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. 2021 May 10:12:657499.
doi: 10.3389/fgene.2021.657499. eCollection 2021.

Identifying Susceptibility Loci for Cutaneous Squamous Cell Carcinoma Using a Fast Sequence Kernel Association Test

Manyan Huang  1 , Chen Lyu  1 , Xin Li  2   3 , Abrar A Qureshi  4 , Jiali Han  2   3 , Ming Li  1
Affiliations

Identifying Susceptibility Loci for Cutaneous Squamous Cell Carcinoma Using a Fast Sequence Kernel Association Test

Manyan Huang et al. Front Genet. .

Abstract

Cutaneous squamous cell carcinoma (cSCC) accounts for about 20% of all skin cancers, the most common type of malignancy in the United States. Genome-wide association studies (GWAS) have successfully identified multiple genetic variants associated with the risk of cSCC. Most of these studies were single-locus-based, testing genetic variants one-at-a-time. In this article, we performed gene-based association tests to evaluate the joint effect of multiple variants, especially rare variants, on the risk of cSCC by using a fast sequence kernel association test (fastSKAT). The study included 1,710 cSCC cases and 24,304 cancer-free controls from the Nurses' Health Study, the Nurses' Health Study II and the Health Professionals Follow-up Study. We used UCSC Genome Browser to define gene units as candidate loci, and further evaluated the association between all variants within each gene unit and disease outcome. Four genes HP1BP3, DAG1, SEPT7P2, and SLFN12 were identified using Bonferroni adjusted significance level. Our study is complementary to the existing GWASs, and our findings may provide additional insights into the etiology of cSCC. Further studies are needed to validate these findings.

Keywords: cutaneous squamous cell carcinoma; fast sequence kernel association test; generalized genetic random field; rare variants; region-based association test.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Replication of 18 GWAS identified SNPs using fastSKAT. The p-values of fastSKAT were based on Fisher’s method combining its testing p-values from the same NHS and HPFS populations used in previous publications.
FIGURE 2
FIGURE 2
The Manhattan plots by rare variants analysis in each population (A) Affymetrix. (B) Illumina. (C) OmniExpress. (D) OncoArray. (E) HumanCore. (F) Fisher.
FIGURE 3
FIGURE 3
The Manhattan plots by common variants analysis in each population (A) Affymetrix. (B) Illumina. (C) OmniExpress. (D) OncoArray. (E) HumanCore. (F) Fisher.
FIGURE 4
FIGURE 4
The Manhattan plots by all variants analysis in each population (A) Affymetrix. (B) Illumina. (C) OmniExpress. (D) OncoArray. (E) HumanCore. (F) Fisher.
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