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

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Fältnamn	Indikatorer	Metadata
000		09805naa a2201717 4500
001		oai:DiVA.org:umu-174908
003		SwePub
008		200911s2020 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
009		oai:lup.lub.lu.se:ad6ffbaa-ae0f-4f96-8700-738d7ed561cd
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1749082 URI
024	7	a https://doi.org/10.1161/CIRCULATIONAHA.120.0459562 DOI
024	7	a https://lup.lub.lu.se/record/ad6ffbaa-ae0f-4f96-8700-738d7ed561cd2 URI
040		a (SwePub)umud (SwePub)lu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Lahrouchi, Najimu University of Amsterdam,Academic Medical Center of University of Amsterdam (AMC)4 aut
245	1 0	a Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
264	1	b Lippincott Williams & Wilkins,c 2020
338		a electronic2 rdacarrier
520		a 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<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Kardiologi0 (SwePub)302062 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Cardiac and Cardiovascular Systems0 (SwePub)302062 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Medicinsk genetik0 (SwePub)301072 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medical Genetics0 (SwePub)301072 hsv//eng
653		a genome-wide association study
653		a inheritance patterns
653		a long QT syndrome
653		a genome-wide association study
653		a inheritance patterns
653		a long QT syndrome
700	1	a Tadros, Rafik4 aut
700	1	a Crotti, Lia4 aut
700	1	a Mizusawa, Yuka4 aut
700	1	a Postema, Pieter G.4 aut
700	1	a Beekman, Leander4 aut
700	1	a Walsh, Roddy4 aut
700	1	a Hasegawa, Kanae4 aut
700	1	a Barc, Julien4 aut
700	1	a Ernsting, Marko4 aut
700	1	a Turkowski, Kari L.4 aut
700	1	a Mazzanti, Andrea4 aut
700	1	a Beckmann, Britt M.4 aut
700	1	a Shimamoto, Keiko4 aut
700	1	a Diamant, Ulla-Brittu Umeå universitet,Pediatrik,European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart4 aut0 (Swepub:umu)uldi0001
700	1	a Wijeyeratne, Yanushi D.4 aut
700	1	a Kucho, Yu4 aut
700	1	a Robyns, Tomas4 aut
700	1	a Ishikawa, Taisuke4 aut
700	1	a Arbelo, Elena4 aut
700	1	a Christiansen, Michael4 aut
700	1	a Winbo, Annika4 aut
700	1	a Jabbari, Reza4 aut
700	1	a Lubitz, Steven A.4 aut
700	1	a Steinfurt, Johannes4 aut
700	1	a Rudic, Boris4 aut
700	1	a Loeys, Bart4 aut
700	1	a Shoemaker, M. Ben4 aut
700	1	a Weeke, Peter E.4 aut
700	1	a Pfeiffer, Ryan4 aut
700	1	a Davies, Brianna4 aut
700	1	a Andorin, Antoine4 aut
700	1	a Hofman, Nynke4 aut
700	1	a Dagradi, Federica4 aut
700	1	a Pedrazzini, Matteo4 aut
700	1	a Tester, David J.4 aut
700	1	a Bos, J. Martijn4 aut
700	1	a Sarquella-Brugada, Georgia4 aut
700	1	a Campuzano, Oscar4 aut
700	1	a Platonov, Pyotru Lund University,Lunds universitet,Electrocardiology Research Group - CIEL,Forskargrupper vid Lunds universitet,Lund University Research Groups4 aut0 (Swepub:lu)kard-ppl
700	1	a Stallmeyer, Birgit4 aut
700	1	a Zumhagen, Sven4 aut
700	1	a Nannenberg, Eline A.4 aut
700	1	a Veldink, Jan H.4 aut
700	1	a van den Berg, Leonard H.4 aut
700	1	a Al-Chalabi, Ammar4 aut
700	1	a Shaw, Christopher E.4 aut
700	1	a Shaw, Pamela J.4 aut
700	1	a Morrison, Karen E.4 aut
700	1	a Andersen, Peter M.,d 1962-u Umeå universitet,Klinisk neurovetenskap,Department of Neurology, Ulm University, Germany (P.M.A.)4 aut0 (Swepub:umu)pean0001
700	1	a Mueller-Nurasyid, Martina4 aut
700	1	a Cusi, Daniele4 aut
700	1	a Barlassina, Cristina4 aut
700	1	a Galan, Pilar4 aut
700	1	a Lathrop, Mark4 aut
700	1	a Munter, Markus4 aut
700	1	a Werge, Thomas4 aut
700	1	a Ribases, Marta4 aut
700	1	a Aung, Tin4 aut
700	1	a Khor, Chiea C.4 aut
700	1	a Ozaki, Mineo4 aut
700	1	a Lichtner, Peter4 aut
700	1	a Meitinger, Thomas4 aut
700	1	a van Tintelen, J. Peter4 aut
700	1	a Hoedemaekers, Yvonne4 aut
700	1	a Denjoy, Isabelle4 aut
700	1	a Leenhardt, Antoine4 aut
700	1	a Napolitano, Carlo4 aut
700	1	a Shimizu, Wataru4 aut
700	1	a Schott, Jean-Jacques4 aut
700	1	a Gourraud, Jean-Baptiste4 aut
700	1	a Makiyama, Takeru4 aut
700	1	a Ohno, Seiko4 aut
700	1	a Itoh, Hideki4 aut
700	1	a Krahn, Andrew D.4 aut
700	1	a Antzelevitch, Charles4 aut
700	1	a Roden, Dan M.4 aut
700	1	a Saenen, Johan4 aut
700	1	a Borggrefe, Martin4 aut
700	1	a Odening, Katja E.4 aut
700	1	a Ellinor, Patrick T.4 aut
700	1	a Tfelt-Hansen, Jacob4 aut
700	1	a Skinner, Jonathan R.4 aut
700	1	a van den Berg, Maarten P.4 aut
700	1	a Olesen, Morten Salling4 aut
700	1	a Brugada, Josep4 aut
700	1	a Brugada, Ramon4 aut
700	1	a Makita, Naomasa4 aut
700	1	a Breckpot, Jeroen4 aut
700	1	a Yoshinaga, Masao4 aut
700	1	a Behr, Elijah R.4 aut
700	1	a Rydberg, Annikau Umeå universitet,Pediatrik,European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart4 aut0 (Swepub:umu)anry0014
700	1	a Aiba, Takeshi4 aut
700	1	a Kaeaeb, Stefan4 aut
700	1	a Priori, Silvia G.4 aut
700	1	a Guicheney, Pascale4 aut
700	1	a Tan, Hanno L.4 aut
700	1	a Newton-Cheh, Christopher4 aut
700	1	a Ackerman, Michael J.4 aut
700	1	a Schwartz, Peter J.4 aut
700	1	a Schulze-Bahr, Eric4 aut
700	1	a Probst, Vincent4 aut
700	1	a Horie, Minoru4 aut
700	1	a Wilde, Arthur A.4 aut
700	1	a Tanck, Michael W. T.4 aut
700	1	a Bezzina, Connie R.u Academic Medical Center of University of Amsterdam (AMC)4 aut
710	2	a University of Amsterdamb Academic Medical Center of University of Amsterdam (AMC)4 org
710	2	a et al.
773	0	t Circulationd : Lippincott Williams & Wilkinsg 142:4, s. 324-338q 142:4<324-338x 0009-7322x 1524-4539
856	4	u https://doi.org/10.1161/CIRCULATIONAHA.120.045956y Fulltext
856	4	u https://umu.diva-portal.org/smash/get/diva2:1466263/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4	u http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956x freey FULLTEXT
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-174908
856	4 8	u https://doi.org/10.1161/CIRCULATIONAHA.120.045956
856	4 8	u https://lup.lub.lu.se/record/ad6ffbaa-ae0f-4f96-8700-738d7ed561cd

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Av författaren/redakt...: Lahrouchi, Najim; Tadros, Rafik; Crotti, Lia; Mizusawa, Yuka; Postema, Pieter ...; Beekman, Leander; visa fler...; Walsh, Roddy; Hasegawa, Kanae; Barc, Julien; Ernsting, Marko; Turkowski, Kari ...; Mazzanti, Andrea; Beckmann, Britt ...; Shimamoto, Keiko; Diamant, Ulla-Br ...; Wijeyeratne, Yan ...; Kucho, Yu; Robyns, Tomas; Ishikawa, Taisuk ...; Arbelo, Elena; Christiansen, Mi ...; Winbo, Annika; Jabbari, Reza; Lubitz, Steven A ...; Steinfurt, Johan ...; Rudic, Boris; Loeys, Bart; Shoemaker, M. Be ...; Weeke, Peter E.; Pfeiffer, Ryan; Davies, Brianna; Andorin, Antoine; Hofman, Nynke; Dagradi, Federic ...; Pedrazzini, Matt ...; Tester, David J.; Bos, J. Martijn; Sarquella-Brugad ...; Campuzano, Oscar; Platonov, Pyotr; Stallmeyer, Birg ...; Zumhagen, Sven; Nannenberg, Elin ...; Veldink, Jan H.; van den Berg, Le ...; Al-Chalabi, Amma ...; Shaw, Christophe ...; Shaw, Pamela J.; Morrison, Karen ...; Andersen, Peter ...; Mueller-Nurasyid ...; Cusi, Daniele; Barlassina, Cris ...; Galan, Pilar; Lathrop, Mark; Munter, Markus; Werge, Thomas; Ribases, Marta; Aung, Tin; Khor, Chiea C.; Ozaki, Mineo; Lichtner, Peter; Meitinger, Thoma ...; van Tintelen, J. ...; Hoedemaekers, Yv ...; Denjoy, Isabelle; Leenhardt, Antoi ...; Napolitano, Carl ...; Shimizu, Wataru; Schott, Jean-Jac ...; Gourraud, Jean-B ...; Makiyama, Takeru; Ohno, Seiko; Itoh, Hideki; Krahn, Andrew D.; Antzelevitch, Ch ...; Roden, Dan M.; Saenen, Johan; Borggrefe, Marti ...; Odening, Katja E ...; Ellinor, Patrick ...; Tfelt-Hansen, Ja ...; Skinner, Jonatha ...; van den Berg, Ma ...; Olesen, Morten S ...; Brugada, Josep; Brugada, Ramon; Makita, Naomasa; Breckpot, Jeroen; Yoshinaga, Masao; Behr, Elijah R.; Rydberg, Annika; Aiba, Takeshi; Kaeaeb, Stefan; Priori, Silvia G ...; Guicheney, Pasca ...; Tan, Hanno L.; Newton-Cheh, Chr ...; Ackerman, Michae ...; Schwartz, Peter ...; Schulze-Bahr, Er ...; Probst, Vincent; Horie, Minoru; Wilde, Arthur A.; Tanck, Michael W ...; Bezzina, Connie ...; visa färre...

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