Runs of homozygosity associate with decreased risks of lung cancer in never-smoking East Asian females

Abstract

Although genome-wide association studies (GWASs) have identified some risk single-nucleotide polymorphisms in East Asian never-smoking females, the unexplained missing heritability is still required to be investigated. Runs of homozygosity (ROHs) are thought to be a type of genetic variation acting on human complex traits and diseases. We detected ROHs in 8,881 East Asian never-smoking women. The summed ROHs were used to fit a logistic regression model which noteworthily revealed a significant association between ROHs and the decreased risk of lung cancer (P < 0.05). We identified 4 common ROHs regions located at 2p22.1, which were significantly associated with decreased risk of lung cancer (P = 2.00 × 10^-4 - 1.35 × 10^-4). Functional annotation was conducted to investigate the regulatory function of ROHs. The common ROHs were overlapped with potential regulatory elements, such as active epigenome elements and chromatin states in lung-derived cell lines. SOS1 and ARHGEF33 were significantly up-regulated as the putative target genes of the identified ROHs in lung cancer samples according to the analysis of differently expressed genes. Our results suggest that ROHs could act as recessive contributing factors and regulatory elements to influence the risk of lung cancer in never-smoking East Asian females.

Keywords: GWASs; genetic risk factors; lung cancer; regulatory elements; runs of homozygosity.

Figure 1

Functional annotation for the common ROHs regions. The common ROHs regions overlapped with histone marks which classified as active enhancer in A549 cell line, including H3k4me1, H3k4me2 and H3k27ac, and annotated as enhancers according to 15-state chromatin state segmentation.

Figure 2

Regulatory annotation of the common ROHs regions in IMR90 cell line. ROH_14342 and ROH_14857 were annotated with enhancers and interactions within the chromosome regions in IMR90 cell line. SOS1 and ARHGEF33 with active promoters were the target genes of the enhancer region overlapped with ROH_14342. Status of the enhancer regions were annotated according to 15-state chromatin state segmentation data generated by ChromHMM based on the Roadmap histone modification data. The interactions between regions on the chromosome detected by chromatin capture Hi-C are shown in the center.