Whole Genome Sequencing Reveals Epistasis Effects Within RET for Hirschsprung Disease

Overview

Journal Sci Rep

Specialty Science

Date 2022 Nov 28

PMID 36443333

Authors

Yanbing Wang

Timothy Shin Heng Mak

Saloni Dattani

Maria-Merce Garcia-Barcelo

Alexander Xi Fu

Kevin Y Yip

Elly Sau-Wai Ngan

Paul Kwang-Hang Tam

Clara Sze-Man Tang

Pak Chung Sham

Affiliations

Soon will be listed here.

Abstract

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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