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Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.
Tuesday,2021-07-20 14:13 America/Los_Angeles — ecterry
| Title | Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. |
| Publication Type | Journal Article |
| Year of Publication | 2021 |
| Authors | Goodrich, JK, Singer-Berk, M, Son, R, Sveden, A, Wood, J, England, E, Cole, JB, Weisburd, B, Watts, N, Caulkins, L, Dornbos, P, Koesterer, R, Zappala, Z, Zhang, H, Maloney, KA, Dahl, A, Aguilar-Salinas, CA, Atzmon, G, Barajas-Olmos, F, Barzilai, N, Blangero, J, Boerwinkle, E, Bonnycastle, LL, Bottinger, E, Bowden, DW, Centeno-Cruz, F, Chambers, JC, Chami, N, Chan, E, Chan, J, Cheng, C-Y, Cho, YS, Contreras-Cubas, C, Córdova, E, Correa, A, DeFronzo, RA, Duggirala, R, Dupuis, J, Garay-Sevilla, MEugenia, García-Ortiz, H, Gieger, C, Glaser, B, González-Villalpando, C, Gonzalez, MElena, Grarup, N, Groop, L, Gross, M, Haiman, C, Han, S, Hanis, CL, Hansen, T, Heard-Costa, NL, Henderson, BE, Hernandez, JManuel Mal, Hwang, MYeong, Islas-Andrade, S, Jørgensen, ME, Kang, HMin, Kim, B-J, Kim, YJin, Koistinen, HA, Kooner, JSingh, Kuusisto, J, Kwak, S-H, Laakso, M, Lange, L, Lee, J-Y, Lee, J, Lehman, DM, Linneberg, A, Liu, J, Loos, RJF, Lyssenko, V, Ma, RCW, Martínez-Hernández, A, Meigs, JB, Meitinger, T, Mendoza-Caamal, E, Mohlke, KL, Morris, AD, Morrison, AC, C Y Ng, M, Nilsson, PM, O'Donnell, CJ, Orozco, L, Palmer, CNA, Park, KSoo, Post, WS, Pedersen, O, Preuss, M, Psaty, BM, Reiner, AP, Revilla-Monsalve, C, Rich, SS, Rotter, JI, Saleheen, D, Schurmann, C, Sim, X, Sladek, R, Small, KS, So, WYee, Spector, TD, Strauch, K, Strom, TM, Tai, SE, Tam, CHT, Teo, YYing, Thameem, F, Tomlinson, B, Tracy, RP, Tuomi, T, Tuomilehto, J, Tusié-Luna, T, van Dam, RM, Vasan, RS, Wilson, JG, Witte, DR, Wong, T-Y, Burtt, NP, Zaitlen, N, McCarthy, MI, Boehnke, M, Pollin, TI, Flannick, J, Mercader, JM, O'Donnell-Luria, A, Baxter, S, Florez, JC, MacArthur, DG, Udler, MS |
| Corporate/Institutional Authors | AMP-T2D-GENES Consortia |
| Journal | Nat Commun |
| Volume | 12 |
| Issue | 1 |
| Pagination | 3505 |
| Date Published | 2021 06 09 |
| ISSN | 2041-1723 |
| Keywords | Adult, Biological Variation, Population, Biomarkers, Diabetes Mellitus, Type 2, Dyslipidemias, Exome, Genetic Predisposition to Disease, Genotype, Humans, Multifactorial Inheritance, Penetrance, Risk Assessment |
| Abstract | <p>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.</p> |
| DOI | 10.1038/s41467-021-23556-4 |
| Alternate Journal | Nat Commun |
| PubMed ID | 34108472 |
| PubMed Central ID | PMC8190084 |
| Grant List | K24 DK110550 / DK / NIDDK NIH HHS / United States R56 DK062370 / DK / NIDDK NIH HHS / United States K12 HD052896 / HD / NICHD NIH HHS / United States K23 DK114551 / DK / NIDDK NIH HHS / United States R01 DK062370 / DK / NIDDK NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States U01 DK105554 / DK / NIDDK NIH HHS / United States |
ePub date:
21/06