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. 2020 May 20.
doi: 10.1161/CIRCULATIONAHA.120.045956. Online ahead of print.

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

Najim Lahrouchi  1 Rafik Tadros  2 Lia Crotti  3 Yuka Mizusawa  1 Pieter G Postema  1 Leander Beekman  1 Roddy Walsh  1 Kanae Hasegawa  4 Julien Barc  5 Marko Ernsting  6 Kari L Turkowski  7 Andrea Mazzanti  8 Britt M Beckmann  9 Keiko Shimamoto  10 Ulla-Britt Diamant  11 Yanushi D Wijeyeratne  12 Yu Kucho  13 Tomas Robyns  14 Taisuke Ishikawa  15 Elena Arbelo  16 Michael Christiansen  17 Annika Winbo  18 Reza Jabbari  19 Steven A Lubitz  20 Johannes Steinfurt  21 Boris Rudic  22 Bart Loeys  23 M Ben Shoemaker  24 Peter E Weeke  25 Ryan Pfeiffer  26 Brianna Davies  27 Antoine Andorin  28 Nynke Hofman  1 Federica Dagradi  29 Matteo Pedrazzini  30 David J Tester  7 J Martijn Bos  7 Georgia Sarquella-Brugada  31 Óscar Campuzano  32 Pyotr G Platonov  33 Birgit Stallmeyer  34 Sven Zumhagen  34 Eline A Nannenberg  35 Jan H Veldink  36 Leonard H van den Berg  36 Ammar Al-Chalabi  37 Christopher E Shaw  38 Pamela J Shaw  39 Karen E Morrison  40 Peter M Andersen  41 Martina Müller-Nurasyid  42 Daniele Cusi  43 Cristina Barlassina  43 Pilar Galan  44 Mark Lathrop  45 Markus Munter  45 Thomas Werge  46 Marta Ribasés  47 Tin Aung  48 Chiea C Khor  49 Mineo Ozaki  50 Peter Lichtner  51 Thomas Meitinger  51 J Peter van Tintelen  52 Yvonne Hoedemaekers  53 Isabelle Denjoy  54 Antoine Leenhardt  54 Carlo Napolitano  8 Wataru Shimizu  55 Jean-Jacques Schott  56 Jean-Baptiste Gourraud  56 Takeru Makiyama  57 Seiko Ohno  58 Hideki Itoh  59 Andrew D Krahn  27 Charles Antzelevitch  60 Dan M Roden  61 Johan Saenen  62 Martin Borggrefe  22 Katja E Odening  21 Patrick T Ellinor  20 Jacob Tfelt-Hansen  63 Jonathan R Skinner  64 Maarten P van den Berg  65 Morten Salling Olesen  66 Josep Brugada  67 Ramón Brugada  68 Naomasa Makita  69 Jeroen Breckpot  70 Masao Yoshinaga  13 Elijah R Behr  12 Annika Rydberg  11 Takeshi Aiba  10 Stefan Kääb  9 Silvia G Priori  8 Pascale Guicheney  71 Hanno L Tan  72 Christopher Newton-Cheh  73 Michael J Ackerman  7 Peter J Schwartz  74 Eric Schulze-Bahr  6 Vincent Probst  75 Minoru Horie  59 Arthur A Wilde  1 Michael W T Tanck  76 Connie R Bezzina  1
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Najim Lahrouchi et al. Circulation. .

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 (GWAS) followed by transethnic meta-analysis in 1,656 unrelated LQTS patients of European or Japanese ancestry and 9,890 controls to identify susceptibility single nucleotide polymorphisms (SNPs). We estimated the SNP heritability (h2SNP) of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 SNPs previously associated with QTc in the general population using a polygenic risk score (PRSQT). Results: Genome-wide association analysis identified three loci associated with LQTS at genome-wide statistical significance (P<5x10-8) near NOS1AP, KCNQ1 and KLF12, and one 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 [SE] 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT interval in the general population (rg=0.40, P=3.2x10-3). PRSQT was greater in LQTS cases compared to controls (P<10-13), and notably, among LQTS patients PRSQT was greater in genotype negative compared to genotype positive patients (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: QT-interval; heritability; long QT syndrome; polygenic risk score.

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