Phenome risk classification enables phenotypic imputation and gene discovery in developmental stuttering.
Phenome risk classification enables phenotypic imputation and gene discovery in developmental stuttering.
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DOI：
10.1016/j.ajhg.2021.11.004
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发表时间：
2021-12-02
影响因子：
9.8
通讯作者：
Below JE
中科院分区：
文献类型：
--
作者：
Shaw DM;Polikowsky HP;Pruett DG;Chen HH;Petty LE;Viljoen KZ;Beilby JM;Jones RM;Kraft SJ;Below JE
发展性口吃是一种言语障碍，其特征是言语向前运动中断。这种中断包括部分单词和单音节重复、重复和阻碍音节和单词的无意识紧张，这种疾病的终生患病率为6- 12%。在范德比尔特的电子健康记录（EHR）链接的生物储存库（BioVU）中，92，762名参与者中只有142人（0.15%）被识别为诊断ICD 9/10代码，这表明很大一部分口吃的人在EHR中没有诊断记录。为了在我们的EHR中识别受口吃影响的个体，我们建立了一个PheCode驱动的基于Gini杂质的分类和回归树模型PheML，通过使用受口吃影响的个体中丰富的合并症作为预测特征，并将口吃状态作为结果变量。在BioVU中应用PheML确定了9，239名基因型受影响的个体（临床患病率约10%），用于下游遗传分析。PheML插补的受影响个体和匹配对照个体的分层GWAS鉴定出rs 12613255，这是2号染色体上CYRIA附近的一种变体（B = 0.323; p值= 1.31 × 10−8），在欧洲血统分析和rs7837758中（B = 0.518; p值= 5.07 × 10−8），在非洲血统分析中，在8号染色体上的ZMAT 4基因内发现的内含子变体。多基因风险预测和一致性分析在一个独立的临床确定的样本发育性口吃病例验证了我们的GWAS的研究结果在PheML插补的影响和控制个人，并证明了我们的人口为基础的口吃风险分析的临床相关性。
Developmental stuttering is a speech disorder characterized by disruption in the forward movement of speech. This disruption includes part-word and single-syllable repetitions, prolongations, and involuntary tension that blocks syllables and words, and the disorder has a life-time prevalence of 6–12%. Within Vanderbilt’s electronic health record (EHR)-linked biorepository (BioVU), only 142 individuals out of 92,762 participants (0.15%) are identified with diagnostic ICD9/10 codes, suggesting a large portion of people who stutter do not have a record of diagnosis within the EHR. To identify individuals affected by stuttering within our EHR, we built a PheCode-driven Gini impurity-based classification and regression tree model, PheML, by using comorbidities enriched in individuals affected by stuttering as predicting features and imputing stuttering status as the outcome variable. Applying PheML in BioVU identified 9,239 genotyped affected individuals (a clinical prevalence of ∼10%) for downstream genetic analysis. Ancestry-stratified GWAS of PheML-imputed affected individuals and matched control individuals identified rs12613255, a variant near CYRIA on chromosome 2 (B = 0.323; p value = 1.31 × 10−8) in European-ancestry analysis and rs7837758 (B = 0.518; p value = 5.07 × 10−8), an intronic variant found within the ZMAT4 gene on chromosome 8, in African-ancestry analysis. Polygenic-risk prediction and concordance analysis in an independent clinically ascertained sample of developmental stuttering cases validate our GWAS findings in PheML-imputed affected and control individuals and demonstrate the clinical relevance of our population-based analysis for stuttering risk.
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影响因子：
2
作者：
Frigerio-Domingues C;Drayna D
通讯作者：
Drayna D
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
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Fuchsberger, Christian
影响因子：
46.9
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影响因子：
30.8
作者：
Loh, Po-Ru;Danecek, Petr;Palamara, Pier Francesco;Fuchsberger, Christian;Reshef, Yakir A.;Finucane, Hilary K.;Schoenherr, Sebastian;Forer, Lukas;McCarthy, Shane;Abecasis, Goncalo R.;Durbin, Richard;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
2.5
作者：
Mohammadi, Hiwa;Joghataei, Mohammad Taghi;Mehrpour, Masoud
通讯作者：
Mehrpour, Masoud