Genetic feature engineering enables characterisation of shared risk factors in immune-mediated diseases.
Genetic feature engineering enables characterisation of shared risk factors in immune-mediated diseases.
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DOI：
10.1186/s13073-020-00797-4
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发表时间：
2020-11-25
期刊：
影响因子：
12.3
通讯作者：
Wallace C
中科院分区：
文献类型：
--
作者：
Burren OS;Reales G;Wong L;Bowes J;Lee JC;Barton A;Lyons PA;Smith KGC;Thomson W;Kirk PDW;Wallace C
全基因组关联研究（GWAS）已经确定了多种免疫介导疾病（IMD）中普遍存在的遗传结构共享。通过从常见疾病中学习IMD风险的遗传基础，可以利用这种共享来分析不太常见的IMD，由于样本量有限，传统的GWAS技术具有挑战性。利用贝叶斯遗传精细映射的思想，我们开发了一种以疾病为中心的收缩方法，使我们能够从一组相关疾病的GWAS汇总统计中提取遗传风险成分。我们将这种技术应用于13个较大的GWAS的共同IMD，得出一个减少的维度“基础”，总结了遗传风险的多维组成部分。我们使用了包括英国生物银行在内的独立数据集来评估基础和独立轴的性能。最后，我们预测了小于1000例的较小IMD研究的总结GWAS数据，以评估该方法是否能够为不太常见的IMD或IMD亚型的遗传结构提供额外的见解，其中队列收集具有挑战性。我们确定了13种IMD遗传风险成分。独立的英国生物库数据的预测证明了IMD的特异性和基础的准确性，即使对于病例数量非常有限的性状（例如白癜风，150例）。其他IMD相关研究的预测使我们能够对特定成分进行生物学解释，例如与血液中嗜酸性粒细胞计数升高和趋化因子CXCL 10（IP-10）血清浓度相关。在应用于22种罕见的IMD和IMD亚型时，我们不仅能够突出亚型鉴别轴（例如青少年特发性关节炎），而且还提出了8种新的遗传关联。我们的无监督方法只需要摘要级数据，可以在更少的维度上描述任何临床相关性状的遗传结构。这有助于通过在更广泛的疾病领域匹配遗传和生物风险的共享轴来分析样本量适中的研究，并为可能的治疗再利用机会提供证据基础。
Genome-wide association studies (GWAS) have identified pervasive sharing of genetic architectures across multiple immune-mediated diseases (IMD). By learning the genetic basis of IMD risk from common diseases, this sharing can be exploited to enable analysis of less frequent IMD where, due to limited sample size, traditional GWAS techniques are challenging. Exploiting ideas from Bayesian genetic fine-mapping, we developed a disease-focused shrinkage approach to allow us to distill genetic risk components from GWAS summary statistics for a set of related diseases. We applied this technique to 13 larger GWAS of common IMD, deriving a reduced dimension “basis” that summarised the multidimensional components of genetic risk. We used independent datasets including the UK Biobank to assess the performance of the basis and characterise individual axes. Finally, we projected summary GWAS data for smaller IMD studies, with less than 1000 cases, to assess whether the approach was able to provide additional insights into genetic architecture of less common IMD or IMD subtypes, where cohort collection is challenging. We identified 13 IMD genetic risk components. The projection of independent UK Biobank data demonstrated the IMD specificity and accuracy of the basis even for traits with very limited case-size (e.g. vitiligo, 150 cases). Projection of additional IMD-relevant studies allowed us to add biological interpretation to specific components, e.g. related to raised eosinophil counts in blood and serum concentration of the chemokine CXCL10 (IP-10). On application to 22 rare IMD and IMD subtypes, we were able to not only highlight subtype-discriminating axes (e.g. for juvenile idiopathic arthritis) but also suggest eight novel genetic associations. Requiring only summary-level data, our unsupervised approach allows the genetic architectures across any range of clinically related traits to be characterised in fewer dimensions. This facilitates the analysis of studies with modest sample size by matching shared axes of both genetic and biological risk across a wider disease domain, and provides an evidence base for possible therapeutic repurposing opportunities.
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影响因子：
4.6
作者：
Kong, K. O.;Tan, A. W.;Howe, H. S.
通讯作者：
Howe, H. S.
影响因子：
4.5
作者：
Avery CL;He Q;North KE;Ambite JL;Boerwinkle E;Fornage M;Hindorff LA;Kooperberg C;Meigs JB;Pankow JS;Pendergrass SA;Psaty BM;Ritchie MD;Rotter JI;Taylor KD;Wilkens LR;Heiss G;Lin DY
通讯作者：
Lin DY
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
30.8
作者：
Hinks, Anne;Cobb, Joanna;Marion, Miranda C.;Prahalad, Sampath;Sudman, Marc;Bowes, John;Martin, Paul;Comeau, Mary E.;Sajuthi, Satria;Andrews, Robert;Brown, Milton;Chen, Wei-Min;Concannon, Patrick;Deloukas, Panos;Edkins, Sarah;Eyre, Stephen;Gaffney, Patrick M.;Guthery, Stephen L.;Guthridge, Joel M.;Hunt, Sarah E.;James, Judith A.;Keddache, Mehdi;Moser, Kathy L.;Nigrovic, Peter A.;Onengut-Gumuscu, Suna;Onslow, Mitchell L.;Rose, Carlos D.;Rich, Stephen S.;Steel, Kathryn J. A.;Wakeland, Edward K.;Wallace, Carol A.;Wedderburn, Lucy R.;Woo, Patricia;Bohnsack, John F.;Haas, Johannes Peter;Glass, David N.;Langefeld, Carl D.;Thomson, Wendy;Thompson, Susan D.
通讯作者：
Thompson, Susan D.
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen