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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Lahrouchi, N; Tadros, R; Crotti, L; Mizusawa, Y; Postema, PG; Beekman, L; Walsh, R; Hasegawa, K; Barc, J; Ernsting, M; et al. Lahrouchi, N; Tadros, R; Crotti, L; Mizusawa, Y; Postema, PG; Beekman, L; Walsh, R; Hasegawa, K; Barc, J; Ernsting, M; Turkowski, KL; Mazzanti, A; Beckmann, BM; Shimamoto, K; Diamant, U-B; Wijeyeratne, YD; Kucho, Y; Robyns, T; Ishikawa, T; Arbelo, E; Christiansen, M; Winbo, A; Jabbari, R; Lubitz, SA; Steinfurt, J; Rudic, B; Loeys, B; Shoemaker, MB; Weeke, PE; Pfeiffer, R; Davies, B; Andorin, A; Hofman, N; Dagradi, F; Pedrazzini, M; Tester, DJ; Bos, JM; Sarquella-Brugada, G; Campuzano, Ó; Platonov, PG; Stallmeyer, B; Zumhagen, S; Nannenberg, EA; Veldink, JH; van den Berg, LH; Al-Chalabi, A; Shaw, CE; Shaw, PJ; Morrison, KE; Andersen, PM; Müller-Nurasyid, M; Cusi, D; Barlassina, C; Galan, P; Lathrop, M; Munter, M; Werge, T; Ribasés, M; Aung, T; Khor, CC; Ozaki, M; Lichtner, P; Meitinger, T; van Tintelen, JP; Hoedemaekers, Y; Denjoy, I; Leenhardt, A; Napolitano, C; Shimizu, W; Schott, J-J; Gourraud, J-B; Makiyama, T; Ohno, S; Itoh, H; Krahn, AD; Antzelevitch, C; Roden, DM; Saenen, J; Borggrefe, M; Odening, KE; Ellinor, PT; Tfelt-Hansen, J; Skinner, JR; van den Berg, MP; Olesen, MS; Brugada, J; Brugada, R; Makita, N; Breckpot, J; Yoshinaga, M; Behr, ER; Rydberg, A; Aiba, T; Kääb, S; Priori, SG; Guicheney, P; Tan, HL; Newton-Cheh, C; Ackerman, MJ; Schwartz, PJ; Schulze-Bahr, E; Probst, V; Horie, M; Wilde, AA; Tanck, MWT; Bezzina, CR (2020) Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation, 142 (4). pp. 324-338. ISSN 1524-4539 https://doi.org/10.1161/CIRCULATIONAHA.120.045956
SGUL Authors: Behr, Elijah Raphael

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Abstract

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Item Type: Article
Additional Information: © 2020 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
Keywords: genome-wide association study, inheritance patterns, long QT syndrome, QT-interval, heritability, long QT syndrome, polygenic risk score, Cardiovascular System & Hematology, 1103 Clinical Sciences, 1102 Cardiorespiratory Medicine and Haematology, 1117 Public Health and Health Services
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Circulation
ISSN: 1524-4539
Language: eng
Dates:
DateEvent
28 July 2020Published
20 May 2020Published Online
24 April 2020Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
076113Wellcome Trusthttp://dx.doi.org/10.13039/100004440
085475Wellcome Trusthttp://dx.doi.org/10.13039/100004440
090355Wellcome Trusthttp://dx.doi.org/10.13039/100004440
CVON 2018-30 PREDICT2Dutch Heart FoundationUNSPECIFIED
016.150.610Netherlands Organization for Scientific ResearchUNSPECIFIED
733381Horizon 2020UNSPECIFIED
18CVD05Leducq Foundation for Cardiovascular ResearchUNSPECIFIED
RC17_0357Hopitaux Universitaires du Grand Ouest and Fondation Maladies RaresUNSPECIFIED
RISTRAD-661617Horizon 2020UNSPECIFIED
DEQ20140329545Fondation pour la Recherche MédicaleUNSPECIFIED
ANR-GENSUD-14-CE10-0001National Agency for ResearchUNSPECIFIED
H22-032Ministry of Health, Labour and Welfarehttp://dx.doi.org/10.13039/501100003478
H24-033Ministry of Health, Labour and Welfarehttp://dx.doi.org/10.13039/501100003478
H26-040Ministry of Health, Labour and Welfarehttp://dx.doi.org/10.13039/501100003478
PI16/0120Instituto de Salud Carlos IIIhttp://dx.doi.org/10.13039/501100004587
PI17/0169Instituto de Salud Carlos IIIhttp://dx.doi.org/10.13039/501100004587
NNF17OC0031204Novo Nordiskhttp://dx.doi.org/10.13039/501100004191
14CVD01Fondation Leducqhttp://dx.doi.org/10.13039/501100001674
1RO1HL092577National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01HL128914National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
K24HL105780National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
18SFRN34110082American Heart Associationhttp://dx.doi.org/10.13039/100000968
1R01HL139731National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
18SFRN34250007American Heart Associationhttp://dx.doi.org/10.13039/100000968
HL47678National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
HL138103National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
20180444Swedish Heart-Lung FoundationUNSPECIFIED
PubMed ID: 32429735
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111978
Publisher's version: https://doi.org/10.1161/CIRCULATIONAHA.120.045956

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