Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
Authors: Lahrouchi Najim , Tadros Rafik , Crotti Lia , Mizusawa Yuka , Postema Pieter G. , Beekman Leander , Walsh Roddy , Hasegawa Kanae , Barc Julien , Ernsting Marko , Turkowski Kari L. , Mazzanti Andrea , Beckmann Britt M. , Shimamoto Keiko , Diamant Ulla-Britt , Wijeyeratne Yanushi D. , Kucho Yu , Robyns Tomas , Ishikawa Taisuke , Arbelo Elena , Christiansen Michael , Winbo Annika , Jabbari Reza , Lubitz Steven A. , Steinfurt Johannes , Rudic Boris , Loeys Bart , Shoemaker M. Ben , Weeke Peter E. , Pfeiffer Ryan , Davies Brianna , Andorin Antoine , Hofman Nynke , Dagradi Federica , Pedrazzini Matteo , Tester David J. , Bos J. Martijn , Sarquella-Brugada Georgia , Campuzano Óscar , Platonov Pyotr G. , Stallmeyer Birgit , Zumhagen Sven , Nannenberg Eline A. , Veldink Jan H. , van den Berg Leonard H. , Al-Chalabi Ammar , Shaw Christopher E. , Shaw Pamela J. , Morrison Karen E. , Andersen Peter M. , Müller-Nurasyid Martina , Cusi Daniele , Barlassina Cristina , Galan Pilar , Lathrop Mark , Munter Markus , Werge Thomas , Ribasés Marta , Aung Tin , Khor Chiea C. , Ozaki Mineo , Lichtner Peter , Meitinger Thomas , van Tintelen J. Peter , Hoedemaekers Yvonne , Denjoy Isabelle , Leenhardt Antoine , Napolitano Carlo , Shimizu Wataru , Schott Jean-Jacques , Gourraud Jean-Baptiste , Makiyama Takeru , Ohno Seiko , Itoh Hideki , Krahn Andrew D. , Antzelevitch Charles , Roden Dan M. , Saenen Johan , Borggrefe Martin , Odening Katja E. , Ellinor Patrick T. , Tfelt-Hansen Jacob , Skinner Jonathan R. , van den Berg Maarten P. , Olesen Morten Salling , Brugada Josep , Brugada Ramón , Makita Naomasa , Breckpot Jeroen , Yoshinaga Masao , Behr Elijah R. , Rydberg Annika , Aiba Takeshi , Kääb Stefan , Priori Silvia G. , Guicheney Pascale , Tan Hanno L. , Newton-Cheh Christopher , Ackerman Michael J. , Schwartz Peter J. , Schulze-Bahr Eric , Probst Vincent , Horie Minoru , Wilde Arthur A. , Tanck Michael W.T. , Bezzina Connie R. 
Published: May 2020

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 (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.