Goodrich, Julia KSinger-Berk, MorielSon, RachelSveden, AbigailWood, JordanEngland, EleinaCole, Joanne BWeisburd, BenWatts, NickCaulkins, LizzDornbos, PeterKoesterer, RyanZappala, ZacharyZhang, HaichenMaloney, Kristin ADahl, AndyAguilar-Salinas, Carlos AAtzmon, GilBarajas-Olmos, FranciscoBarzilai, NirBlangero, JohnBoerwinkle, EricBonnycastle, Lori LBottinger, ErwinBowden, Donald WCenteno-Cruz, FedericoChambers, John CChami, NathalieChan, EdmundChan, JulianaCheng, Ching-YuCho, Yoon ShinContreras-Cubas, CeciliaCórdova, EmilioCorrea, AdolfoDeFronzo, Ralph ADuggirala, RavindranathDupuis, JoséeGaray-Sevilla, María EugeniaGarcía-Ortiz, HumbertoGieger, ChristianGlaser, BenjaminGonzález-Villalpando, ClicerioGonzalez, Ma ElenaGrarup, NielsGroop, LeifGross, MyronHaiman, ChristopherHan, SoheeHanis, Craig LHansen, TorbenHeard-Costa, Nancy LHenderson, Brian EMalacara Hernández, Juan ManuelHwang, Mi YeongIslas-Andrade, SergioJørgensen, Marit EKang, Hyun MinKim, Bong-JoKim, Young JinKoistinen, Heikki AKooner, Jaspal SinghKuusisto, JohannaKwak, Soo-HeonLaakso, MarkkuLange, LeslieLee, Jong-YoungLee, JuyoungLehman, Donna MLinneberg, AllanLiu, JianjunLoos, Ruth J FLyssenko, ValeriyaMa, Ronald CWMartínez-Hernández, AngélicaMeigs, James BMeitinger, ThomasMendoza-Caamal, ElviaMohlke, Karen LMorris, Andrew DMorrison, Alanna CNg, Maggie C YNilsson, Peter MO'Donnell, Christopher JOrozco, LorenaPalmer, Colin NAPark, Kyong SooPost, Wendy SPedersen, OlufPreuss, MichaelPsaty, Bruce MReiner, Alexander PRevilla-Monsalve, CristinaRich, Stephen SRotter, Jerome ISaleheen, DanishSchurmann, ClaudiaSim, XuelingSladek, RobSmall, Kerrin SSo, Wing YeeSpector, Timothy DStrauch, KonstantinStrom, Tim MTai, E-ShyongTam, Claudia H TTeo, Yik YingThameem, FarookTomlinson, BrianTracy, Russell PTuomi, TiinamaijaTuomilehto, JaakkoTusié-Luna, Teresavan Dam, Rob MVasan, Ramachandran SWilson, James GWitte, Daniel RWong, Tien-YinBurtt, Noël PZaitlen, NoahMcCarthy, Mark IBoehnke, MichaelPollin, Toni IFlannick, JasonMercader, Josep MO'Donnell-Luria, AnneBaxter, SamanthaFlorez, Jose CMacArthur, Daniel GUdler, Miriam SAMP-T2D-GENES Consortia2022-07-202022-07-202021-06-09Nat Commun. 2021 Jun 9;12(1):3505.http://hdl.handle.net/20.500.12105/14737Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.engVoRhttp://creativecommons.org/licenses/by/4.0/AdultBiological Variation, PopulationBiomarkersDiabetes Mellitus, Type 2DyslipidemiasExomeGenetic Predisposition to DiseaseGenotypeHumansMultifactorial InheritancePenetranceRisk AssessmentAtribución 4.0 Internacional34108472121350510.1038/s41467-021-23556-42041-1723Nature Communicationsopen access