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

TitleDeterminants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.
Publication TypeJournal Article
Year of Publication2021
AuthorsGoodrich, 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, YShin, 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, E Tai, S, Tam, CHT, Teo, YYing, Thameem, F, Tomlinson, B, Tracy, RP, Tuomi, T, Tuomilehto, J, Tusie-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 AuthorsAMP-T2D-GENES Consortia
JournalNat Commun
Date Published2021 Jun 09
KeywordsAdult, Biological Variation, Population, Biomarkers, Diabetes Mellitus, Type 2, Dyslipidemias, Exome, Genetic Predisposition to Disease, Genotype, Humans, Multifactorial Inheritance, Penetrance, Risk Assessment

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.

Alternate JournalNat Commun
PubMed ID34108472
PubMed Central IDPMC8190084
Grant ListR01 DK093757 / DK / NIDDK NIH HHS / United States
R56 DK062370 / DK / NIDDK NIH HHS / United States
K23 DK114551 / DK / NIDDK NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
MC_PC_13040 / MRC_ / Medical Research Council / United Kingdom
R01 DK062370 / DK / NIDDK NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
UM1 DK078616 / DK / NIDDK NIH HHS / United States
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
R01 DK125490 / DK / NIDDK NIH HHS / United States
K24 DK110550 / DK / NIDDK NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
MR/M501633/1 / MRC_ / Medical Research Council / United Kingdom
K12 HD052896 / HD / NICHD NIH HHS / United States
R01 HG006399 / HG / NHGRI NIH HHS / United States
K99 DK127196 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
U01 DK105554 / DK / NIDDK NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
P60 DK020541 / DK / NIDDK NIH HHS / United States

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