2025
Improving polygenic prediction from whole-genome sequencing data by leveraging predicted epigenomic features
Zeng W, Guo H, Liu Q, Wong H. Improving polygenic prediction from whole-genome sequencing data by leveraging predicted epigenomic features. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2419202122. PMID: 40504151, PMCID: PMC12184400, DOI: 10.1073/pnas.2419202122.Peer-Reviewed Original ResearchConceptsWhole-genome sequencingWhole-genome sequencing dataPolygenic risk scoresVariant effectsIndividual susceptibility to complex diseasesAdvent of whole-genome sequencingSusceptibility to complex diseasesPolygenic risk score approachPolygenic risk score performanceRare variant effectsComplex genetic architecturePolygenic risk score methodsDe novo variantsEpigenomic contextEpigenomic featuresGenomic regionsGenetic architectureSequence dataEpigenomic signalsVariant contributionsPolygenic predictionVariant impactDiploid genotypesGenetic variantsDisease risk predictionAlcohol use disorder and body mass index show genetic pleiotropy and shared neural associations
Malone S, Davis C, Piserchia Z, Setzer M, Toikumo S, Zhou H, Winterlind E, Gelernter J, Justice A, Leggio L, Rentsch C, Kranzler H, Gray J. Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations. Nature Human Behaviour 2025, 9: 1056-1066. PMID: 40164914, DOI: 10.1038/s41562-025-02148-y.Peer-Reviewed Original ResearchConceptsAlcohol use disorderUse disorderBrain regionsGenotype-Tissue ExpressionSingle-nucleotide polymorphismsPolygenic overlapAssociated with alcohol use disorderCaudate nucleus volumeBody mass indexMultiple brain regionsConjunctional false discovery rateNeurobiological overlapExecutive functionNeurobiological mechanismsNeural associationsBrain phenotypesNucleus volumeFalse discovery rate methodFalse discovery rateGenetic architectureVariant effectsMass indexGenetic pleiotropyDiscovery rateTissue enrichmentIdentification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities
Loesch D, Garg M, Matelska D, Vitsios D, Jiang X, Ritchie S, Sun B, Runz H, Whelan C, Holman R, Mentz R, Moura F, Wiviott S, Sabatine M, Udler M, Gause-Nilsson I, Petrovski S, Oscarsson J, Nag A, Paul D, Inouye M. Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities. Nature Communications 2025, 16: 2124. PMID: 40032831, PMCID: PMC11876343, DOI: 10.1038/s41467-025-56695-z.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkersCardiovascular DiseasesComorbidityDiabetes Mellitus, Type 2Extracellular Matrix ProteinsFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansInsulin-Like Growth Factor Binding Protein 2MaleMiddle AgedMultifactorial InheritanceProteomicsRisk FactorsUnited KingdomConceptsPolygenic scoresNon-coding variantsEtiology of type 2 diabetesMolecular dataVariant effectsPathway enrichmentPlasma proteomic markersPotential therapeutic targetType 2 diabetesProteinDisease biologyPolygenic riskUK BiobankProteomic markersTherapeutic targetPathwayCirculating proteinsGenomeRisk of type 2 diabetesCardiometabolic scoreBiologyInteractive portalVariantsEnrichmentDiabetes comorbidities
2024
High-throughput assays to assess variant effects on disease
Ma K, Gauthier L, Cheung F, Huang S, Lek M. High-throughput assays to assess variant effects on disease. Disease Models & Mechanisms 2024, 17: dmm050573. PMID: 38940340, PMCID: PMC11225591, DOI: 10.1242/dmm.050573.Peer-Reviewed Original ResearchConceptsDeep mutational scanningGenetic variantsRare disease diagnosticsRare genetic variantsDisease mechanismsHigh-throughput assaySequencing effortsInvestigation of variantsMutational scanningModel cell lineVariant effectsMolecular toolsCell linesCell survival rateFunctional assaysDrug resistanceDisease diagnosticsDisease-relevant assaysVariantsClinical case reportBiological mechanismsAssayCase reportClinical reportsSurvival rate
2023
Massively parallel base editing to map variant effects in human hematopoiesis
Martin-Rufino J, Castano N, Pang M, Grody E, Joubran S, Caulier A, Wahlster L, Li T, Qiu X, Riera-Escandell A, Newby G, Al'Khafaji A, Chaudhary S, Black S, Weng C, Munson G, Liu D, Wlodarski M, Sims K, Oakley J, Fasano R, Xavier R, Lander E, Klein D, Sankaran V. Massively parallel base editing to map variant effects in human hematopoiesis. Cell 2023, 186: 2456-2474.e24. PMID: 37137305, PMCID: PMC10225359, DOI: 10.1016/j.cell.2023.03.035.Peer-Reviewed Original ResearchConceptsHuman hematopoiesisVariant effectsNon-coding variantsDisease-Associated VariantsSingle-cell genotypingHuman hematopoietic stemFetal hemoglobin expressionHigh-throughput variantGenome engineeringSequencing readoutHematopoietic differentiationFunctional screenHemoglobin expressionDifferentiation stateDefines mechanismsHematopoietic stemPrimary cellsGenetic variantsProgenitor cellsSpecific mutationsDiverse diseasesHuman physiologyRich phenotypingHematopoiesisImmunotherapy approaches
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