESULTS: Childhood trauma was associated with higher levels (P < .01) of overall neurobehavioral symptom burden in women independent of BI and specifically associated with RPQ Emotional and Somatic subscale symptoms (P ≤ .05). BI was positively associated with somatic symptoms in the full sample and cognitive neurobehavioral symptoms in the sample of women with IPV-related BI (P < .05) independent of childhood trauma. Posttraumatic stress symptoms, but not alexithymia, partially mediated the effect of childhood trauma effect on neurobehavioral symptoms. CONCLUSION: Childhood trauma and BI should not be overlooked as part of efforts to meet the needs of IPV survivors who may experience a range of emotional, somatic, and cognitive symptoms.

Preoperative antithrombotic treatment in acutely symptomatic carotid artery stenosis.

OBJECTIVES: Early recurrence of cerebral ischemia in acutely symptomatic carotid artery stenosis can precede revascularization. The optimal antithrombotic regimen for this high-risk population is not well established. Although antiplatelet agents are commonly used, there is limited evidence for the use of anticoagulants. We sought to understand the safety and efficacy of short-term preoperative anticoagulants in secondary prevention of recurrent cerebral ischemic events from acutely symptomatic carotid stenosis in patients awaiting carotid endarterectomy (CEA). MATERIALS AND METHODS: A retrospective query of a prospective single institution registry of carotid revascularization was performed. Patients who presented with acute ischemic stroke or transient ischemic attack (TIA) attributable to an ipsilateral internal carotid artery stenosis (ICA) were included. Antiplatelet (AP) only and anticoagulation (AC) treatment arms were compared. The primary outcome was a composite of preoperative recurrent ischemic stroke or TIA. The primary safety outcome was symptomatic intracranial hemorrhage. RESULTS: Out of 443 CEA patients, 342 were in the AC group and 101 in the AP group. Baseline characteristics between groups (AC vs AP) were similar apart from age (71±10.5 vs 73±9.5, p=0.04), premorbid modified Rankin scale (mRS) score (1.0±1.2 vs 1.4±1.3, p=0.03) and stroke as presenting symptom (65.8 vs 53.5%, p=0.02). Patients in the AC group had a lower incidence of recurrent stroke/TIA (3.8 vs 10.9%, p=0.006). One patient had symptomatic intracranial hemorrhage in the AC group, and none in the AP group. In multivariate analysis controlling for age, premorbid mRS, stroke severity, degree of stenosis, presence of intraluminal thrombus (ILT) and time to surgery, AC was protective (OR 0.30, p=0.007). This effect persisted in the cohort exclusively without ILT (OR 0.23, p=0.002). CONCLUSIONS: Short term preoperative anticoagulation in patients with acutely symptomatic carotid stenosis appears safe and effective compared to antiplatelet agents alone in the prevention of recurrent cerebral ischemic events while awaiting CEA.

Posttraumatic stress disorder and changes in diet quality over 20 years among US women.

BACKGROUND: Individuals with posttraumatic stress disorder (PTSD) are at increased risk of various chronic diseases. One hypothesized pathway is via changes in diet quality. This study evaluated whether PTSD was associated with deterioration in diet quality over time. METHODS: Data were from 51 965 women in the Nurses' Health Study II PTSD sub-study followed over 20 years. Diet, assessed at 4-year intervals, was characterized via the Alternative Healthy Eating Index-2010 (AHEI). Based on information from the Brief Trauma Questionnaire and Short Screening Scale for DSM-IV PTSD, trauma/PTSD status was classified as no trauma exposure, prevalent exposure (trauma/PTSD onset before study entry), or new-onset (trauma/PTSD onset during follow-up). We further categorized women with prevalent exposure as having trauma with no PTSD symptoms, trauma with low PTSD symptoms, and trauma with high PTSD symptoms, and created similar categories for women with new-onset exposure, resulting in seven comparison groups. Multivariable linear mixed-effects spline models tested differences in diet quality changes by trauma/PTSD status over follow-up. RESULTS: Overall, diet quality improved over time regardless of PTSD status. In age-adjusted models, compared to those with no trauma, women with prevalent high PTSD and women with new-onset high PTSD symptoms had 3.3% and 3.6% lower improvement in diet quality, respectively, during follow-up. Associations remained consistent after adjusting for health conditions, sociodemographics, and behavioral characteristics. CONCLUSIONS: PTSD is associated with less healthy changes in overall diet quality over time. Poor diet quality may be one pathway linking PTSD with a higher risk of chronic disease development.

Variance components genetic association test for zero-inflated count outcomes.

Commonly in biomedical research, studies collect data in which an outcome measure contains informative excess zeros; for example, when observing the burden of neuritic plaques (NPs) in brain pathology studies, those who show none contribute to our understanding of neurodegenerative disease. The outcome may be characterized by a mixture distribution with one component being the "structural zero" and the other component being a Poisson distribution. We propose a novel variance components score test of genetic association between a set of genetic markers and a zero-inflated count outcome from a mixture distribution. This test shares advantageous properties with single-nucleotide polymorphism (SNP)-set tests which have been previously devised for standard continuous or binary outcomes, such as the sequence kernel association test. In particular, our method has superior statistical power compared to competing methods, especially when there is correlation within the group of markers, and when the SNPs are associated with both the mixing proportion and the rate of the Poisson distribution. We apply the method to Alzheimer's data from the Rush University Religious Orders Study and Memory and Aging Project, where as proof of principle we find highly significant associations with the APOE gene, in both the "structural zero" and "count" parameters, when applied to a zero-inflated NPs count outcome.

Time Trends in Survival Following First Hemorrhagic or Ischemic Stroke Between 1991 and 2015 in the Rotterdam Study.

Background and Purpose- The introduction of stroke units and the implementation of evidence-based interventions have been a breakthrough in the management of patients with stroke over the past decade. Survival following stroke is an important indicator in monitoring stroke burden. Recent data on survival by stroke subtype in the general population is scarce. We assessed (1) recent temporal time trends in survival; (2) age-standardized death rates; (3) survival probabilities at 6 months, 1, 2, and 3 years following first hemorrhagic or ischemic stroke. Methods- Within the population-based Rotterdam Study between 1991 and 2015, we assessed time trends in survival among 162 with first-ever hemorrhagic and 988 patients with first-ever ischemic stroke across 3 time periods (1991-1998; 1999-2007; 2008-2015) using time-varying Cox regression model and calculated age-standardized death rates according to the European 2010 census population. Results- In the hemorrhagic stroke group, a total of 144 deaths occurred during 386 person-years. Following a hemorrhagic stroke, we observed similar mortality rates over the years with 30 per 100 person-years in 2015 compared with 25/100 person-years in 1991. Similarly, compared with the earliest study period (1991-1998), mortality rates remained unchanged in the latest study period (2008-2015; hazard ratio, 0.97 [95% CI, 0.61-1.57]; P=0.93). In the ischemic stroke group, a total of 711 deaths occurred during 4897 person-years. We observed a decline in mortality rates in 2015 (11 per 100 person-years) compared with 1991 (29/100 person-years). This translated to favorable trends in the latest study period 2008 to 2015 (hazard ratio, 0.71 [95% CI, 0.56-0.90]; P<0.01). Conclusions- Survival following ischemic stroke has improved over the past decade, while no change was observed in survival following hemorrhagic stroke.

Sex differences in the genetic predictors of Alzheimer's pathology.

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways.

INTRODUCTION: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. METHODS: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. RESULTS: Suggestive associations (P < 1.0 × 10-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10-7 ), chromosome 7 (rs60465337,P = 4.06 × 10-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10-7 ) and 4 (rs1304013, P = 7.73 × 10-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. DISCUSSION: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.

Variation in blood pressure and long-term risk of dementia: A population-based cohort study.

BACKGROUND: Variation in blood pressure may relate to dementia risk via autonomic disturbance or hemodynamic mechanisms, but the long-term associations are unclear. We aimed to determine whether blood pressure variation over a period of years, considering both magnitude and direction, is associated with the risk of dementia. METHODS AND FINDINGS: In a prospective cohort study ongoing since 1989 in the Netherlands, 5,273 dementia-free participants (58.1% women; mean [SD] age, 67.6 [8.0] years) were included. As of 2016, 1,059 dementia cases occurred during a median follow-up of 14.6 years. Absolute variation in systolic blood pressure (SBP) was assessed as the absolute difference in SBP divided by the mean over two sequential visits every 4.2 (median) years, with the first quantile set as the reference level. The direction was the rise or fall in SBP, with the third quantile set as the reference level. We estimated the risk of dementia in relation to SBP variation measured at different time windows (i.e., at least 0, 5, 10, and 15 years) prior to dementia diagnosis, with adjustments for age, sex, education, apolipoprotein E (APOE) genotype, vascular risk factors, and history of cardiovascular disease. We repeated the above analysis for variation in diastolic blood pressure (DBP). A large SBP variation was associated with an increased dementia risk, which became more pronounced with longer intervals between the assessment of SBP variation and the diagnosis of dementia. The hazard ratio (HR) associated with large variation (the highest quintile) increased from 1.08 (95% confidence interval [CI] 0.88-1.34, P = 0.337) for risk within 5 years of SBP variation measurement to 3.13 (95% CI 2.05-4.77; P < 0.001) for risk after at least 15 years since the measurement of SBP variation. The increased long-term risk was associated with both large rises (HR for the highest quintile, 3.31 [95% CI 2.11-5.18], P < 0.001) and large falls in SBP (HR for the lowest quintile, 2.20 [95% CI 1.33-3.63], P = 0.002), whereas the higher short-term risk was only associated with large falls in SBP (HR, 1.21 [95% CI 1.00-1.48], P = 0.017). Similar findings were observed for variation in DBP. Despite our assessment of major confounders, potential residual confounding is possible, and the findings on blood pressure variability over periods of years may not be generalizable to variability over periods of days and other shorter periods. CONCLUSIONS: Results of this study showed that a large blood pressure variation over a period of years was associated with an increased long-term risk of dementia. The association between blood pressure variation and dementia appears most pronounced when this variation occurred long before the diagnosis. An elevated long-term risk of dementia was observed with both a large rise and fall in blood pressure.

Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells.

Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-ß 42 (Aß42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aß42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aß42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (ß = - 0.03, p = 4.25 × 10-8; ß = 0.03, p = 3.97 × 10-8) than males (ß = - 0.02, p = 0.009; ß = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (ß = 0.05, p = 4.57 × 10-10) compared to males (ß = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.