Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.
Julia K GoodrichMoriel Singer-BerkRachel SonAbigail SvedenJordan WoodEleina EnglandJoanne B ColeBen WeisburdNick WattsLizz CaulkinsPeter DornbosRyan KoestererZachary ZappalaHaichen ZhangKristin A MaloneyAndrew W DahlCarlos A Aguilar-SalinasGil AtzmonFrancisco Barajas-OlmosNir BarzilaiJohn E BlangeroEric BoerwinkleLori L BonnycastleErwin BottingerDonald W BowdenFederico Centeno-CruzJohn C ChambersNathalie ChamiEdmund ChanJuliana ChanChing-Yu ChengYoon Shin ChoCecilia Contreras-CubasEmilio CórdovaAdolfo CorreaRalph A DeFronzoRavindranath DuggiralaJosée DupuisMa Eugenia Garay-SevillaHumberto Garcia-OrtizChristian GiegerBenjamin GlaserClicerio González-VillalpandoMa Elena GonzalezNiels GrarupLeif C GroopMyron GrossChristopher HaimanSohee HanCraig L HanisTorben HansenNancy Heard- CostaBrian E HendersonJuan Manuel Malacara HernandezMi Yeong HwangSergio Islas-AndradeMarit E JørgensenHyun Min KangBong-Jo KimYoung Jin KimHeikki A KoistinenJaspal Singh KoonerJohanna KuusistoSoo-Heon KwakMarkku LaaksoLeslie LangeJong Young LeeJuyoung LeeDonna M LehmanAllan LinnebergJian-Jun LiuRuth J F LoosValeriya LyssenkoRonald Ching-Wan MaAngélica Martínez-HernándezJames B MeigsThomas MeitingerElvia Mendoza-CaamalKaren L MohlkeAndrew D MorrisAlanna C MorrisonMaggie C Y NgPeter M NilsssonChristopher J O'DonnellLorena Orozco-OrozcoColin Neil Alexander PalmerKyong-Soo ParkWendy S PostOluf PedersenMichael H PreussBruce M PsatyAlexander P ReinerCristina Revilla-MonsalveStephen S RichJerome I RotterDanish SaleheenClaudia SchurmannXueling S SimRobert SladekKerrin S SmallWing Yee SoTimothy D SpectorKonstantin StrauchTim M StromE Shyong TaiClaudia Ha-Ting TamYik Ying TeoFarook ThameemChristopher Wai Kei LamRussell P TracyTiinamaija TuomiJaakko TuomilehtoTeresa Tusié-LunaRob M van DamRamachandran S VasanJames G WilsonDaniel R WitteTien-Yin Wongnull nullNoël P BurttNoah ZaitlenMark I McCarthyMichael BoehnkeToni I PollinJason FlannickJosep Maria MercaderAnne H O'Donnell-LuriaSamantha BaxterJose C FlorezDaniel G MacArthurMiriam S UdlerPublished in: Nature communications (2021)
Hundreds 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.
Keyphrases
- type diabetes
- copy number
- cardiovascular disease
- healthcare
- genome wide
- glycemic control
- high resolution
- metabolic syndrome
- young adults
- early onset
- electronic health record
- gene expression
- dna methylation
- adipose tissue
- cross sectional
- mass spectrometry
- big data
- health insurance
- chronic pain
- high throughput sequencing