Examining rare and low-frequency genetic variants previously associated with lone or familial forms of atrial fibrillation in an electronic medical record system: a cautionary note.
Examining rare and low-frequency genetic variants previously associated with lone or familial forms of atrial fibrillation in an electronic medical record system: a cautionary note.
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DOI：
10.1161/circgenetics.114.000718
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Roden DM
中科院分区：
文献类型：
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作者：
Weeke P;Denny JC;Basterache L;Shaffer C;Bowton E;Ingram C;Darbar D;Roden DM
在个体或小激酶的研究中，使用连锁和分离分析、功能表征和公共数据库中的罕见性，发现孤立性和家族性房颤（AF）中25个不同基因的罕见变异。在这里，我们使用了20，204名欧洲或非洲血统的患者的电子病历（EMR）和外显子组芯片数据，以比较这些罕见变体的携带者和非携带者之间的AF频率。外显子组芯片包括9个基因中的19/115种罕见变异，这些变异先前与孤立性或家族性AF相关。使用经验证的算法查询临床记录、结构化账单代码、ECG报告和程序代码的组合，我们确定了1，056例AF病例在范德比尔特电子病历关联DNA库BioVU的Illumina HumanExome BeadChip v.1.0上，AF和4 q25常见变异之间的已知相关性被复制。19种先前与AF相关的变异在AF病例中均未过度表达（所有病例P >0.1），14/19例非AF对照中变异携带者的频率>0.1%。对年龄>60岁（n= 14，904）、>70岁（n= 9，670）和>80岁（n= 4，729）的非AF对照进行重复分析，对这些结果没有影响。罕见的变异，以前牵连在孤独或家族性形式AF外显子组芯片上检测到在一般人群中的低频率，但不与AF。这些研究结果强调，需要谨慎时，归因于致病性或致病性的变异。
Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and familial atrial fibrillation (AF) using linkage and segregation analysis, functional characterization, and rarity in public databases. Here we used a cohort of 20,204 patients of European or African ancestry with electronic medical records (EMRs) and exome chip data to compare the frequency of AF among carriers and non-carriers of these rare variants. The exome chip included 19/115 rare variants, in 9 genes, previously associated with lone or familial AF. Using validated algorithms querying a combination of clinical notes, structured billing codes, ECG reports, and procedure codes, we identified 1,056 AF cases (>18 years) and 19,148 non-AF controls (>50 years) with available genotype data on the Illumina HumanExome BeadChip v.1.0 in the Vanderbilt electronic medical record-linked DNA repository, BioVU. Known correlations between AF and common variants at 4q25 were replicated. None of the 19 variants previously associated with AF were overrepresented among AF cases (P >0.1 for all), and the frequency of variant carriers among non-AF controls was >0.1% for 14/19. Repeat analyses using non-AF controls aged >60 (n=14,904) >70 (n=9,670), and >80 (n=4,729) years old did not influence these findings. Rare variants previously implicated in lone or familial forms AF present on the exome chip are detected at low frequencies in a general population but are not associated with AF. These findings emphasize the need for caution when ascribing variants as pathogenic or causative.