663 research outputs found

    Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

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    Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide; however, the molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and of overlapping expression and splicing quantitative trait loci (e/QTLs and sQTLs) in 49 GTEx tissues and retina prioritizesd causal genes for 60% of loci. These genes awere enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealesd that the colocalizing genes and genome-wide POAG and IOP associations awere enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominatesd IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis

    The ins and outs of open-angle Glaucoma:drugs, diet, and defecation

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    Glaucoma is the leading cause of irreversible blindness and second leading cause of blindness. The primary aim of this thesis is to provide insight into the role of systemic effectsin the pathophysiology of OAG.<br/

    Glaucoma: from pathogenic mechanisms to retinal glial cell response to damage

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    Glaucoma is a neurodegenerative disease of the retina characterized by the irreversible loss of retinal ganglion cells (RGCs) leading to visual loss. Degeneration of RGCs and loss of their axons, as well as damage and remodeling of the lamina cribrosa are the main events in the pathogenesis of glaucoma. Different molecular pathways are involved in RGC death, which are triggered and exacerbated as a consequence of a number of risk factors such as elevated intraocular pressure (IOP), age, ocular biomechanics, or low ocular perfusion pressure. Increased IOP is one of the most important risk factors associated with this pathology and the only one for which treatment is currently available, nevertheless, on many cases the progression of the disease continues, despite IOP control. Thus, the IOP elevation is not the only trigger of glaucomatous damage, showing the evidence that other factors can induce RGCs death in this pathology, would be involved in the advance of glaucomatous neurodegeneration. The underlying mechanisms driving the neurodegenerative process in glaucoma include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress and neuroinflammation. In glaucoma, like as other neurodegenerative disorders, the immune system is involved and immunoregulation is conducted mainly by glial cells, microglia, astrocytes, and MĂŒller cells. The increase in IOP produces the activation of glial cells in the retinal tissue. Chronic activation of glial cells in glaucoma may provoke a proinflammatory state at the retinal level inducing blood retinal barrier disruption and RGCs death. The modulation of the immune response in glaucoma as well as the activation of glial cells constitute an interesting new approach in the treatment of glaucoma

    Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea

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    ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (ÎČ2 = 0.18, p-value = 0.07; ÎČ3 = −0.10, p-value = 0.02). SHS exposure at home (ÎČ2 = 0.10, p-value = 0.09; ÎČ3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (ÎČ2 = 0.03, p-value = 0.10; ÎČ3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK

    Funduse sinine ja lĂ€hi-infrapuna autofluorestsentsuuring autosoom-retsessiivse Stardgardti tĂ”ve, koroidereemia, PROM1-maakuli dĂŒstroofia ja okulaarse albinismi patsientidel

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    VĂ€itekirja elektrooniline versioon ei sisalda publikatsiooneFunduse sinine ja lĂ€hi-infrapuna autofluorestsentsuuring autosoom-retsessiivse Stardgardti tĂ”ve, koroidereemia, PROM1-maakuli dĂŒstroofia ja okulaarse albinismi patsientidel PĂ€rilikud vĂ”rkkestahaigused on juhtivaks nĂ€gemiskaotuse pĂ”hjuseks tööealise elanikkonna seas arenenud riikides. Tegemist on kliiniliselt ja geneetiliselt vĂ€ga heterogeense haiguste grupiga, mistĂ”ttu diagnostika ja haiguse patogeneesi uurimine on olnud vaevarikas. VĂ”rkkesta piltdiagnostika on oluline mitte-invasiivne meetod haiguste diagnoosimiseks ja uurimiseks. Konfokaalne skanneeriv laseroftalmoskoop valgustab vĂ”rkkesta erineva lainepikkusega laserkiirega ning salvestab tagasikiirgavat valgust luues silmapĂ”hjast pildi. Funduse autofluorestsents (AF) uuringul kasutatakse Ă€ra silmapĂ”hja enda naturaalseid fluorofoore. Lipofustsiini ergastamiseks kasutatakse sinise spektri laserkiirt (sinine AF) ja melaniini jaoks lĂ€hipuna laserkiirt (lĂ€hipuna AF). Nende fluorofooride jaotus ja kogus silmapĂ”hjas muutub erinevate haigusprotsesside mĂ”jul ning need muutused on tuvastatavad AF uuringul. Antud doktoritöös uurisime sinise ja lĂ€hipuna AF uuringu pilte autosoom-retsesiivse Stargardti tĂ”ve (STGD1), koroidereemia, PROM1-maakuli dĂŒstroofia ning okulaarse albinismi patsientidel. Töö eesmĂ€rgiks oli paremini mĂ”ista sinise ja lĂ€hipuna AF signaali allikaid erinevate haigusseisundite korral, kus vĂ”rkkesta fluorofooride jaotus ning kogused on muutunud. Lisaks kvalitatiivsele piltide hindamisele kasutamise kvantitatiivset AF signaali tugevuse mÔÔtmist hindamaks lipofustsiini ja melaniini taset. Uurimustöös nĂ€itasime, et melaniin on lĂ€hipuna AF signaali peamiseks allikaks. Lisaks nĂ€itasime, et melanin vĂ”ib kaudselt moduleerida lipofustsiinist tuleneva sinise AF signaali, sest okulaarse albinismi kandjate hĂŒpopigmenteeritud vĂ”rkkesta alade sinise AF signal oli tavapĂ€rasest kĂ”rgem. AF signaali tugevuse mÔÔtmisel leidsime, et lipofustsiini kuhjumine vĂ”rkkestas pĂ”hjustab lisaks sinise AF signaali tĂ”usule ka lĂ€hipuna AF signaali tĂ”usu STGD1 patsientidel. Kvantitatiivsel analĂŒĂŒsil nĂ€itasime ka, et PROM1-maakuli dĂŒstroofia patsientide sinise AF signaal oli vĂ”rreldav terve silmapĂ”hja signaali tugevusega, eristades seda fenotĂŒĂŒbiliselt sarnasest STGD1 haigusest ning viidates ka sellele, et lipofustsiini ĂŒleliigne kuhjumine ei ole antud haigusele omane mehhanism. Koroidereemia ja STGD1 haigete uurimisel leidsime, et pigmentepiteeli rakkude kĂ€rbumine on nĂ€htav AF signaali hÀÀbumisena, samas lĂ€hipuna AF uuringaitab tuvastada varasemaid muutusi kui sinine AF uuring. Lipofustsiin ja melanin on mĂ”lemad olulised vĂ”rkkesta rakkude seisundi biomarkerid, mida on vĂ”imalik mitte-invasiivsel moel AF uuringu abil analĂŒĂŒsida ning hinnata haiguse progressiooni.Inherited retinal diseases are the leading cause of visual impairment among the working age-group in the developed countries. Because of genetic and phenotypical heterogeneity, diagnosis and understanding pathogenesis of inherited retinal disease has been challenging. Retinal imaging studies which are noninvasive, are an invaluable source of information. Fundus autofluorescence (FAF) utilizes natural fluorophores to create an image of the retina. Lipofuscin is the primary source for short-wavelength autofluorescence (SW-AF) and melanin for near-infrared autofluorescence (NIR-AF). The amount and distribution of these fluorophores changes in the different disease processes and is detectable in FAF images. In this study we analyzed SW-AF and NIR-AF images in cases of genetically confirmed recessive Stargardt disease (STGD1), choroideremia, PROM1-macular disease and ocular albinism. The aim was to qualitatively describe FAF in conditions with varying levels of lipofuscin or melanin as well as to quantify FAF signal intensities. We also aimed at finding new clinical implications for autofluorescence imaging in evaluating inherited retinal disease. We confirmed that melanin is the major source of NIR-AF signal by analyzing ocular albinism carriers and mice models with varying fundus pigmentation, but we also found that presence of melanin can modulate SW-AF signal strength. As a novel finding we confirmed that lipofuscin contributes to NIR-AF signal intensity in cases with excessive bisretinoid lipofuscin levels like seen in STGD1. The analysis of choroideremia and STGD1 patients showed that retinal pigment epithelium atrophy causes loss of signal in both SW-AF and NIR-AF, but NIR-AF could be more sensitive in detecting early cell degeneration. Quantifying the autofluorescence signal intensity helps to further understand disease processes as it is an indirect measure for levels of retinal fluorophores. We showed PROM1-macular dystrophy does not present with elevated levels of SW-AF indicating that excessive lipofuscin accumulation is likely not part of its disease mechanism. That knowledge is valuable in differentiating it from phenotypically similar STGD1 or when developing therapeutic approaches. Lipofuscin and melanin are both valuable retinal biomarkers for evaluating retinal health by using non-invasive autofluorescence imaging.https://www.ester.ee/record=b555738

    Intrauterine and genetic risk factors for proliferative diabetic retinopathy

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    Diabetes is a complex progressive metabolic disorder characterized by hyperglycemia and caused by different etiopathogenic factors. Individuals with diabetes have heterogeneous clinical representation and increased risk of micro- and macrovascular complications. Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes and one of the leading causes of blindness. Currently, existing treatment modalities target a severe sight-threatening form of the disease, proliferative DR (PDR), and are characterized by significant side effects. The prevailing strategy for prevention or slowing down DR progression is glucose-lowering therapy, which is not efficient enough and might be harming to older groups of patients. Risk factors for PDR include duration of diabetes, hypertension, dyslipidemia, genetics and environment, and their interplay. The adverse intrauterine environment, particularly exposure to prenatal famine, was shown to play an important role in predisposition to diverse metabolic disorders in adults such as type 2 diabetes (T2D), hypertension, and cardiovascular diseases (CVD). In this Ph.D. thesis, we aimed to study novel diabetes subgroups based on pathophysiological characteristics of patients, highlighting subgroup(s) with an elevated risk of diabetic complications, particularly PDR. Further, we aimed to investigate the association of intrauterine exposure to famine with the risk of PDR in adult individuals with T2D. Finally, we wanted to study the molecular mechanisms linked to famine-related PDR. In paper 1, we performed a k-means cluster analysis to identify novel subgroups of individuals with new-onset and long-term diabetes, and estimated the risks of diabetic complications using logistic regression. In paper 2, we evaluated effect of intrauterine famine exposure on the risk of PDR in individuals with T2D using logistic regression adjusted for established risk factors such as age, sex, duration of diabetes and HbA1c. In paper 3, we performed candidate gene analysis using generalized estimation equation (GEE) to study the effect of interaction between SNPs and perinatal famine exposure on the risk of PDR. In paper 4, we performed genome-wide association (GWAS) and interaction (GWIS) studies using a linear mixed model (LMM) to investigate molecular underpinnings of famine-related PDR. In paper 1, we identified three subgroups with severe diabetes and two subgroups with mild diabetes. The highest risk of PDR was observed in the severe autoimmune diabetes (SAID) and severe insulin-deficient diabetes (SIDD) subgroups and the lowest in the insulin-resistant obesity-related diabetes 2 (IROD2) subgroup. In paper 2, we demonstrated that individuals with T2D, who were perinatally exposed to famine had an elevated risk of PDR in adult life. In paper 3, we demonstrated a significant association between famine-associated PDR and SNPs which were located in genes with neuronal function. In paper 4, we identified diverse pathways potentially linked to famine-related PDR, among them the most significant were lipid metabolism and inflammation pathways. In conclusion, we suggested that the altered development of neurovascular unit in the retina due to exposure to intrauterine famine may increase susceptibility to PDR later in life. Changes in metabolic adaptations during developmental programming induced by adverse early life events may affect insulin secretion and lipid metabolism, which consequently may increase predisposition to PDR under diabetes environment in adulthood. We suggested that drugs targeting these mechanisms in addition to glucose-lowering treatments may be beneficial for the prevention or slowing down the progression to PDR in the early stages of the disease.Diabetes er en kompleks progressiv metabolsk sykdom som kjennetegnes ved hyperglykemi og er forÄrsaket av forskjellige etiopatogenetiske faktorer. Personer med diabetes har heterogen klinisk representasjon og Þkt risiko for mikro- og makrovaskulÊre komplikasjoner. Diabetisk retinopati (DR) er den hyppigste mikrovaskulÊre komplikasjonen ved diabetes og en av de viktigste Ärsakene til blindhet. For tiden er eksisterende behandlingsmetoder rettet mot en alvorlig synstruende form av sykdommen, proliferativ DR (PDR), og medfÞrer betydelige bivirkninger. Den rÄdende strategien for forebygging eller forsinking av DR-progresjon er glukosesenkende terapi, som ikke er effektiv nok og kan vÊre skadelig for eldre pasienter. Risikofaktorer for PDR inkluderer varighet av diabetes, hypertensjon, dyslipidemi, genetikk og miljÞ, og deres samspill. Det ugunstige intrauterine miljÞet, spesielt eksponering for prenatal hungersnÞd, ble vist Ä spille en viktig rolle i predisposisjon for ulike metabolske forstyrrelser hos voksne som type 2 diabetes (T2D), hypertensjon og kardiovaskulÊre sykdommer (CVD). I denne doktorgradsavhandlingen, har vi hatt som mÄl Ä studere nye diabetes-undergrupper basert pÄ patofysiologiske egenskaper hos pasienter, og fremheve undergruppe(r) med Þkt risiko for diabetiske komplikasjoner, spesielt PDR. Videre hadde vi som mÄl Ä undersÞke sammenheng mellom intrauterin eksponering for hungersnÞd og risikoen for utvikling av PDR hos voksne med T2D. Til slutt Þnsket vi Ä studere de molekylÊre mekanismene knyttet til hungersnÞd-relatert PDR. I artikkel 1 utfÞrte vi en k-means-klyngeanalyse for Ä identifisere nye undergrupper av individer med nyoppstÄtt og langvarig diabetes, og estimerte risikoen for diabetiske komplikasjoner ved hjelp av logistisk regresjon. I artikkel 2 evaluerte vi effekten av eksponering for intrauterin hungersnÞd pÄ risikoen for PDR hos individer med T2D ved bruk av logistisk regresjon justert for etablerte risikofaktorer som alder, kjÞnn, varighet av diabetes og HbA1c. I artikkel 3 utfÞrte vi kandidatgenanalyse ved Ä bruke generalisert estimeringsligning (GEE) for Ä studere effekten av interaksjon mellom SNP-er og perinatal hungersnÞdeksponering pÄ risikoen for PDR. I artikkel 4 utfÞrte vi genomomfattende assosiasjonsstudier (GWAS) og interaksjonsstudier (GWIS) ved Ä bruke en lineÊr blandet modell (LMM) for Ä undersÞke molekylÊrt grunnlag for hungersnÞdrelatert PDR. I artikkel 1 identifiserte vi tre undergrupper med alvorlig diabetes og to undergrupper med mild diabetes. Den hÞyeste risikoen for PDR ble observert i undergruppene med alvorlig diabetes type 1 (SAID) og alvorlig diabetes type 2 (SIDD), og den laveste i undergruppen insulinresistent fedme-relatert diabetes 2 (IROD2). I artikkel 2 viste vi at personer med T2D, som ble perinatalt utsatt for hungersnÞd, hadde en forhÞyet risiko for utvikling av PDR i voksenlivet. I artikkel 3 viste vi en signifikant sammenheng mellom hungersnÞdassosiert PDR og SNP-er som var lokalisert i gener med nevronal funksjon. I artikkel 4 identifiserte vi ulike veier som er potensielt knyttet til hungersnÞd-relatert PDR, blant dem var de mest betydningsfulle lipidmetabolisme og betennelsesveier. Avslutningsvis foreslo vi at den endrede utviklingen av nevrovaskulÊr kretslÞp i netthinnen pÄ grunn av eksponering for intrauterin hungersnÞd kan Þke fÞlsomheten for PDR senere i livet. Endringer i metabolske tilpasninger under utviklingsprogrammering indusert av uÞnskede hendelser i tidlig liv kan pÄvirke insulinsekresjon og lipidmetabolisme, som fÞlgelig kan Þke predisposisjon for PDR under diabetesmiljÞ i voksen alder. Vi foreslo at medikamenter som retter seg mot disse mekanismene i tillegg til glukosesenkende behandlinger kan vÊre gunstig for forebygging eller forsinke progresjon til PDR i de tidlige stadiene av sykdommen.Doktorgradsavhandlin

    Anwendungen maschinellen Lernens fĂŒr datengetriebene PrĂ€vention auf Populationsebene

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    Healthcare costs are systematically rising, and current therapy-focused healthcare systems are not sustainable in the long run. While disease prevention is a viable instrument for reducing costs and suffering, it requires risk modeling to stratify populations, identify high- risk individuals and enable personalized interventions. In current clinical practice, however, systematic risk stratification is limited: on the one hand, for the vast majority of endpoints, no risk models exist. On the other hand, available models focus on predicting a single disease at a time, rendering predictor collection burdensome. At the same time, the den- sity of individual patient data is constantly increasing. Especially complex data modalities, such as -omics measurements or images, may contain systemic information on future health trajectories relevant for multiple endpoints simultaneously. However, to date, this data is inaccessible for risk modeling as no dedicated methods exist to extract clinically relevant information. This study built on recent advances in machine learning to investigate the ap- plicability of four distinct data modalities not yet leveraged for risk modeling in primary prevention. For each data modality, a neural network-based survival model was developed to extract predictive information, scrutinize performance gains over commonly collected covariates, and pinpoint potential clinical utility. Notably, the developed methodology was able to integrate polygenic risk scores for cardiovascular prevention, outperforming existing approaches and identifying benefiting subpopulations. Investigating NMR metabolomics, the developed methodology allowed the prediction of future disease onset for many common diseases at once, indicating potential applicability as a drop-in replacement for commonly collected covariates. Extending the methodology to phenome-wide risk modeling, elec- tronic health records were found to be a general source of predictive information with high systemic relevance for thousands of endpoints. Assessing retinal fundus photographs, the developed methodology identified diseases where retinal information most impacted health trajectories. In summary, the results demonstrate the capability of neural survival models to integrate complex data modalities for multi-disease risk modeling in primary prevention and illustrate the tremendous potential of machine learning models to disrupt medical practice toward data-driven prevention at population scale.Die Kosten im Gesundheitswesen steigen systematisch und derzeitige therapieorientierte Gesundheitssysteme sind nicht nachhaltig. Angesichts vieler verhinderbarer Krankheiten stellt die PrĂ€vention ein veritables Instrument zur Verringerung von Kosten und Leiden dar. Risikostratifizierung ist die grundlegende Voraussetzung fĂŒr ein prĂ€ventionszentri- ertes Gesundheitswesen um Personen mit hohem Risiko zu identifizieren und Maßnah- men einzuleiten. Heute ist eine systematische Risikostratifizierung jedoch nur begrenzt möglich, da fĂŒr die meisten Krankheiten keine Risikomodelle existieren und sich verfĂŒg- bare Modelle auf einzelne Krankheiten beschrĂ€nken. Weil fĂŒr deren Berechnung jeweils spezielle Sets an PrĂ€diktoren zu erheben sind werden in Praxis oft nur wenige Modelle angewandt. Gleichzeitig versprechen komplexe DatenmodalitĂ€ten, wie Bilder oder -omics- Messungen, systemische Informationen ĂŒber zukĂŒnftige GesundheitsverlĂ€ufe, mit poten- tieller Relevanz fĂŒr viele Endpunkte gleichzeitig. Da es an dedizierten Methoden zur Ex- traktion klinisch relevanter Informationen fehlt, sind diese Daten jedoch fĂŒr die Risikomod- ellierung unzugĂ€nglich, und ihr Potenzial blieb bislang unbewertet. Diese Studie nutzt ma- chinelles Lernen, um die Anwendbarkeit von vier DatenmodalitĂ€ten in der PrimĂ€rprĂ€ven- tion zu untersuchen: polygene Risikoscores fĂŒr die kardiovaskulĂ€re PrĂ€vention, NMR Meta- bolomicsdaten, elektronische Gesundheitsakten und Netzhautfundusfotos. Pro Datenmodal- itĂ€t wurde ein neuronales Risikomodell entwickelt, um relevante Informationen zu extra- hieren, additive Information gegenĂŒber ĂŒblicherweise erfassten Kovariaten zu quantifizieren und den potenziellen klinischen Nutzen der DatenmodalitĂ€t zu ermitteln. Die entwickelte Me-thodik konnte polygene Risikoscores fĂŒr die kardiovaskulĂ€re PrĂ€vention integrieren. Im Falle der NMR-Metabolomik erschloss die entwickelte Methodik wertvolle Informa- tionen ĂŒber den zukĂŒnftigen Ausbruch von Krankheiten. Unter Einsatz einer phĂ€nomen- weiten Risikomodellierung erwiesen sich elektronische Gesundheitsakten als Quelle prĂ€dik- tiver Information mit hoher systemischer Relevanz. Bei der Analyse von Fundusfotografien der Netzhaut wurden Krankheiten identifiziert fĂŒr deren Vorhersage Netzhautinformationen genutzt werden könnten. Zusammengefasst zeigten die Ergebnisse das Potential neuronaler Risikomodelle die medizinische Praxis in Richtung einer datengesteuerten, prĂ€ventionsori- entierten Medizin zu verĂ€ndern

    The Monogenic Architecture of Retinal and Neurological Diseases

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    Monogenic diseases, or single-gene disorders, are clinical manifestations that can be traced to genetic variation in a single gene that alters the biologically intended (wildtype) function of its protein (or mRNA) product. Although the causal gene and its function are well-understood in many monogenic diseases, this knowledge alone often does not fully encapsulate the extensive clinical spectrum of phenotypes seen in patients. This is due in part to the numerous types of pathogenic variants that can arise in a single gene, all of which can have distinct effects on disease expression. Understanding the relationship between the vast number of possible genotypes and corresponding disease phenotypes defines a gene’s monogenic disease architecture—an important but poorly understood concept that can yield informative mechanistic and clinical insight. This doctoral dissertation integrates traditional sequencing approaches with in-depth characterization of patient phenotypes to elucidate the monogenic disease architecture of three etiologically distinct disorders: retinal degeneration caused by autosomal recessive variation in ABCA4 and neurodevelopmental disease entities caused by autosomal dominant variants in CERT1 and PUM1. Genetic modifiers are identified as a significant factor in the penetrance of the major disease-causing allele of ABCA4 and several other genetic inconsistencies are resolved to create a coherent genotype-phenotype model for the disease. Insight from this model is then applied to demonstrate the effect of allele differences in disease progression and evaluation of treatment efficacy in patients. A large cohort of affected individuals with CERT1 variation is assembled to (1) validate the causal role of CERT1 in disease, (2) delineate the precise mechanism of CERT protein dysfunction in sphingolipid metabolism and (3) demonstrate therapeutic efficacy of an inhibitor compound for a newly described syndrome. Finally, the mutational spectrum of PUM1 is expanded to previously unattributed variant classes with unexpected pathophysiological consequences to patients. Not only do the findings in this dissertation advance the prospects of delivering personalized, precision medicine to patients, the overall impact underscores the importance of this integrated approach in reconciling knowledge gaps between observations at the molecular and organismal level