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; Antoine Leenhardt; 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; 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

doi:10.1161/circulationaha.120.045956

Journal Articles Circulation Year : 2020

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

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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

Isabelle Denjoy

Function : Author

Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases

Antoine Leenhardt

Function : Author

Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases

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

Pascale Guicheney

Function : Author

Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases

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

Function : Author
PersonId : 802646
ORCID : 0000-0002-0633-3514

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.

Keywords

genome-wide association study ◼ inheritance patterns ◼ long QT syndrome

Domains

Life Sciences [q-bio]

Fichier principal

Lahrouchi GWAS LQTS Circ 2020 edito.pdf (1010.8 Ko)

Origin : Files produced by the author(s)

Pascale Guicheney : Connect in order to contact the contributor

https://www.hal.inserm.fr/inserm-04021339

Submitted on : Thursday, March 9, 2023-1:30:59 PM

Last modification on : Tuesday, April 11, 2023-1:05:08 PM

Dates and versions

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

Identifiers

HAL Id : inserm-04021339 , version 1
DOI : 10.1161/circulationaha.120.045956

Cite

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

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