Genetic Predisposition To Disease Research Articles

Effects of Alzheimer’s disease genetic risk on brain morphometric development in three multiple‐ancestry pediatric datasets

AbstractBackgroundFew prior studies have investigated whether genetic risk for Alzheimer’s disease (AD) can manifest through altered neurodevelopment of AD‐vulnerable brain regions. This pre‐registered study tests the effects of AD polygenic risk on morphometric neurodevelopment across 3 large datasets totaling 8,364 youths aged 3‐22 (Table 1)MethodPolygenic risk score (PRS) was calculated using PRS‐CS software, with summary scores from Kunkle et al. (2021) for African ancestry individuals (AA) and Jansen et al. (2019) for European ancestry individuals (EA). For EA only, PRS were calculated with (PRS‐APOE+) and without (PRS‐APOE‐) the APOE locus included. All individuals had T1‐weighted MRI processed with FreeSurfer that passed quality assessment checks. ComBAT was used to harmonize sites within‐cohort. Primary analyses investigated effects of PRS, age and their interaction on bilateral hippocampal volume and AD MetaROI cortical thickness using generalized additive models. Age interactions were not evaluated in ABCD due to limited age range. Exploratory analysis examined effects of age and PRS on cortical thickness, volume, surface area and subcortical volume across Desikan‐Killiany regions, adjusting for multiple comparisons (FDR). For exploratory analyses only, ABCD was split into training and test sets. All analyses were conducted for EA and AA separately; sex, total intracranial volume, image quality (Euler number) and ten genetic principal components were included as model covariates.ResultTable 1 summarizes primary results. Hippocampal volume increased with age in 3/6 datasets, while MetaROI thickness decreased with age in all datasets. Surprisingly, increased PRS was associated with larger hippocampi in three datasets. In one dataset only, greater PRS was associated with increased metaROI thickness (Fig 1). 2/3 AA datasets showed age*PRS interactions on hippocampal volume, but in opposite directions. An age*PRS interaction on metaROI thickness was found in one dataset (Fig. 2A‐C). For exploratory analyses, no regions survived multiple comparisons for any contrast in 5/6 datasets; APOE only PRS was associated with larger supramarginal surface area in one dataset (Fig 2E). Effects were not correlated across studies (Fig 2D)ConclusionThis large, pre‐registered study provides little evidence that AD genetic risk manifests during pediatric brain morphometric development.

Multivariate white matter differences links to cognition in individuals with family history of Alzheimer’s disease and APOE4 genetic risk

AbstractBackgroundGrowing evidence suggests Alzheimer’s disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches.MethodThe MRI data of 105 older adults with a family history of AD from the PREVENT‐AD dataset were analysed. Forty six of these individuals had the APOE4‐3 genotype (greater risk of developing AD), while 59 subjects had the APOE3‐3 genotype (normal risk). Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (Fig1 b‐c). We computed the voxel‐wise Mahalanobis distance (D2) in WM between APOE4‐3 individuals and a reference group (APOE3‐3) (Fig1). D2 is a multivariate measure that combines several MRI metrics, accounting for their covariance, and yielding a score indicative of the degree of abnormality at each WM voxel (Fig2). Associations between WM D2 and cognitive performance were then investigated (Fig3). Independent component analysis (ICA) was performed on spatial dimensions and linear regression analyses were conducted between D2 in ICA components and scores on items of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We then extracted the contribution of each MRI feature to D2 in the regions where significant associations were found.ResultA significant negative association (R = ‐0.36, p = 0.014) was found between D2 in a component corresponding to the splenium of the corpus callosum (CC) and scores on RBANS‐immediate memory (Fig3), indicating a link between a greater degree of WM abnormality and poorer performance. Proton density (MPM_PD) and longitudinal relaxation rate (MPM_R1), potentially indicative of WM loss, contributed most to D2 in this region.ConclusionOur findings suggest that microstructural alterations in the posterior part of the CC may play a role in memory deficit in older adults who are at greater risk of developing AD. This is in line with other studies that showed a link between CC degeneration and memory impairments in early AD stages.1 1. Qiu et al. (2016). Inter‐hemispheric dysconnectivity in AD and aMCI. Sci.Rep.

Multivariate white matter differences links to cognition in individuals with family history of Alzheimer’s disease and APOE4 genetic risk

AbstractBackgroundGrowing evidence suggests Alzheimer’s disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches.MethodThe MRI data of 105 older adults with a family history of AD from the PREVENT‐AD dataset were analysed. Forty six of these individuals had the APOE4‐3 genotype (greater risk of developing AD), while 59 subjects had the APOE3‐3 genotype (normal risk). Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (Fig1 b‐c). We computed the voxel‐wise Mahalanobis distance (D2) in WM between APOE4‐3 individuals and a reference group (APOE3‐3) (Fig1). D2 is a multivariate measure that combines several MRI metrics, accounting for their covariance, and yielding a score indicative of the degree of abnormality at each WM voxel (Fig2). Associations between WM D2 and cognitive performance were then investigated (Fig3). Independent component analysis (ICA) was performed on spatial dimensions and linear regression analyses were conducted between D2 in ICA components and scores on items of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We then extracted the contribution of each MRI feature to D2 in the regions where significant associations were found.ResultA significant negative association (R = ‐0.36, p = 0.014) was found between D2 in a component corresponding to the splenium of the corpus callosum (CC) and scores on RBANS‐immediate memory (Fig3), indicating a link between a greater degree of WM abnormality and poorer performance. Proton density (MPM_PD) and longitudinal relaxation rate (MPM_R1), potentially indicative of WM loss, contributed most to D2 in this region.ConclusionOur findings suggest that microstructural alterations in the posterior part of the CC may play a role in memory deficit in older adults who are at greater risk of developing AD. This is in line with other studies that showed a link between CC degeneration and memory impairments in early AD stages.1 1. Qiu et al. (2016). Inter‐hemispheric dysconnectivity in AD and aMCI. Sci.Rep.

Alzheimer’s disease genetic risk score and neuroimaging biomarkers in the FINGER multidomain lifestyle randomized controlled trial

AbstractBackgroundA comprehensive genetic risk score (GRS) for Alzheimer’s disease (AD‐GRS) was recently developed based on 83 genome‐wide significant variants (Bellenguez et al. Nat Genet. 2022), excluding APOE. This study investigated AD‐GRS and APOE4 in relation to neuroimaging biomarkers in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER).MethodFINGER included at‐risk individuals without dementia from the general population, aged 60‐77 years. Participants were randomized to either 2‐year multidomain lifestyle‐based intervention or regular health advice. At baseline, 132 participants underwent MRI scans, of which 48 also underwent PET scans (PiB/FDG). Two years later, 112 and 39 repeated their scans, respectively. MRI measures included hippocampus, total gray matter and white matter lesion volumes, and cortical thickness. Composite indices were calculated for PiB and FDG uptake values. We report preliminary results from linear regressions (standardized β‐coefficients, p‐values).ResultAt baseline, higher AD‐GRS tended to relate to lower hippocampus volume (β = ‐0.15, p = 0.07) and FDG‐PET index (β = ‐0.23, p = 0.08); this remained after APOE adjustment. APOE4 was associated with lower hippocampus volume (β = ‐0.27, p = 0.001) and higher PiB‐PET index (β = 0.48, p = 0.001). Overall, AD‐GRS was not related to the 2‐year change in neuroimaging measures, while APOE4 was related to decreasing hippocampus (β = ‐0.27, p = 0.01) and total gray matter (β = ‐0.25, p = 0.01) volumes, and cortical thickness (β = ‐0.28, p = 0.003). There were no significant interactions of AD‐GRS or APOE4 with randomization group in relation to neuroimaging changes. However, in analyses stratified by AD‐GRS (below vs above median), there was less PIB index increase in intervention vs control in the higher AD‐GRS group (β = ‐0.60, p = 0.03); no intervention control‐difference was found in the lower AD‐GRS group (β = 0.04, p = 0.86). In analyses stratified by APOE4, PIB index tended to increase less in intervention vs control in non‐carriers (β = ‐0.38, p = 0.078), with no intervention‐control difference in carriers (β = 0.05, p = 0.89).ConclusionUnlike APOE4, AD‐GRS was not related to 2‐year change in AD‐related neuroimaging measures. AD‐GRS and APOE4 may also have very different impact on potential intervention effects on amyloid, i.e. less accumulation in the higher‐risk group (AD‐GRS) vs lower‐risk group (APOE). However, these exploratory findings need to be verified in larger studies.

Skipping of FCER1G Exon 2 Is Common in Human Brain But Not Associated with the Alzheimer's Disease Genetic Risk Factor rs2070902.

Understanding the mechanisms whereby genetic variants influence the risk of Alzheimer's disease (AD) may provide insights into treatments that could reduce AD risk. Here, we sought to test the hypothesis that a single nucleotide polymorphism (SNP) associated with AD risk, rs2070902, influences splicing of FCER1G exon 2. AD and non-AD brain samples were analyzed for FCER1G expression by genotyping, immunohistochemistry, immunofluorescence, and qPCR. The protein encoded by FCER1G, FcRγ, is robustly expressed in microglia in both AD and non-AD brain. The FCER1G isoform lacking exon 2 (D2-FCER1G) was readily detectable. Moreover, the proportion of FCER1G expressed as this isoform was increased in brains with high AD neuropathology. However, the proportion of FCER1G expressed as the D2-FCER1G isoform was not associated with rs2070902 genotype. In summary, the proportion of FCER1G expressed as the D2-FCER1G isoform is increased with AD neuropathology but is not associated with rs2070902.

RADAR Trial: MRD Response Adapted Trial for Newly Diagnosed Transplant Eligible Myeloma Patients

Background: Achieving and sustaining minimal disease negativity improves clinical outcomes in newly diagnosed transplant eligible myeloma (NDMM). Outcomes in NDMM are influenced by levels of minimal residual disease (MRD) post therapy and genetic risk by FISH or molecular profiling prior to therapy. Trials exploring response adapted post transplant strategies using MRD as a prognostic tool are going. We provide an update of the current UK-MRA RADAR study. Study Design/Methods: The UK-MRA RADAR study is a national multicentre risk adapted response guided multiarm multistage (MAMS) phase II/III trial which will recruit 1400 patients with NDMM eligible for ASCT. Eligible patients receive induction with 4 cycles of RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. Patients with high-risk disease receive Isatuximab in addition to RCyBorD during induction. Genetic risk classification is performed using standard of care FISH testing at local sites. Participants enter the standard or high risk pathway based on presence of atleast two markers: t(4;14), t(14;16), t(14;20), del(17p), del(1p) and gain (1q21). MRD analysis in RADAR uses a multiparametric flow cytometry panel with CD319 and Cd229 used to augment post-isatuximab sample analysis at a central laboratory, with negativity defined at threshold of 10 -5(Figure 1). For standard risk patients, the study addresses two pivotal MRD-related questions: 1) For those with sustained MRD negativity after 12 months of isatuximab maintenance, can treatment be stopped safely to allow patients a treatment-free interval thereby reducing treatment burden? 2) For patients with persistent detectable disease after ASCT, does intensification of consolidation and maintenance therapy augment conversion to MRD negativity compared to lenalidomide maintenance? High risk participants receive intensified consolidation and maintenance regimens post_ASCT aligned to OPTIMUM/MUKnine ( NCT03188172). A further amendment is planned to explore the activity of a BCMA bispecific antibody in high risk patients pre and post transplant. It is hypothesised this will improve both depth (MRD negativity) and ability to sustain response (PFS). Feasibility and benefits of multimodal MRD incorporating imaging and blood-based testing will be tested in the new high risk pathway. In RADAR, we will also gather information on how patients respond to receiving information about their genetic risk assignment and treatment response (MRD). This is a unique opportunity to understand the patients perspective on personalised medicine, which has implications for implementation in clinical care, and future trial design. Trial Progress. RADAR opened to recruitment in May 2021 and is currently recruiting across 87 hospital sites with a further 16 sites in set up. 504 patients have been recruited; 87 are classified as high risk on FISH analysis ( 375 standard risk, 15 unable to determine, 19TBC, 8 withdrawn before FISH analysis). 220 have reached D+100 MRD assessment. Trackable phenotypes were available in 98.2% of patients. Discussion: The RADAR study simultaneously tests escalation and de-escalation strategies, according to disease response, and using MRD to guide post transplant therapy in NDMM patients. Use of central flow cytometry laboratory for MRD has proven feasible in patients to date. Recruitment is on target and outcomes will provide RCT-level evidence for the adaptive use of MRD in treatment allocation and intensification post transplant. The platform design enables adaptation with ability to test new strategies for high risk patients and for standard risk patients who are MRD positive post-transplant. Funding This trial is funded by Cancer Research UK (C9203/A24078), Sanofi Genzyme and Celgene : A BMS company. Sanofi Genzyme and Celgene: A BMS company provide study drug and unrestricted educational grants to support study coordination. This work is also supported by Core Clinical trials unit infrastructure from Cancer Research UK ( C7852/A25447). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the abstract

Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P<0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88). We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Dietary inflammatory index, genetic susceptibility and risk of incident dementia: a prospective cohort study from UK biobank.

Genetic factors, diet and inflammation are associated with the development of dementia. In this study, we aimed at evaluating the impact of the dietary inflammatory index (DII) scores and genetic susceptibility on the development of dementia. This prospective study involved 207,301 participants aged between 39 and 72years from UK biobank. A web-based 24-h dietary questionnaire was collected at least once from participants between 2006 and 2012. The DII was calculated based on inflammatory effect score of nutrients. Individual AD-GRS (Alzheimer's disease genetic risk score) was calculated. Incident dementia was ascertained through hospital or death records. Of all 207,301 participants, 468 incident cases of all-cause dementia (165 AD, 91 VD and 26 FTD) were reported during a follow-up period of 11.4years. The participants in the highest quintile (Q) of DII scores reported a higher risk for all-cause dementia (Q5 vs. Q3, hazard ratio (HR) = 1.702; 95% CI: 1.285-2.255) and VD (Q5 vs. Q3, HR = 2.266, 95% CI: 1.133-4.531) compared to participants in the Q3. Besides, when compared with the Q1, there was a higher risk for AD in the subjects of Q5 (Q5 vs. Q1, HR = 1.590; 95% CI: 1.004-2.519). There was a non-linear relationship between DII score and all-cause incidence (P for non-linear = 0.038) by restricted cubic splines. Subgroup analysis found that the increased risk for all-cause dementia and AD was more pronounced in the elderly, women, and higher educated population. Cox regression models indicated that compared with the participants who had a low AD-GRS risk and in the lowest tertile of DII, participants had a high AD-GRS and the highest tertile of DII were associated with a higher risk of AD (HR = 1.757, 95% CI: 1.082-2.855, P = 0.023). The DII scores were independently associated with an augmented risk for all-cause dementia, AD and VD. Additionally, high AD-GRS with higher DII scores was significantly associated with ahigher risk of AD.

Genetic and Environmental Factors and Cardiovascular Disease Risk in Adolescents

Cardiovascular risk factors in youth have been associated with future cardiovascular disease (CVD), but conventional observational studies are vulnerable to genetic and environmental confounding. To examine the role of genetic and environmental factors shared by full siblings in the association of adolescent cardiovascular risk factors with future CVD. This is a nationwide cohort study with full sibling comparisons. All men who underwent mandatory military conscription examinations in Sweden between 1972 and 1995 were followed up until December 31, 2016. Data analysis was performed from May 1 to November 10, 2022. Body mass index (BMI), cardiorespiratory fitness, blood pressure, handgrip strength, and a combined risk z score in late adolescence. The primary outcome was fatal or nonfatal CVD, as recorded in the National Inpatient Register or the Cause of Death Register before 2017. A total of 1 138 833 men (mean [SD] age, 18.3 [0.8] years), of whom 463 995 were full brothers, were followed up for a median (IQR) of 32.1 (26.7-37.7) years, during which 48 606 experienced a CVD outcome (18 598 among full brothers). All risk factors were associated with CVD, but the effect of controlling for unobserved genetic and environmental factors shared by full siblings varied. In the sibling analysis, hazard ratios for CVD (top vs bottom decile) were 2.10 (95% CI, 1.90-2.32) for BMI, 0.77 (95% CI, 0.68-0.88) for cardiorespiratory fitness, 1.45 (95% CI, 1.32-1.60) for systolic blood pressure, 0.90 (95% CI, 0.82-0.99) for handgrip strength, and 2.19 (95% CI, 1.96-2.46) for the combined z score. The percentage attenuation in these hazard ratios in the sibling vs total cohort analysis ranged from 1.1% for handgrip strength to 40.0% for cardiorespiratory fitness. Consequently, in the sibling analysis, the difference in cumulative CVD incidence at age 60 years (top vs bottom decile) was 7.2% (95% CI, 5.9%-8.6%) for BMI and 1.8% (95% CI, 1.0%-2.5%) for cardiorespiratory fitness. Similarly, in the sibling analysis, hypothetically shifting everyone in the worst deciles of BMI to the middle decile would prevent 14.9% of CVD at age 60 years, whereas the corresponding number for cardiorespiratory fitness was 5.3%. In this Swedish national cohort study, cardiovascular risk factors in late adolescence, especially a high BMI, were important targets for CVD prevention, independently of unobserved genetic and environmental factors shared by full siblings. However, the role of adolescent cardiorespiratory fitness in CVD may have been overstated by conventional observational studies.

Advancing the communication of genetic risk for cardiometabolic diseases: a critical interpretive synthesis

BackgroundGenetics play an important role in risk for cardiometabolic diseases—including type 2 diabetes, cardiovascular disease and obesity. Existing research has explored the clinical utility of genetic risk tools such as polygenic risk scores—and whether interventions communicating genetic risk information using these tools can impact on individuals’ cognitive appraisals of disease risk and/or preventative health behaviours. Previous systematic reviews suggest mixed results. To expand current understanding and address knowledge gaps, we undertook an interpretive, reflexive method of evidence synthesis—questioning the theoretical basis behind current interventions that communicate genetic risk information and exploring how the effects of genetic risk tools can be fully harnessed for cardiometabolic diseases.MethodsWe obtained 189 records from a combination of database, website and grey literature searches—supplemented with reference chaining and expert subject knowledge within the review team. Using pre-defined critical interpretive synthesis methods, quantitative and qualitative evidence was synthesised and critiqued alongside theoretical understanding from surrounding fields of behavioural and social sciences.FindingsExisting interventions communicating genetic risk information focus predominantly on the “self”, targeting individual-level cognitive appraisals, such as perceived risk and perceived behavioural control. This approach risks neglecting the role of contextual factors and upstream determinants that can reinforce individuals’ interpretations of risk. It also assumes target populations to embody an “ascetic subject of compliance”—the idea of a patient who strives to comply diligently with professional medical advice, logically and rationally adopting any recommended lifestyle changes. We developed a synthesising argument—“beyond the ascetic subject of compliance”—grounded in three major limitations of this perspective: (1) difficulty applying existing theories/models to diverse populations, (2) the role of familial variables and (3) the need for a life course perspective.ConclusionsInterventions communicating genetic risk information should account for wider influences that can affect individuals’ responses to risk at different levels—including through interactions with their family systems, socio-cultural environments and wider health provision.Protocol registrationPROSPERO CRD42021289269

Association of epistatic effects of MTHFR, ACE, APOB, and APOE gene polymorphisms with the risk of myocardial infarction and unstable angina in Egyptian patients

Despite remarkable discoveries in the genetic susceptibility of coronary artery disease (CAD), a large part of heritability awaits identification. Epistasis or gene‐gene interaction has a profound influence on CAD and might contribute to its missed genetic variability; however, this impact was largely unexplored. Here, we appraised the associations of gene-gene interactions and haplotypes of five polymorphisms, namely methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, angiotensin converting enzyme (ACE) insertion/deletion (I/D), apolipoprotein B (APOB) R3500Q, and apolipoprotein E (APOE) ε4 with the risk of myocardial infarction (MI) and unstable angina (UA). Gene-environment interactions with traditional risk factors and clinical data were also scrutinized. This study recruited 100 MI, 50 UA patients, and 100 apparently healthy controls. Logistic regression models were employed in association analyses. We remarked that the single locus effect of individual polymorphisms was relatively weak; however, a magnified effect of their combination via gene-gene interaction may predict MI risk after adjustment for multiple comparisons. Only MTHFR C677T, ACE I/D, and APOB R5300Q were associated with the risk of UA, and the ACE I/D-R3500Q interaction posed a decreased UA risk. APOB R3500Q was in strong linkage disequilibrium with MTHFR C677T, ACE I/D, and APE ε4 polymorphisms. The TCDGε3, CADGε4, and TADGε4-C677T-A1298C-ACE I/D-R3500Q-APOE haplotypes were associated with escalating MI risk, while the CDG or CIG-C677T-ACE I/D-R3500Q haplotype was highly protective against UA risk compared to controls. Interestingly, the CADGε4 and CAIGε3 haplotypes were strongly associated with the presence of diabetes and hypertension, respectively in MI patients; both haplotypes stratified patients according to the ECHO results. In UA, the CDG haplotype was negatively associated with the presence of diabetes or dilated heart. Conclusively, our results advocate that a stronger combined effect of polymorphisms in MTHFR, ACE, APOB, and APOE genes via gene-gene and gene-environment interactions might help in risk stratification of MI and UA patients.

Sickle Cell Trait and Mortality Risk: California Newborn Screening Longitudinal Follow up of Births 1991-2013

Sickle cell trait (SCT) represents a significant global public health issue with approximately three million carriers in United States and over 300 million worldwide. Yet, the mortality risk of sickle cell trait is unknown. Early anecdotal research on SCT led to social bias and stigmatization of individuals with the trait, which unfortunately hindered the conduct of well-designed morbidity and mortality studies in this population. This resulted in SCT being perceived as a benign asymptomatic condition that protects against malaria and its importance confined to the genetic risk for sickle cell disease. As research in SCT gradually increased, it became evident that SCT is indeed a risk factor for several complications including exertional related rhabdomyolysis, chronic kidney disease, venous thromboembolism, and other morbidities. SCT red cells in abnormal physiologic conditions sickle and can cause morbidity and mortality. Additionally, SCT could potentially influence the severity of various illnesses. Individuals with SCT commonly experience hyposthenuria and are at risk for dehydration which could further exacerbate the severity of many medical problems. It is essential to determine if SCT is a risk factor for overall mortality. This study is the first population-level investigation of all-cause mortality risk for individuals with SCT. This longitudinal analysis included all live births with SCT identified by the California newborn screening (NBS) program between 1991 and 2013. For each newborn with SCT, three matched controls with hemoglobin AA were randomly selected from the NBS cohort. Controls were matched to SCT cases on year of birth, sex, race/ethnicity, and city of birth. SCT records with incomplete data for the matched variables or those with fewer than three matching controls were excluded from the analysis. SCT cases and controls were linked to all deaths within the state of California for the years 1991-2013 using statewide death data files. Cox proportional hazard ratios and 95% confidence intervals were calculated to compare mortality between individuals with SCT and controls with hemoglobin AA, including stratified by age (&amp;lt;1, 1-4, 5-14, 15-22). The study identified 94,240 live births with SCT (Table 1), which represents 96% of all SCT live births identified by the California NBS program in 1991-2013, and 282,720 matched controls. Between 1991 to 2013, there were 693 (0.74%) SCT deaths and 1,910 (0.68%) control deaths. Those with SCT had an increased mortality hazard rate compared to those with hemoglobin AA (11% higher, p=0.015). When stratified by age, mortality hazard rates in the age strata 1-4 years (44% higher, p= .0009) and 5-14 years (48% higher, p=.0047) were higher than those with hemoglobin AA (Table 2). These age strata describe periods of follow up time, and an individual may appear in more than one stratum. Mortality hazard ratios calculated for each age stratum are conditional to individuals surviving to the starting age of that stratum. This analysis of mortality risk for a cohort of over 94,000 infants identified with SCT is the first of its kind and adds important information to the assessment of health risk for the condition. This is the first study that reports a higher risk of mortality for children and young adults with SCT compared to those with hemoglobin AA. These findings highlight the need for comprehensive research, including confirming the study results in other longitudinal sickle cell trait population-level studies and investigation into underlying causes of death, to inform clinical management and counseling for individuals with SCT.

29 Smoking as a Risk Factor: Altered Brain Activity in Areas Associated with Preclinical Alzheimer's Disease

Objective:Those at genetic risk for Alzheimer's Disease (AD) because of the ApoE ε4 allele show differences in activation during olfactory information processing and memory in areas such as MTL structures, entorhinal cortex, posterior cingulate, precuneus, and inferior parietal lobule, suggesting preclinical AD neuropathology and olfactory impairment as a biomarker for predicting later AD onset (Murphy, 2019). The effects of smoking on AD have varied, with early studies suggesting either no effect or protective effects, and recent studies suggesting smoking as a risk factor for AD but with the need for further investigation in preclinical stages. Therefore, this study focused on olfaction and smoking as risk factors for preclinical AD neuropathology by studying differences in fMRI BOLD signal changes in smokers and nonsmokers during olfactory tasks.Participants and Methods:Archival data from 25 non-demented older adults recruited from the UCSD Alzheimer's Disease Research Center who completed an Assessment Scale-Cognitive Subscale (ADAS-Cog) and functional MRI scans at 3T, acquired during performance of an odor identification task. Odor Identification (OI) measured correct (hits) or incorrect (misses) identification of odors presented by an olfactometer to deliver the odor stimuli in short, controlled durations during fMRI scanning.Results:fMRI data were preprocessed using fMRIprep, smoothed at 4mm, scaled, and first level analyses were conducted using 3dDeconvolve in AFNI with time points corresponding to hits and misses as regressors. Differences between smokers and nonsmokers revealed smokers show a larger difference in BOLD signal change from hits minus misses at five significant clusters (p = 0.01 with the minimum cluster size [voxels] at 42). Peak areas of significant clusters included the right precuneus, right calcarine gyrus, left inferior parietal lobule, left superior parietal lobule, and left middle occipital gyrus. Analyses suggested a greater difference in activity between hits and misses in smokers compared to nonsmokers, with more activity during hits.Conclusions:Differences in activation between smokers and nonsmokers during an olfactory identification task, with greater activity in smokers during hits, suggests greater effort to correctly identify an odor. These findings of hyperactivation in areas (such as the precuneus and inferior parietal lobule) are similar to findings of hyperactivation during odor memory observed in studies of ε4 carriers during preclinical stages. Results provide further insight into smoking as a risk factor for AD. Moreover, results suggest the risk of smoking could potentially be reflected in altered activity in olfactory information processing networks in preclinical stages of AD. The study highlights the need for research to further understand the role smoking plays in the development of AD and the use of olfaction as a biomarker to aid in disease detection, prevention, and stage-associated treatments.

6 Exercise Induced Growth Factor Increases Directly and Indirectly Reduce Systemic Vascular Risk Parameters: Translational Project Amongst Midlife Human and Animal Models of Preclinical Alzheimer’s disease and Vascular Dementia

Objective:Using a humanized APOE3/4 (Alzheimer’s disease genetic risk allele) mouse model we investigated the potential modulating effects of exercise on systemic risk factors and the ability of this mouse model to translate to active or sedentary, midlife, human participants. We present preliminary results of an ongoing, translational pilot study.Participants and Methods:26 Midlife individuals, ages 40-65, were recruited from the community and dichotomized into active or sedentary groups following health screening and cognitive assessment. Blood samples were drawn from human participants for lipid assessment and other general health measures as well as peripheral growth factors concentrations (VEGF, BDNF and FGF21). Traditional, transgenic mouse models have helped the scientific community to understand biological mechanisms of Alzheimer’s disease (AD), but they do not develop significant neuronal loss, a hallmark of AD pathology. The MODEL-AD consortium has created a new “humanized” APOE4 model that has the human APOE4 allelic sequence in place of the mouse APOE gene; the model has shown known human phenotypes including deficits in cholesterol trafficking, amyloid clearance and BBB integrity. Of upmost importance, this model does not develop a full AD phenotype indicating that additional genetics and/or environmental factors are required as would be seen in human populations. We used males and females of this model to complete identical sedentary and active measures of each APOE genotype.Results:Lipid and general health marker assessment between mouse and human were similar and reproduced published literature. In both humans and mice we saw increased total cholesterol and HDL in active females and decreased total cholesterol and HDL in active males. We also saw similar relationships between APOE genotype, sex, and activity with regards to triglycerides. Although total cholesterol, HDL and LDL measures are the primary lipids needed to confirm or deny translation, other lipid measurements were not equivalent between the two models. Growth factor assessment in both species are also similar and reproduce published literature with regards to VEGF and BDNF as we see trending elevated levels in the active group. Less published on is the finding seen between active females and these elevated growth factors levels; our results indicates that although elevated as a result of exercise, this increase may be more prominent in females.Conclusions:Based on the results found here we conclude that The Jackson Laboratory’s humanized APOE3/4 mouse model is a translatable model of vascular dysfunction, dementia and Alzheimer’s disease. We also conclude that exercise modulates these aspects by growth factor activation and increases resulting in downstream effects that reduce peripheral vascular risk factors and therefore reduce the risk of Alzheimer’s disease as a result of neuroinflammation. Complete, APOE genotype results from human participants are still ongoing. Descriptive analysis is limited by human samples size.

Association Between Slow-Wave Sleep Loss and Incident Dementia

Slow-wave sleep (SWS) supports the aging brain in many ways, including facilitating the glymphatic clearance of proteins that aggregate in Alzheimer disease. However, the role of SWS in the development of dementia remains equivocal. To determine whether SWS loss with aging is associated with the risk of incident dementia and examine whether Alzheimer disease genetic risk or hippocampal volumes suggestive of early neurodegeneration were associated with SWS loss. This prospective cohort study included participants in the Framingham Heart Study who completed 2 overnight polysomnography (PSG) studies in the time periods 1995 to 1998 and 2001 to 2003. Additional criteria for individuals in this study sample were an age of 60 years or older and no dementia at the time of the second overnight PSG. Data analysis was performed from January 2020 to August 2023. Changes in SWS percentage measured across repeated overnight sleep studies over a mean of 5.2 years apart (range, 4.8-7.1 years). Risk of incident all-cause dementia adjudicated over 17 years of follow-up from the second PSG. From the 868 Framingham Heart Study participants who returned for a second PSG, this cohort included 346 participants with a mean age of 69 years (range, 60-87 years); 179 (52%) were female. Aging was associated with SWS loss across repeated overnight sleep studies (mean [SD] change, -0.6 [1.5%] per year; P < .001). Over the next 17 years of follow-up, there were 52 cases of incident dementia. In Cox regression models adjusted for age, sex, cohort, positivity for at least 1 APOE ε4 allele, smoking status, sleeping medication use, antidepressant use, and anxiolytic use, each percentage decrease in SWS per year was associated with a 27% increase in the risk of dementia (hazard ratio, 1.27; 95% CI, 1.06-1.54; P = .01). SWS loss with aging was accelerated in the presence of Alzheimer disease genetic risk (ie, APOE ε4 allele) but not hippocampal volumes measured proximal to the first PSG. This cohort study found that slow-wave sleep percentage declined with aging and Alzheimer disease genetic risk, with greater reductions associated with the risk of incident dementia. These findings suggest that SWS loss may be a modifiable dementia risk factor.

Cost-effectiveness analysis of Next generation sequencing tests in critically ill pediatric patients

Abstract Rare genetic diseases in the pediatric population constitute an urgent global public health issue; overall, more than 300 million people are affected worldwide. Next Generation Sequencing techniques, as Whole genome sequencing (WGS) and Whole exome sequencing (WES), have proven to be significantly supportive in diagnosing these complex conditions. The aim is to evaluate the cost-effectiveness of WGS versus WES in pediatric patients with suspected genetic disorders. A Bayesian Markov model was calibrated among this target population, comparing WGS to WES. Model parameters were retrieved from the scientific literature. Costs and benefits were discounted at a rate of 3%. A lifetime time horizon and the National Health Service perspective was chosen. The Eurozone threshold, ranging from €30,000 to €50,000, was adopted. Markov Chain Monte Carlo was used as the simulation method for Bayesian inference. Uncertainty was explored through a probabilistic sensitivity analysis (PSA) and a value of information analysis (VOI), illustrated through Cost-Effectiveness Acceptability Curve (CEAC) and Expected Value of Perfect Information (EVPI). Results were reported as Incremental Cost-Effectiveness Ratio (ICER), expressed as euros per additional diagnosis. The base case findings highlighted that WGS was cost-effective with an ICER of €31,973. The CEAC showed that for all thresholds over the ICER, WGS had the highest probability of being cost-effective. The EVPI per patient was estimated to be €6,535 on a threshold of €50,000/diagnosis. In addition to being cost-effective, WGS could allow early genetic diagnosis shortening the diagnostic odyssey. The use of WGS in the diagnostic workup has the potential to revolutionise personalised medicine and to play a significant role in achieving SDG 3 by providing personalised healthcare, identifying genetic risk factors for diseases, and informing public health policies for a target population that represents the human capital of the future. Key messages • This analysis informs that WGS is cost-effective and possibly cost-saving in the long term. • WGS could be implemented in the diagnostic workup of children with suspected rare disorders.

Participant-guided development of bilingual genomic educational infographics for Electronic Medical Records and Genomics Phase IV study.

Developing targeted, culturally competent educational materials is critical for participant understanding of engagement in a large genomic study that uses computational pipelines to produce genome-informed risk assessments. Guided by the Smerecnik framework that theorizes understanding of multifactorial genetic disease through 3 knowledge types, we developed English and Spanish infographics for individuals enrolled in the Electronic Medical Records and Genomics Network. Infographics were developed to explain concepts in lay language and visualizations. We conducted iterative sessions using a modified "think-aloud" process with 10 participants (6 English, 4 Spanish-speaking) to explore comprehension of and attitudes towards the infographics. We found that all but one participant had "awareness knowledge" of genetic disease risk factors upon viewing the infographics. Many participants had difficulty with "how-to" knowledge of applying genetic risk factors to specific monogenic and polygenic risks. Participant attitudes towards the iteratively-refined infographics indicated that design saturation was reached. There were several elements that contributed to the participants' comprehension (or misunderstanding) of the infographics. Visualization and iconography techniques best resonated with those who could draw on prior experiences or knowledge and were absent in those without. Limited graphicacy interfered with the understanding of absolute and relative risks when presented in graph format. Notably, narrative and storytelling theory that informed the creation of a vignette infographic was most accessible to all participants. Engagement with the intended audience who can identify strengths and points for improvement of the intervention is necessary to the development of effective infographics.

Metabolic syndrome, genetic susceptibility, and risk of chronic obstructive pulmonary disease: The UK Biobank Study.

To investigate the effect of metabolic syndrome (MetS), genetic predisposition, and their interactions, on the risk of developing chronic obstructive pulmonary disease (COPD). Cohort analyses included 287 868 participants from the UK Biobank Study. A genetic risk score for COPD was created using 277 single nucleotide polymorphisms. Cox proportional hazard models were used to evaluate the hazard ratios (HRs) with 95% confidence intervals (CIs) for COPD in relation to exposure factors. During 2 658 936 person-years of follow-up, 5877 incident cases of COPD were documented. Compared with participants without MetS, those with MetS had a higher risk of COPD (HR 1.24, 95% CI 1.17-1.32). Compared to participants with low genetic predisposition, those with high genetic predisposition had a 17% increased risk of COPD. In the joint analysis, compared with participants without MetS and low genetic predisposition, the HR for COPD for those with MetS and high genetic predisposition was 1.50 (95% CI 1.36-1.65; P < 0.001). However, no significant interaction between MetS and genetic risk was found. Metabolic syndrome was found to be associated with an increased risk of COPD, regardless of genetic risk. It is crucial to conduct further randomized control trials to determine whether managing MetS and its individual components can potentially reduce the likelihood of developing COPD.

Genetic risk of glaucoma is associated with vascular and retinal nerve fibre wedge defects.

To evaluate the association between localised vascular and retinal nerve fibre layer (RNFL) loss and genetic risk for glaucoma and cardiovascular disease using polygenic risk scores (PRS). 858 eyes were included from 455 individuals with suspect and early manifest primary open angle glaucoma. Eyes were characterised as having localised vascular and/or RNFL wedge-shaped defects by scrutiny of optical coherence tomography angiography (OCTA) and OCT images, respectively. Investigations included associations with pre-established scores for genetic risk of glaucoma and cardiovascular disease in the context of glaucoma risk factors and systemic vascular disease outcomes. Higher genetic risk for glaucoma was associated with both vascular wedge defects and RNFL defects (p < 0.001 and p = 0.020, respectively). A greater genetic risk of glaucoma was associated with the presence of multiple vascular wedges per eye (p = 0.005). Glaucoma progression based on global RNFL loss was associated with vascular and RNFL wedge defects (p ≤ 0.001 and p = 0.008, respectively). The glaucoma PRS was significantly associated with vascular, but not RNFL, wedge defects after controlling for disc haemorrhage (p = 0.007 and p = 0.070, respectively). Vascular wedge defects were not related to the cardiovascular PRS. Individuals with a higher genetic risk of glaucoma based on the PRS were more likely to have retinal vascular defects, as well as structural glaucomatous loss, but this did not relate to systemic cardiovascular risk. This possibly implies a local pathophysiology for the vascular defects in some cases, which may have clinical relevance in the early stages of glaucoma and in individuals at high genetic risk.

Identification of Rare Genetic Variants in Familial Spontaneous Coronary Artery Dissection and Evidence for Shared Biological Pathways.

Rare familial spontaneous coronary artery dissection (SCAD) kindreds implicate genetic disease predisposition and provide a unique opportunity for candidate gene discovery. Whole-genome sequencing was performed in fifteen probands with non-syndromic SCAD who had a relative with SCAD, eight of whom had a second relative with extra-coronary arteriopathy. Co-segregating variants and associated genes were prioritized by quantitative variant, gene, and disease-level metrics. Curated public databases were queried for functional relationships among encoded proteins. Fifty-four heterozygous coding variants in thirteen families co-segregated with disease and fulfilled primary filters of rarity, gene variation constraint, and predicted-deleterious protein effect. Secondary filters yielded 11 prioritized candidate genes in 12 families, with high arterial tissue expression (n = 7), high-confidence protein-level interactions with genes associated with SCAD previously (n = 10), and/or previous associations with connective tissue disorders and aortopathies (n = 3) or other vascular phenotypes in mice or humans (n = 11). High-confidence associations were identified among 10 familial SCAD candidate-gene-encoded proteins. A collagen-encoding gene was identified in five families, two with distinct variants in COL4A2. Familial SCAD is genetically heterogeneous, yet perturbations of extracellular matrix, cytoskeletal, and cell-cell adhesion proteins implicate common disease-susceptibility pathways. Incomplete penetrance and variable expression suggest genetic or environmental modifiers.