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 (P5×10 -8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P10 -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 (r g=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 (P10-13), 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 (P0.005). 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.
Original language | English |
---|---|
Pages (from-to) | 324-338 |
Number of pages | 15 |
Journal | Circulation |
Volume | 142 |
Issue number | 4 |
Early online date | 20 May 2020 |
DOIs | |
Publication status | Published - 28 Jul 2020 |
Keywords
- genome-wide association study
- inheritance patterns
- long QT syndrome
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In: Circulation, Vol. 142, No. 4, 28.07.2020, p. 324-338.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
AU - Lahrouchi, Najim
AU - Tadros, Rafik
AU - Crotti, Lia
AU - Mizusawa, Yuka
AU - Postema, Pieter G
AU - Beekman, Leander
AU - Walsh, Roddy
AU - Hasegawa, Kanae
AU - Barc, Julien
AU - Ernsting, Marko
AU - Turkowski, Kari L
AU - Mazzanti, Andrea
AU - Beckmann, Britt M
AU - Shimamoto, Keiko
AU - Diamant, Ulla-Britt
AU - Wijeyeratne, Yanushi D
AU - Kucho, Yu
AU - Robyns, Tomas
AU - Ishikawa, Taisuke
AU - Arbelo, Elena
AU - Christiansen, Michael
AU - Winbo, Annika
AU - Jabbari, Reza
AU - Lubitz, Steven A
AU - Steinfurt, Johannes
AU - Rudic, Boris
AU - Loeys, Bart
AU - Shoemaker, M Ben
AU - Weeke, Peter E
AU - Pfeiffer, Ryan
AU - Davies, Brianna
AU - Andorin, Antoine
AU - Hofman, Nynke
AU - Dagradi, Federica
AU - Pedrazzini, Matteo
AU - Tester, David J
AU - Bos, J Martijn
AU - Sarquella-Brugada, Georgia
AU - Campuzano, Óscar
AU - Platonov, Pyotr G
AU - Stallmeyer, Birgit
AU - Zumhagen, Sven
AU - Nannenberg, Eline A
AU - Veldink, Jan H
AU - van den Berg, Leonard H
AU - Al-Chalabi, Ammar
AU - Shaw, Christopher E
AU - Shaw, Pamela J
AU - Morrison, Karen E
AU - Andersen, Peter M
AU - Müller-Nurasyid, Martina
AU - Cusi, Daniele
AU - Barlassina, Cristina
AU - Galan, Pilar
AU - Lathrop, Mark
AU - Munter, Markus
AU - Werge, Thomas
AU - Ribasés, Marta
AU - Aung, Tin
AU - Khor, Chiea C
AU - Ozaki, Mineo
AU - Lichtner, Peter
AU - Meitinger, Thomas
AU - van Tintelen, J Peter
AU - Hoedemaekers, Yvonne
AU - Denjoy, Isabelle
AU - Leenhardt, Antoine
AU - Napolitano, Carlo
AU - Shimizu, Wataru
AU - Schott, Jean-Jacques
AU - Gourraud, Jean-Baptiste
AU - Makiyama, Takeru
AU - Ohno, Seiko
AU - Itoh, Hideki
AU - Krahn, Andrew D
AU - Antzelevitch, Charles
AU - Roden, Dan M
AU - Saenen, Johan
AU - Borggrefe, Martin
AU - Odening, Katja E
AU - Ellinor, Patrick T
AU - Tfelt-Hansen, Jacob
AU - Skinner, Jonathan R
AU - van den Berg, Maarten P
AU - Olesen, Morten Salling
AU - Brugada, Josep
AU - Brugada, Ramón
AU - Makita, Naomasa
AU - Breckpot, Jeroen
AU - Yoshinaga, Masao
AU - Behr, Elijah R
AU - Rydberg, Annika
AU - Aiba, Takeshi
AU - Kääb, Stefan
AU - Priori, Silvia G
AU - Guicheney, Pascale
AU - Tan, Hanno L
AU - Newton-Cheh, Christopher
AU - Ackerman, Michael J
AU - Schwartz, Peter J
AU - Schulze-Bahr, Eric
AU - Probst, Vincent
AU - Horie, Minoru
AU - Wilde, Arthur A
AU - Tanck, Michael W T
AU - Bezzina, Connie R
N1 - Funding Information: Najim Lahrouchi was supported by the Kenneth M. Rosen Fellowship in Cardiac Pacing and Electrophysiology Scholarship of the Heart Rhythm Society, the CVON-PREDICT Young Talent Program of the Dutch Heart Foundation, and the SADS Foundation Courts K. Cleveland Jr. Young Investigator Award in Cardiac Channelopathy Research. Drs Bezzina, Lahrouchi, Wilde, van Tintelen, and Tan acknowledge the support from the Dutch Heart Foundation (CVON 2018-30 PREDICT2 project to Drs Bezzina, Tan, and Wilde) and the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610, to Dr Bez-zina). Dr Tan has received funding from the European Union’s Horizon 2020 research and innovation program under acronym ESCAPE-NET (The European Sudden Cardiac Arrest network toward Prevention, Education, New Effective Treatment), registered under grant agreement No 733381. Dr Tadros received support from the Canadian Heart Rhythm Society (George Mines Award), the European Society of Cardiology (research award), and the Philippa and Marvin Carsley Cardiology Chair and is currently a clinical research scholar of the Fonds de Recherche du Québec—Santé. Drs Shaw and Crotti acknowledge the support of the Leducq Foundation for cardiovascular research grant 18CVD05: Toward Precision Medicine with Human iPSCs for Cardiac Channelopathies. Drs Probst and Gourraud were supported by a grant from Hopitaux Universitaires du Grand Ouest and Fondation Maladies Rares (RC17_0357). Dr Breckpot was supported by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617) and by the Regional Council of Pays-de-la-Loire (Etoile montante: REGIOCARD). Dr Schott was supported by the Fondation pour la Recherche Médicale (DEQ20140329545) and by the National Agency for Research (ANR-GENSUD-14-CE10-0001). Drs Rydberg and Diamant are supported by The Swedish Heart-Lung Foundation. Dr Behr is supported by the Higher Education Funding Council for England and the British Heart Foundation and acknowledges support from Cardiac Risk in the Young. Dr Wijeyeratne had received support through an Academic Clinical Fellowship from the National Institute of Health Research. Drs Wijeyeratne and Behr gratefully acknowledge funding and ongoing support from the James Lancaster Memorial Fund sponsored by McColl’s RG Ltd. This work was partly supported by a Health and Labor Sciences Research Grant from the Ministry of Health, Labor, and Welfare of Japan (H22-032, H24-033, H26-040, and H29-055) to Dr Yoshinaga. Dr Makita is supported by AMED (19kk0305011h0001). Drs Shimizu and Aung acknowledge support from a Health Science Research Grant from the Ministry of Health, Labor and Welfare of Japan for Clinical Research on Measures for Intractable Diseases (H24-033, H26-040, and H27-032). Dr Arbelo is supported by Insti-tuto de Salud Carlos III (FIS PI16/01203 and PI17/01690) cofunded by ERDF/ESF, “Investing in Your Future.” This work was supported by the John and Birthe Meyer Foundation, The Hallas-Møller Emerging Investigator Novo Nordisk (NN-F17OC0031204). The iPSYCH study was funded by the Lundbeck Foundation Initiative for Integrative Psychiatric Research. This research has been conducted using the Danish National Biobank resource. The Cardiac Inherited Disease Registry has been supported by Cure Kids. AW is supported by the Hugh Green Foundation. Dr Ellinor is supported by the Fondation Leducq (14CVD01), by grants from the National Institutes of Health (1RO1HL092577, R01HL128914, K24HL105780) and the American Heart Association (18SFRN34110082). SAL is supported by National Institutes for Health grant 1R01HL139731 and American Heart Association 18SFRN34250007. Dr Loeys is supported by a European Research Council consolidator grant. Dr Roden is supported by P50 GM115305 and MBS by K23 HL127704. Dr Antzelevitch is supported by grants from the National Institutes for Health, HL47678 and HL138103. Dr Postema is supported by The Swedish Heart-Lung Foundation, grant #20180444. Drs Turkowski, Tester, Bos, and Ackerman were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Funding Information: Dr Behr received previous research funds from Biotronik and consulting for Medtronic. Dr Arbelo received speaking fees from Biosense Webster. Dr Lub-itz receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb/Pfizer and Bayer AG. Dr Weeke is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. Dr Weeke has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. Dr Cusi is a scientific consultant for Bio4Dreams. Dr Ackerman is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, Myokardia, and St. Jude Medical. Dr Ackerman and Mayo Clinic have an equity/royalty-based licensing agreement with Alive-Cor. The other authors report no conflicts. Funding Information: The authors thank Estelle Baron, Simon Lecointe, Annabelle Rajalu, Aurélie Thol-let, and Florence Kyndt for their help in DNA sample preparation and regulatory processes at the Nantes center, the Nantes biological resource center for biobank-ing (CHU Nantes, Hôtel Dieu, Center de Resources Biologiques, Nantes, F-44093, France [BRIF: BB-0033-00040]), and the National Referral Center for Inherited Cardiac Arrhythmias of Nantes and its associated competence centers. We thank Professor Pier D. Lambiase and Professor Patricia B. Munroe for sharing summary statistics. We thank Dr Nicky Whiffin for help with using CardioClassifier. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München–German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data are available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475, and 090355. Publisher Copyright: © 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/7/28
Y1 - 2020/7/28
N2 - 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 (P5×10 -8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P10 -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 (r g=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 (P10-13), 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 (P0.005). 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.
AB - 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 (P5×10 -8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P10 -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 (r g=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 (P10-13), 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 (P0.005). 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.
KW - genome-wide association study
KW - inheritance patterns
KW - long QT syndrome
UR - http://www.scopus.com/inward/record.url?scp=85088849122&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.120.045956
DO - 10.1161/CIRCULATIONAHA.120.045956
M3 - Article
C2 - 32429735
SN - 0009-7322
VL - 142
SP - 324
EP - 338
JO - Circulation
JF - Circulation
IS - 4
ER -