👤 Umair Khurshid

BackgroundPrevious whole exome and whole genome sequencing (WES/WGS) studies identified genome-wide significant associations for late-onset Alzheimer's disease (AD) with rare variants but highlighted the need for larger samples.ObjectiveIdentify associations of rare coding variants with AD risk in a large-scale, multi-ancestry exome-wide.MethodsWe combined non-overlapping portions of the Alzheimer's Disease Sequencing Project (ADSP) WES (n = 18 717) and WGS (n = 35 014) datasets obtaining a sample (n = 34 202) including participants ages ≥ 60 from four genomic similarity clusters consistent with European ancestry (EA, 9 744 AD cases and 9 095 controls), African American (AA, 1 944 AD cases and 4 215 controls), Caribbean Hispanic (CH 2 344 AD cases and 3 465 controls), and Native American Hispanic (NAH 743 AD cases and 2 652 AD controls) populations. Association of AD with 253,421 bi-allelic variants with minor allele count ≥ 20 in the total sample and each population group was evaluated using GENESIS. Gene-based tests comprising predicted moderate and high-impact variants were performed using SAIGE.ResultsNovel study-wide significant associations (p < 1.97 × 10 Show less

Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC Show less

The genetic influences on normal aortic valve function and their impact on aortic stenosis risk are of substantial interest. We used deep learning to measure peak velocity, mean gradient and aortic valve area from magnetic resonance imaging and conducted genome-wide association studies (GWAS) in 59,571 participants in the UK Biobank. Incorporating the aortic valve measurement GWAS with aortic stenosis GWAS using multitrait analysis of GWAS (MTAG), we identified 166 distinct loci (134 with aortic valve traits, 134 with aortic stenosis and 166 unique loci across all GWAS), including PCSK9 and LDLR. The MTAG aortic stenosis PGS was associated with aortic stenosis in All of Us (hazard ratio (HR) = 3.32 for top 5% versus all others, P = 8.8 × 10 Show less

Early-onset severe obesity is rare and largely treatment-resistant to standard measures. Etiologies include syndromic disorders (Prader-Willi, Bardet-Biedl and Alström syndromes), monogenic defects of appetite-regulating pathways - most significantly melanocortin-4-receptor (MC4R) deficiency, but also leptin receptor (LEPR), pro-opiomelanocortin (POMC), and secondary hypothalamic injury, most commonly craniopharyngiomas. Most childhood obesity, however, is polygenic, arising from interactions of environmental and genetic factors. In many patients, no clear etiology is identified. Treatment remains challenging, particularly if hyperphagia and reduced satiety are predominant presenting features. We describe the case of a 19-year-old male with a history of autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), type 2 diabetes mellitus (T2DM) and morbid obesity, who showed a clinically significant response to tirzepatide therapy following failed conventional interventions. This case highlights the potential role of dual incretin therapy in adolescents with severe early-onset obesity and hyperphagia, even in the absence (based on present knowledge) of identifiable hypothalamic or genetic pathology. Show less

Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP×TL interaction term. AD risk was associated with shorter TL (β = -0.18, We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis. Show less

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r Show less

Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism ( We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us). We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development. Show less

Glycation is among the underlying mechanisms attributed to ageing and associated morbidities. There is no drug available to combat this deleterious phenomenon. The present study aimed to explore phloroglucinol (PHL) for its anti-glycation potential at preclinical level. The rats were treated with methylglyoxal (MGO, 17.25 mg/kg, i.p. for 14 days) to induce glvcative stress. The treatment groups received additional administration of test drug (PHL; 0.25mg/kg, 0.5mg/kg, and 1mg/kg) or standard aminoguanidine (AG, 50 mg/kg) or saline (control, 5ml/kg). During 14 days, the weight and food intake was noted. Afterwards, the cognitive function was evaluated using Morris Water Maze (MWM) while hepatic and renal functions were assessed through liver function test (bilirubin, alkaline phosphatase, SGPT, and SGOT) and creatinine respectively, using chemical analyzer. The carboxymethyllysine (CML) levels were quantified in the blood using ELISA technique. Histopathological study was performed on the brain, liver, and kidney using H&E staining. Additionally, the qPCR was used to quantify the expression of TNF-α, RAGE and BACE-1 (brain), RAGE, TNF-α, and glyoxalase-I (liver) and RAGE, TNF-α, and VEGF (kidney), while glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a reference housekeeping gene. The data regarding weight and food intake did not reveal significant alterations. In MWM, the MGO treatment caused significant increase in the time to reach target quadrant, while decrease in the time spent in target quadrant and number of crossings through platform position. All these effects were inhibited by both AG and PHL. The navigation maps also exhibit that the retention of spatial memory. Additionally, the MGO-induced alteration in hepatic and renal function indicators was ameliorated by both AG and PHL treatments. The plasma CML levels were found to be elevated following MGO treatment, while the concomitant administration of AG and PHL has resisted this raise. Histopathological assessment revealed no specific pathology in liver kidney and brain tissues. The qPCR data revealed enhanced expression of all genes, especially TNF-α and BACE, which were found to be reduced following both AG and PHL treatments. PHL prevented the brain, hepatic, and renal impairments caused by MGO induced glycative stress. Hence, the PHL, a clinically used anti-spasmodic drug, presents itself as a potential candidate to be repurposed as anti-glycation drug. Show less

Developing highly potent covalent inhibitors of Fibroblast growth factor receptors 1 (FGFR1) has always been a challenging task. In the current study, various computational techniques, such as 3D-QSAR, covalent docking, fingerprinting analysis, MD simulation followed by MMGB/PBSA, and per-residue energy decomposition analysis were used to explore the binding mechanism of pyrazolo[3,4-d]pyridazinone derivatives to FGFR1. The high q2 and r2 values for the CoMFA and CoMSIA models, suggest that the constructed 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The structural requirements revealed by the model's contour maps were strategically used to computationally create an in-house library of more than 100 new FGFR1 inhibitors using the R-group exploration technique implemented in the Spark Show less

Artificial intelligence (AI) models applied to 12-lead ECG waveforms can predict atrial fibrillation (AF), a heritable and morbid arrhythmia. However, the factors forming the basis of risk predictions from AI models are usually not well understood. We hypothesized that there might be a genetic basis for an AI algorithm for predicting the 5-year risk of new-onset AF using 12-lead ECGs (ECG-AI)-based risk estimates. We applied a validated ECG-AI model for predicting incident AF to ECGs from 39 986 UK Biobank participants without AF. We then performed a genome-wide association study (GWAS) of the predicted AF risk and compared it with an AF GWAS and a GWAS of risk estimates from a clinical variable model. In the ECG-AI GWAS, we identified 3 signals ( Predicted AF risk from an ECG-AI model is influenced by genetic variation implicating sarcomeric, ion channel and body height pathways. ECG-AI models may identify individuals at risk for disease via specific biological pathways. Show less