Citations

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Abstract Background : Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods : Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE -ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results : Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion : TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

Abstract INTRODUCTION Repetitive head impacts (RHI) from contact sports may cause a unique pattern of white matter hyperintensities (WMH) on T2‐weighted fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), termed RHI‐associated WMH (RHI‐WMH). These lesions are punctate, circular, and located at the gray–white matter boundary, an area vulnerable to trauma‐related damage. METHODS We investigated the association of RHI with these lesions in two aging cohorts: (1) former American football players versus asymptomatic unexposed men and (2) individuals with RHI from various contact sports versus non‐RHI participants. RHI‐WMH were assessed using visual ratings and a novel automated quantification pipeline. RESULTS Individuals with RHI had greater RHI‐WMH by both detection methods in both cohorts. RHI‐WMH were associated with plasma neurofilament light and p‐tau231, and flortaucipir positron emission tomography (PET) uptake. DISCUSSION RHI‐WMH may represent a new supportive biomarker for the detection of RHI‐related neuropathologies later in life.

Abstract Objective: Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. Method: Former American football players ( n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ 1-42 , p-tau 181 , t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. Results: Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. Conclusions: SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only postmortem , but can present with an array of cognitive, behavioral, mood, and motor symptoms. However, traumatic brain injury is also associated with increased risk of Alzheimer’s disease (AD) and may lead to comorbid neuropathology. Characterization of the in vivo biomarkers of CTE is a necessary next step to facilitate accurate diagnoses. We examined the profile of cerebrospinal fluid (CSF) biomarkers of amyloid-β, total tau (tTau), and phospho-tau (pTau) in a cohort of former professional (PRO, n = 100) and college (COL, n = 40) football players at high risk of CTE compared to asymptomatic unexposed controls (UE, n = 43). CSF was collected under controlled conditions using collection, processing, and cryostorage kits provided by the DIAGNOSE CTE Research Project Biomarker Core, and concentrations of Aβ 40 , Aβ 42 , tTau, and pTau (pTau 181 , pTau 217 , pTau 231 ) were measured at the University of Gothenburg, Sweden, using immunoassays. Associations between CSF biomarker levels with football history, and diagnosis of traumatic encephalopathy syndrome (TES) were examined using linear regression, and corrected for age, education, APOE -ε4 allele status, race, and body mass index. Our analysis revealed that football exposure affected both CSF Aβ 40 ( p = 0.039) and Aβ 42 ( p = 0.038), particularly among those under 60 years of age in the PRO compared to the UE exposure group. Among former football players, estimates of RHI exposure were not generally associated with CSF Aβ, tTau, and pTau biomarker levels. CSF Aβ 40 ( p = 0.0041) and Aβ 42 ( p = 0.011) were lower in former football players with TES diagnosis compared to unexposed participants, although CSF Aβ, tTau, and pTau biomarker levels did not differ between former players with and without a TES diagnosis. Among former football players, reduced CSF Aβ 40 ( p = 0.011) and Aβ 42 (p = 6e-04) were observed in those with cognitive impairment compared to those with neurobehavioral dysregulation. The findings of significant associations of reduced CSF Aβ levels with RHI in elite football players are in line with recent postmortem studies; however, the lack of relationship with CSF tTau and pTau species observed to be altered in the setting of AD suggests that the pathological features of CTE reflected in fluid biomarkers are complex and require further study. The overlapping comorbid age-dependent features of neurodegeneration that occur in those at risk for CTE suggest that tau pathology in CTE is not reliably reflected by currently available fluid biomarkers and that the use of multiple biomarkers related to the compound characteristics of CTE may be required for early detection.

Abstract Background In vivo biomarkers that can detect long‐term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p ‐tau217 as a potential biomarker for CTE p ‐tau pathology, and examined the concordance between plasma p ‐tau217 and Aβ pathology in an at‐risk for CTE sample. Method The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F‐florbetapir (Aβ+=SUVR≥1.10), and 18F‐flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p ‐tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post‐mortem tissue. ANCOVA examined group differences in p ‐tau217 (football vs controls; TES‐CTE no, TES‐CTE suggestive, TES‐CTE possible/probable). Multivariable regression models tested associations between p ‐tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4 . Result Sample characteristics are in Table 1. p ‐tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=‐0.217, p = 0.005). There were no group differences in Aβ‐PET SUVR. No differences were found across TES‐CTE certainty levels. In football players, higher p ‐tau217 was associated with higher Aβ‐PET SUVR (B=1.380, 95%CI[0.597‐2.155], p = 0.001) but not when Aβ+ ( n = 17) participants and those with kidney/liver disease ( n = 5) were excluded. Aβ+ participants had the highest p ‐tau217 (Figure 1). When compared against Aβ‐PET, several false Aβ‐positives (high p ‐tau217, Aβ‐) were identified, including one extreme outlier (assay related) and a cluster of Aβ‐ participants with p ‐tau217 between 0.60–1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p ‐tau217 outliers had autopsy‐confirmed CTE stage III (AD‐, Table 2). Of the remaining donors, all were AD‐ and four had CTE (stages II‐IV) with ptau217 between 0.125‐0.449. Conclusion Plasma p ‐tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at‐risk for CTE sample, p ‐tau217 and Aβ‐PET were associated at the group level. At the individual level, false Aβ‐positives (and negatives) existed, including Aβ‐ participants with high p ‐tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N‐terminal binding in p ‐tau assays.

Abstract Background Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI). Autopsy studies show that RHI influences risk for other later‐life neuropathologies, particularly white matter and vascular injury. We have observed a unique pattern of white matter hyperintensities (WMH) on FLAIR MRI in people exposed to RHI (RHI‐WMH) characterized by small, discrete lesions near the depths of sulci (Figure 1a). The objective of this study was to characterize this pattern empirically in former American football players and to investigate neuropathology co‐localizing with the WMH. Method The sample included 164 male former football players ( n = 111 professional, n = 53 college) and 55 asymptomatic males without RHI from the DIAGNOSE CTE Project (Table 1). Visual ratings of WMH blind to the participant's RHI and clinical status were conducted to count lesions that were a.) within 1.0cm of the gray/white matter boundary, b.) as bright as the cortex, c.) spherical and d.) <1.0cm in size. ANCOVA compared groups on total number of WMH adjusted for age and vascular risk factors. We selected one individual (former professional player) with the typical RHI‐WMH pattern and who donated their brain for neuropathological examination. Guided by in vivo MRI, ex vivo MRI was done to locate the WMH near the depths of the sulci in the tissue. Tissue sections were tested for phosphorylated tau immunoreactivity and reactive astrocytes and microglia in areas surrounding the lesion seen on MRI. Result Number of RHI‐WMH was greater in football players compared to controls ( p = 0.007) (Figure 1b). Number of RHI‐WMH was greater in former professional players compared to controls ( p = 0.001) but not compared to the college players ( p = 0.983). In the neuropathology case study, we located the punctate RHI‐WMH on ex vivo MRI. Immunostaining revealed that the RHI‐WMH was adjacent to a sulcus with the pathognomonic CTE p ‐tau lesion and was characterized by myelin pallor, dense GFAP‐positive glial scarring, and increased total and activated microglia (Figure 2). Conclusion We provide empirical support for exposure to RHI as potentially leading to a unique pattern of WMH. Importantly, histopathological evidence showed that the RHI‐WMH co‐localized with RHI and CTE‐related neuropathologies at the depths of the sulci.

Abstract Background Exposure to repetitive head impacts (RHI) is associated with developing chronic traumatic encephalopathy (CTE) neuropathology. Cognitive and behavioral symptoms have been associated with CTE neuropathology, but efforts to define the specific clinical syndrome are ongoing. This study characterizes the current use of centrally acting medications (CAMs), chronic pain, and number of orthopedic surgeries in former American football players and evaluates for associations with cognitive and behavioral symptoms. Methods This study analyzed data from the DIAGNOSE CTE Research Project, which includes 120 former professional football players, 60 collegiate football players, and 56 asymptomatic men without history of RHI. Medical history was obtained by self‐report, and participants completed the Montreal Cognitive Assessment (MoCA), Brief Pain Inventory, Barratt Impulsiveness Scale‐11 (BIS‐11), BRIEF‐A Behavioral Regulation Index (BRI), Beck Depression Inventory‐II (BDI‐II), Beck Anxiety Index (BAI), and Brown‐Goodwin Lifetime History of Aggression adulthood score (BGLHA). Logistic regression assessed the association of CAMs, average pain score, and orthopedic surgeries on the cognitive impairment and neurobehavioral dysregulation components of the NINDS traumatic encephalopathy syndrome (TES) research criteria, in former American football players. Linear regression assessed the associations with MoCA and behavioral scales. Models were adjusted for age, education, race, and years of football played. Results Tables 1 and 2 describe the sample and CAM burden. More orthopedic surgeries, CAMs, and higher average pain were observed in former American football players. Number of CAMs was associated with neurobehavioral dysregulation (OR = 2.18), lower MoCA (β = ‐0.47), and higher BIS‐11 (β = 2.23), BDI‐II (β = 2.01), BRI (β = 3.71), BAI (β = 2.04), and BGLHA (β = 0.68) scores. Higher average pain was associated with neurobehavioral dysregulation (OR = 1.57) and higher BIS‐11 (β = 2.20), BDI‐II (β = 1.98), BRI (β = 2.20), BAI (β = 1.84), and BGLHA (β = 0.52) scores. No associations were observed with orthopedic surgeries. Conclusions In former American football players, the number of CAMs and higher average pain were associated with neurobehavioral dysregulation. No associations were observed with diagnosis of cognitive impairment by TES criteria, though the number of CAMs was associated with decreased MoCA.