Whole genome sequencing reveals epistasis effects within RET for Hirschsprung disease

被引:0
|
作者
Wang, Yanbing [1 ]
Mak, Timothy Shin Heng [2 ]
Dattani, Saloni [3 ,4 ]
Garcia-Barcelo, Maria-Merce [1 ]
Fu, Alexander Xi [5 ]
Yip, Kevin Y. [5 ,6 ]
Ngan, Elly Sau-Wai [1 ]
Tam, Paul Kwang-Hang [1 ,7 ,8 ]
Tang, Clara Sze-Man [1 ,7 ]
Sham, Pak Chung [3 ,9 ]
机构
[1] Univ Hong Kong, Dept Surg, Hong Kong, Peoples R China
[2] Fano Labs, Hong Kong, Peoples R China
[3] Univ Hong Kong, Dept Psychiat, Hong Kong, Peoples R China
[4] Kings Coll London, Inst Psychiat Psychology & Neurosci, Social Genet & Dev Psychiat Ctr, London, England
[5] Chinese Univ Hong Kong, Dept Comp Sci & Engn, Hong Kong, Peoples R China
[6] Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA 92037 USA
[7] Univ Hong Kong, Karolinska Inst Collaborat Regenerat Med, Dr Li DakSum Res Ctr, Hong Kong, Peoples R China
[8] Macau Univ Sci & Technol, Fac Med, Macau, Peoples R China
[9] Univ Hong Kong, State Key Lab Brain & Cognit Sci, Hong Kong, Peoples R China
关键词
WIDE ASSOCIATION; COMMON; NRG1; GENE; RISK; 3D;
D O I
10.1038/s41598-022-24077-w
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Common variants in RET and NRG1 have been associated with Hirschsprung disease (HSCR), a congenital disorder characterised by incomplete innervation of distal gut, in East Asian (EA) populations. However, the allelic effects so far identified do not fully explain its heritability, suggesting the presence of epistasis, where effect of one genetic variant differs depending on other (modifier) variants. Few instances of epistasis have been documented in complex diseases due to modelling complexity and data challenges. We proposed four epistasis models to comprehensively capture epistasis for HSCR between and within RET and NRG1 loci using whole genome sequencing (WGS) data in EA samples. 65 variants within the Topologically Associating Domain (TAD) of RET demonstrated significant epistasis with the lead enhancer variant (RET+3; rs2435357). These epistatic variants formed two linkage disequilibrium (LD) clusters represented by rs2506026 and rs2506028 that differed in minor allele frequency and the best-supported epistatic model. Intriguingly, rs2506028 is in high LD with one cis-regulatory variant (rs2506030) highlighted previously, suggesting that detected epistasis might be mediated through synergistic effects on transcription regulation of RET. Our findings demonstrated the advantages of WGS data for detecting epistasis, and support the presence of interactive effects of regulatory variants in RET for HSCR.
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页数:10
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