Whole-genome association scans and meta-analysis identify deletions or excess homozygosity associated with head and neck cancer susceptibility

Because currently identified genetic variants and exogenous risk factors explain only a modest proportion of susceptibility to head and neck squamous cell carcinoma (HNSCC) and because deletion variants and copy number variants remain largely understudied for human complex diseases, we attempt to identify additional common genetic variants that influence HNSCC susceptibility by performing a whole-genome analysis of the association between deletions or excess homozygosity and susceptibility to HNSCC. The design of the standard genome-wide association studies is a point-wise approach to finding individual disease-associated SNPs. In contrast, we propose to use segment-wise approaches to finding small chromosomal segments of varying sizes that influence HNSCC susceptibility. We conducted two distinct whole-genome scans of associations using 733,202 SNPs, with 1,154 cases and 1,542 controls in batch 1 and 1,031 cases and 2,965 controls in batch 2, as well as the meta-analysis that synthesizes the association summary statistics from each batch. The method is designed for examining statistical evidence of marginal association of one SNP at a time in the first stage, followed by a cluster-based approach that combines the overall assessment of individual marginal associations of neighboring SNPs in distinct genomic regions in the second stage. We identified nine short candidate deleted segments in which at least 2 neighboring top SNPs (with p-value ≤1 × 10 −4 ) were overly aggregated on chromosomes 3p22.2 (batch 1), 1p31.1, 5q33.2, 11q12.3 (batch 2), 5p15.2, 6p22.2, 9q21.31, 12q12, and 12q13.12 (from meta-analysis) at a corrected 0.05 nominal significance level, adjusted for multiple comparison procedures. These short segments contain or overlap several genes: SCN5A, AK5, CARMIL1, and MUC19, which are associated with various diseases, including cardiac events, sudden infant death syndrome, colon cancer, liver cancer, HNSCC, and Crohn’s disease.