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Journal Articles Circulation Year : 2020

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

Najim Lahrouchi , Rafik Tadros , Lia Crotti , Yuka Mizusawa , Pieter G Postema , Leander Beekman , Roddy Walsh , Kanae Hasegawa , Julien Barc , Marko Ernsting , Kari L Turkowski , Andrea Mazzanti , Britt M Beckmann , Keiko Shimamoto , Ulla-Britt Diamant , Yanushi D Wijeyeratne , Yu Kucho , Tomas Robyns , Taisuke Ishikawa , Elena Arbelo , Michael Christiansen , Annika Winbo , Reza Jabbari , Steven A Lubitz , Johannes Steinfurt , Boris Rudic , Bart Loeys , M Ben Shoemaker , Peter E Weeke , Ryan Pfeiffer , Brianna Davies , Antoine Andorin , Nynke Hofman , Federica Dagradi , Matteo Pedrazzini , David J Tester , J Martijn Bos , Georgia Sarquella-Brugada , Óscar Campuzano , Pyotr G Platonov , Birgit Stallmeyer , Sven Zumhagen , Eline A Nannenberg , Jan H Veldink , Leonard H van den Berg , Ammar Al-Chalabi , Christopher E Shaw , Pamela J Shaw , Karen E Morrison , Peter M Andersen , Martina Müller-Nurasyid , Daniele Cusi , Cristina Barlassina , Pilar Galan , Mark Lathrop , Markus Munter , Thomas Werge , Marta Ribasés , Tin Aung , Chiea C Khor , Mineo Ozaki , Peter Lichtner , Thomas Meitinger , J Peter van Tintelen , Yvonne Hoedemaekers , Isabelle Denjoy (1) , Antoine Leenhardt (1) , Carlo Napolitano , Wataru Shimizu , Jean-Jacques Schott , Jean-Baptiste Gourraud , Takeru Makiyama , Seiko Ohno , Hideki Itoh , Andrew D Krahn , Charles Antzelevitch , Dan M Roden , Johan Saenen , Martin Borggrefe , Katja E Odening , Patrick T Ellinor , Jacob Tfelt-Hansen , Jonathan R Skinner , Maarten P van den Berg , Morten Salling Olesen , Josep Brugada , Ramón Brugada , Naomasa Makita , Jeroen Breckpot , Masao Yoshinaga , Elijah R Behr , Annika Rydberg , Takeshi Aiba , Stefan Kääb , Silvia G Priori , Pascale Guicheney (1) , Hanno L Tan , Christopher Newton-Cheh , Michael J Ackerman , Peter J Schwartz , Eric Schulze-Bahr , Vincent Probst , Minoru Horie , Arthur A Wilde , Michael W T Tanck , Connie R Bezzina
Najim Lahrouchi
  • Function : Author
Rafik Tadros
  • Function : Author
Lia Crotti
  • Function : Author
Yuka Mizusawa
  • Function : Author
Pieter G Postema
  • Function : Author
Leander Beekman
  • Function : Author
Roddy Walsh
  • Function : Author
Kanae Hasegawa
  • Function : Author
Julien Barc
  • Function : Author
Marko Ernsting
  • Function : Author
Kari L Turkowski
  • Function : Author
Andrea Mazzanti
  • Function : Author
Britt M Beckmann
  • Function : Author
Keiko Shimamoto
  • Function : Author
Ulla-Britt Diamant
  • Function : Author
Yanushi D Wijeyeratne
  • Function : Author
Yu Kucho
  • Function : Author
Tomas Robyns
  • Function : Author
Taisuke Ishikawa
  • Function : Author
Elena Arbelo
  • Function : Author
Michael Christiansen
  • Function : Author
Annika Winbo
  • Function : Author
Reza Jabbari
  • Function : Author
Steven A Lubitz
  • Function : Author
Johannes Steinfurt
  • Function : Author
Boris Rudic
  • Function : Author
Bart Loeys
  • Function : Author
M Ben Shoemaker
  • Function : Author
Peter E Weeke
  • Function : Author
Ryan Pfeiffer
  • Function : Author
Brianna Davies
  • Function : Author
Antoine Andorin
  • Function : Author
Nynke Hofman
  • Function : Author
Federica Dagradi
  • Function : Author
Matteo Pedrazzini
  • Function : Author
David J Tester
  • Function : Author
J Martijn Bos
  • Function : Author
Georgia Sarquella-Brugada
  • Function : Author
Óscar Campuzano
  • Function : Author
Pyotr G Platonov
  • Function : Author
Birgit Stallmeyer
  • Function : Author
Sven Zumhagen
  • Function : Author
Eline A Nannenberg
  • Function : Author
Jan H Veldink
  • Function : Author
Leonard H van den Berg
  • Function : Author
Ammar Al-Chalabi
  • Function : Author
Christopher E Shaw
  • Function : Author
Pamela J Shaw
  • Function : Author
Karen E Morrison
  • Function : Author
Peter M Andersen
  • Function : Author
Martina Müller-Nurasyid
  • Function : Author
Daniele Cusi
  • Function : Author
Cristina Barlassina
  • Function : Author
Pilar Galan
  • Function : Author
Mark Lathrop
  • Function : Author
Markus Munter
  • Function : Author
Thomas Werge
  • Function : Author
Marta Ribasés
  • Function : Author
Tin Aung
  • Function : Author
Chiea C Khor
  • Function : Author
Mineo Ozaki
  • Function : Author
Peter Lichtner
  • Function : Author
Thomas Meitinger
  • Function : Author
J Peter van Tintelen
  • Function : Author
Yvonne Hoedemaekers
  • Function : Author
Carlo Napolitano
  • Function : Author
Wataru Shimizu
  • Function : Author
Jean-Jacques Schott
  • Function : Author
Jean-Baptiste Gourraud
  • Function : Author
Takeru Makiyama
  • Function : Author
Seiko Ohno
  • Function : Author
Hideki Itoh
  • Function : Author
Andrew D Krahn
  • Function : Author
Charles Antzelevitch
  • Function : Author
Dan M Roden
  • Function : Author
Johan Saenen
  • Function : Author
Martin Borggrefe
  • Function : Author
Katja E Odening
  • Function : Author
Patrick T Ellinor
  • Function : Author
Jacob Tfelt-Hansen
  • Function : Author
Jonathan R Skinner
  • Function : Author
Maarten P van den Berg
  • Function : Author
Morten Salling Olesen
  • Function : Author
Josep Brugada
  • Function : Author
Ramón Brugada
  • Function : Author
Naomasa Makita
  • Function : Author
Jeroen Breckpot
  • Function : Author
Masao Yoshinaga
  • Function : Author
Elijah R Behr
  • Function : Author
Annika Rydberg
  • Function : Author
Takeshi Aiba
  • Function : Author
Stefan Kääb
  • Function : Author
Silvia G Priori
  • Function : Author
Hanno L Tan
  • Function : Author
Christopher Newton-Cheh
  • Function : Author
Michael J Ackerman
  • Function : Author
Peter J Schwartz
  • Function : Author
Eric Schulze-Bahr
  • Function : Author
Vincent Probst
  • Function : Author
Minoru Horie
  • Function : Author
Arthur A Wilde
  • Function : Author
Michael W T Tanck
  • Function : Author
Connie R Bezzina

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 (h 2 SNP 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 (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.
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Dates and versions

inserm-04021339 , version 1 (09-03-2023)

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Najim Lahrouchi, Rafik Tadros, Lia Crotti, Yuka Mizusawa, Pieter G Postema, et al.. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation, 2020, 142, pp.324 - 338. ⟨10.1161/circulationaha.120.045956⟩. ⟨inserm-04021339⟩
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