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Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.
Tuesday,2022-10-11 20:55 America/Los_Angeles — ecterry
| Title | Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes. |
| Publication Type | Journal Article |
| Year of Publication | 2022 |
| Authors | Halford, JL, Morrill, VN, Choi, SHoan, Jurgens, SJ, Melloni, G, Marston, NA, Weng, L-C, Nauffal, V, Hall, AW, Gunn, S, Austin-Tse, CA, Pirruccello, JP, Khurshid, S, Rehm, HL, Benjamin, EJ, Boerwinkle, E, Brody, JA, Correa, A, Fornwalt, BK, Gupta, N, Haggerty, CM, Harris, S, Heckbert, SR, Hong, CC, Kooperberg, C, Lin, HJ, Loos, RJF, Mitchell, BD, Morrison, AC, Post, W, Psaty, BM, Redline, S, Rice, KM, Rich, SS, Rotter, JI, Schnatz, PF, Soliman, EZ, Sotoodehnia, N, Wong, EK, Sabatine, MS, Ruff, CT, Lunetta, KL, Ellinor, PT, Lubitz, SA |
| Corporate/Institutional Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium |
| Journal | Nat Commun |
| Volume | 13 |
| Issue | 1 |
| Pagination | 5106 |
| Date Published | 2022 08 30 |
| ISSN | 2041-1723 |
| Keywords | Disease Susceptibility, Endophenotypes, Humans, Long QT Syndrome, Virulence |
| Abstract | <p>Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.</p> |
| DOI | 10.1038/s41467-022-32009-5 |
| Alternate Journal | Nat Commun |
| PubMed ID | 36042188 |
| PubMed Central ID | PMC9427940 |
| Grant List | HHSN268201800015I / HB / NHLBI NIH HHS / United States HHSN268201500015C / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01HC95169 / HL / NHLBI NIH HHS / United States 75N92021D00001 / HL / NHLBI NIH HHS / United States 75N92020D00007 / HL / NHLBI NIH HHS / United States R01 HL139731 / HL / NHLBI NIH HHS / United States R01 HL071251 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States HHSN268201800001C / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States N01HC95161 / HL / NHLBI NIH HHS / United States 75N92020D00001 / HL / NHLBI NIH HHS / United States UL1 TR001881 / TR / NCATS NIH HHS / United States 75N92019D00031 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States 75N92020D00005 / HL / NHLBI NIH HHS / United States HHSN268201700001I / HL / NHLBI NIH HHS / United States R01 HL098433 / HL / NHLBI NIH HHS / United States R01 HL071259 / HL / NHLBI NIH HHS / United States N01HC95168 / HL / NHLBI NIH HHS / United States R35 HL135818 / HL / NHLBI NIH HHS / United States 75N92021D00006 / HL / NHLBI NIH HHS / United States K24 HL105780 / HL / NHLBI NIH HHS / United States R01 HL113338 / HL / NHLBI NIH HHS / United States HHSN268201500014C / HL / NHLBI NIH HHS / United States 75N92021D00004 / WH / WHI NIH HHS / United States HHSN268201700004I / HL / NHLBI NIH HHS / United States N01HC95162 / HL / NHLBI NIH HHS / United States R01 HL071051 / HL / NHLBI NIH HHS / United States 75N92020D00004 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States UL1 TR001420 / TR / NCATS NIH HHS / United States HHSN268201800010I / HB / NHLBI NIH HHS / United States 75N92021D00005 / WH / WHI NIH HHS / United States KL2 RR024990 / RR / NCRR NIH HHS / United States N02 HL64278 / HL / NHLBI NIH HHS / United States R01 HL071205 / HL / NHLBI NIH HHS / United States HHSN268201800012I / HB / NHLBI NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States N01HC95165 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States R01 HL071258 / HL / NHLBI NIH HHS / United States 75N92021D00003 / WH / WHI NIH HHS / United States N01HC95167 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States U01 HG007417 / HG / NHGRI NIH HHS / United States R01 HL046380 / HL / NHLBI NIH HHS / United States HHSN268201700002I / HL / NHLBI NIH HHS / United States N01HC95159 / HL / NHLBI NIH HHS / United States N01HC95163 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States 75N92020D00002 / HL / NHLBI NIH HHS / United States R01 HL121007 / HL / NHLBI NIH HHS / United States HHSN268201700005I / HL / NHLBI NIH HHS / United States K08 HL159346 / HL / NHLBI NIH HHS / United States 75N92020D00003 / HL / NHLBI NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States HHSN268201800011I / HB / NHLBI NIH HHS / United States UL1 RR033176 / RR / NCRR NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States HHSN268201700003I / HL / NHLBI NIH HHS / United States HHSN268201500003I / HL / NHLBI NIH HHS / United States N01HC95164 / HL / NHLBI NIH HHS / United States HHSN268201800014I / HB / NHLBI NIH HHS / United States R01 HL092577 / HL / NHLBI NIH HHS / United States 75N92020D00006 / HL / NHLBI NIH HHS / United States UL1 TR001079 / TR / NCATS NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States N01HC95166 / HL / NHLBI NIH HHS / United States U01 HL072515 / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States UL1 TR000040 / TR / NCATS NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States HHSN268201800013I / MD / NIMHD NIH HHS / United States R01 HL071250 / HL / NHLBI NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States HHSN268201100037C / HL / NHLBI NIH HHS / United States R01 HL117626 / HL / NHLBI NIH HHS / United States K08 HL153950 / HL / NHLBI NIH HHS / United States 75N92021D00002 / HL / NHLBI NIH HHS / United States |
ePub date:
22/08