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Goodrich, J.K.* ; Singer-Berk, M.* ; Son, R.* ; Sveden, A.* ; Wood, J.* ; England, E.* ; Cole, J.B.* ; Weisburd, B.* ; Watts, N.* ; Caulkins, L.* ; Dornbos, P.* ; Koesterer, R.* ; Zappala, Z.* ; Zhang, H.* ; Maloney, K.A.* ; Dahl, A.* ; Aguilar-Salinas, C.A.* ; Atzmon, G.* ; Barajas-Olmos, F.* ; Barzilai, N.* ; Blangero, J.* ; Boerwinkle, E.* ; Bonnycastle, L.L.* ; Bottinger, E.B.* ; Bowden, D.W.* ; Centeno-Cruz, F.* ; Chambers, J.C.* ; Chami, N.* ; Chan, E.* ; Chan, J.* ; Cheng, C.Y.* ; Cho, Y.S.* ; Contreras-Cubas, C.* ; Córdova, E.* ; Correa, A.* ; DeFronzo, R.A.* ; Duggirala, R.* ; Dupuis, J.* ; Garay-Sevilla, M.E.* ; García-Ortiz, H.* ; Gieger, C. ; Glaser, B.* ; González-Villalpando, C.* ; Gonzalez, M.E.* ; Grarup, N.* ; Groop, L.* ; Gross, M.* ; Haiman, C.* ; Han, S.* ; Hanis, C.L.* ; Hansen, T.* ; Heard-Costa, N.L.* ; Henderson, B.E.* ; Hernandez, J.M.M.* ; Hwang, M.Y.* ; Islas-Andrade, S.* ; Jørgensen, M.E.* ; Kang, H.M.* ; Kim, B.J.* ; Kim, Y.J.* ; Koistinen, H.A.* ; Kooner, J.S.* ; Kuusisto, J.* ; Kwak, S.H.* ; Laakso, M.* ; Lange, L.* ; Lee, J.Y.* ; Lee, J.* ; Lehman, D.M.* ; Linneberg, A.* ; Liu, J.* ; Loos, R.J.F.* ; Lyssenko, V.* ; Ma, R.C.W.* ; Martínez-Hernández, A.* ; Meigs, J.B.* ; Meitinger, T.* ; Mendoza-Caamal, E.* ; Mohlke, K.L.* ; Morris, A.D.* ; Morrison, A.C.* ; Ng, M.C.Y.* ; Nilsson, P.M.* ; O’Donnell, C.J.* ; Orozco, L.* ; Palmer, C.N.A.* ; Park, K.S.* ; Post, W.S.* ; Pedersen, O.* ; Preuss, M.* ; Psaty, B.M.* ; Reiner, A.P.* ; Revilla-Monsalve, C.* ; Rich, S.S.* ; Rotter, J.I.* ; Saleheen, D.* ; Schurmann, C.* ; Sim, X.* ; Sladek, R.* ; Small, K.S.* ; So, W.Y.* ; Spector, T.D.* ; Strauch, K. ; Strom, T.M. ; Tai, E.S.* ; Tam, C.H.T.* ; Teo, Y.Y.* ; Thameem, F.* ; Tomlinson, B.* ; Tracy, R.P.* ; Tuomi, T.* ; Tuomilehto, J.* ; Tusié-Luna, T.* ; van Dam, R.M.* ; Vasan, R.S.* ; Wilson, J.G.* ; Witte, D.R* ; Wong, T.-Y.* ; Burtt, N.P.* ; Zaitlen, N.* ; McCarthy, M.I.* ; Boehnke, M.* ; Pollin, T.I.* ; Flannick, J.* ; Mercader, J.M.* ; O'Donnell-Luria, A.* ; Baxter, A.* ; Florez, J.C* ; MacArthur, D.G.* ; Udler, M.S.*

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat. Commun. 12:3505 (2021)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ld Score Regression; Medical Genetics; American-college; Clinical Exome; Rare Variants; Low-frequency; Mutations; Risk; Disease; Association
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 12, Issue: 1, Pages: , Article Number: 3505 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)
Grants NICHD NIH HHS
NIDDK NIH HHS