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Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis
Circulation: Genomic and Precision Medicine ( IF 7.4 ) Pub Date : 2021-07-28 , DOI: 10.1161/circgen.120.003300
Seung Hoan Choi 1 , Sean J Jurgens 1 , Christopher M Haggerty 2, 3 , Amelia W Hall 1, 4 , Jennifer L Halford 1, 5 , Valerie N Morrill 1, 4 , Lu-Chen Weng 1, 4 , Braxton Lagerman 6 , Tooraj Mirshahi 7 , Mary Pettinger 8 , Xiuqing Guo 9 , Henry J Lin 9 , Alvaro Alonso 10 , Elsayed Z Soliman 11 , Jelena Kornej 12, 13 , Honghuang Lin 14 , Arden Moscati 15 , Girish N Nadkarni 15, 16 , Jennifer A Brody 17 , Kerri L Wiggins 17 , Brian E Cade 18, 19 , Jiwon Lee 20 , Christina Austin-Tse 5, 21, 22 , Tom Blackwell 23 , Mark D Chaffin 1 , Christina J-Y Lee 1 , Heidi L Rehm 1, 5, 21 , Carolina Roselli 1 , , Susan Redline 24 , Braxton D Mitchell 25, 26 , Nona Sotoodehnia 17, 27 , Bruce M Psaty 17, 28, 29, 30 , Susan R Heckbert 17, 28 , Ruth J F Loos 15, 31 , Ramachandran S Vasan 12, 13, 32 , Emelia J Benjamin 12, 32, 33 , Adolfo Correa 34 , Eric Boerwinkle 35 , Dan E Arking 36 , Jerome I Rotter 9 , Stephen S Rich 37 , Eric A Whitsel 38, 39 , Marco Perez 40 , Charles Kooperberg 8 , Brandon K Fornwalt 2, 3, 41 , Kathryn L Lunetta 42 , Patrick T Ellinor 1, 4, 43 , Steven A Lubitz 1, 4, 43 ,
Affiliation  

Background:Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.Methods:Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).Results:We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10−5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10−25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.Conclusions:Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

中文翻译:

与心电图间隔相关的罕见编码变异识别单基因心律失常易感基因:多祖先分析

背景:心电图 (ECG) 间期的改变是众所周知的心律失常和心源性猝死 (SCD) 风险标志。虽然已经研究了心律失常综合征的遗传学,但人们对心电图间期与人群水平的罕见遗传变异之间的关系知之甚少。方法:使用 29000 名个体的发现样本,通过 Trans-Omics in Precision Medicine and replication 进行全基因组测序在来自 UK Biobank 和 MyCode 的近 100,000 个全外显子组测序中,我们检查了低频和稀有编码变异与 5 种常规测量的心电图特征(RR、P 波、PR 和 QRS 间期和校正的 QT 间期)之间的关联。结果:KCNQ1KCNH2SCN5A),一个有争议的单基因 SCD 基因(KCNE1),以及参与心脏传导的新基因( PAMMFGE8 )。0.1% 的个体携带功能丧失和致病性SCN5A变异,与一度房室传导阻滞的几率增加近 6 倍相关 ( P =8.4×10 -5 )。KCNQ1KCNH2中的类似变异(0.2% 的个体)与显着校正 QT 间期延长的几率增加 23 倍相关(P =4×10 -25), SCD 风险的标志。这种有害变异的不完全外显率很常见,因为超过 70% 的携带者心电图间期正常。结论:我们的研究结果表明,大规模高深度序列数据和心电图分析确定了单基因心律失常易感基因和具有较大影响的罕见变异。常规心律失常和 SCD 基因的已知致病变异表现出不完全外显率,并且仅占显着心电图间期延长的一小部分。
更新日期:2021-08-17
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