Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
(2020) In Circulation 142(4). p.324-338- 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.... (More)
- 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 (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/ad6ffbaa-ae0f-4f96-8700-738d7ed561cd
- author
- Lahrouchi, Najim ; Platonov, Pyotr LU and Bezzina, Connie R.
- author collaboration
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- genome-wide association study, inheritance patterns, long QT syndrome
- in
- Circulation
- volume
- 142
- issue
- 4
- pages
- 15 pages
- publisher
- Lippincott Williams & Wilkins
- external identifiers
-
- scopus:85088849122
- pmid:32429735
- ISSN
- 1524-4539
- DOI
- 10.1161/CIRCULATIONAHA.120.045956
- language
- English
- LU publication?
- yes
- id
- ad6ffbaa-ae0f-4f96-8700-738d7ed561cd
- date added to LUP
- 2020-08-10 09:32:05
- date last changed
- 2022-04-19 00:02:40
@article{ad6ffbaa-ae0f-4f96-8700-738d7ed561cd,
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}},
author = {{Lahrouchi, Najim and Platonov, Pyotr and Bezzina, Connie R.}},
issn = {{1524-4539}},
keywords = {{genome-wide association study; inheritance patterns; long QT syndrome}},
language = {{eng}},
number = {{4}},
pages = {{324--338}},
publisher = {{Lippincott Williams & Wilkins}},
series = {{Circulation}},
title = {{Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome}},
url = {{http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956}},
doi = {{10.1161/CIRCULATIONAHA.120.045956}},
volume = {{142}},
year = {{2020}},
}