教師資料查詢 | 類別: 期刊論文 | 教師: 謝璦如 HSIEH, AI-RU (瀏覽個人網頁)

標題:Maximal Segmental Score Method for Localizing Recessive Disease Variants Based on Sequence Data
學年108
學期2
出版(發表)日期2020/06/12
作品名稱Maximal Segmental Score Method for Localizing Recessive Disease Variants Based on Sequence Data
作品名稱(其他語言)
著者Ai-Ru Hsieh(謝璦如); Jia Jyun Sie; Chien Ching Chang; Jurg Ott; Ie-Bin Lian; Cathy S J Fann
單位
出版者
著錄名稱、卷期、頁數Frontiers in Genetics 11, 555
摘要Background: Due to the affordability of whole-genome sequencing, the genetic association design can now address rare diseases. However, some common statistical association methods only consider homozygosity mapping and need several criteria, such as sliding windows of a given size and statistical significance threshold setting, such as P-value < 0.05 to achieve good power in rare disease association detection.

Methods: Our region-specific method, called expanded maximal segmental score (eMSS), converts p-values into continuous scores based on the maximal segmental score (MSS) (Lin et al., 2014) for detecting disease-associated segments. Our eMSS considers the whole genome sequence data, not only regions of homozygosity in candidate genes. Unlike sliding window methods of a given size, eMSS does not need predetermined parameters, such as window size or minimum or maximum number of SNPs in a segment. The performance of eMSS was evaluated by simulations and real data analysis for autosomal recessive diseases multiple intestinal atresia (MIA) and osteogenesis imperfecta (OI), where the number of cases is extremely small. For the real data, the results by eMSS were compared with a state-of-the-art method, HDR-del (Imai et al., 2016).

Results: Our simulation results show that eMSS had higher power as the number of non-causal haplotype blocks decreased. The type I error for eMSS under different scenarios was well controlled, p < 0.05. For our observed data, the bone morphogenetic protein 1 (BMP1) gene on chromosome 8, the Violaxanthin de-epoxidase-related chloroplast (VDR) gene on chromosome 12 associated with OI, and the tetratricopeptide repeat domain 7A (TTC7A) gene on chromosome 2 associated with MIA have previously been identified as harboring the relevant pathogenic mutations.

Conclusions: When compared to HDR-del, our eMSS is powerful in analyzing even small numbers of recessive cases, and the results show that the method can further reduce numbers of candidate variants to a very small set of susceptibility pathogenic variants underlying OI and MIA. When we conduct whole-genome sequence analysis, eMSS used 3/5 the computation time of HDR-del. Without additional parameters needing to be set in the segment detection, the computational burden for eMSS is lower compared with that in other region-specific approaches.
關鍵字whole-genome sequencing;rare disease;autosomal recessive disease;maximal segmental score;ALSPAC
語言英文
ISSN1664-8021
期刊性質國外
收錄於SCI;
產學合作
通訊作者
審稿制度
國別瑞士
公開徵稿
出版型式,電子版
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