Genome-wide association study identifies nidogen 1 (NID1) as a susceptibility locus to cutaneous nevi and melanoma risk

Abstract

We conducted a genome-wide association study on the number of melanocytic nevi reported by 9136 individuals of European ancestry, with follow-up replication in 3581 individuals. We identified the nidogen 1 (NID1) gene on 1q42 associated with nevus count (two linked single nucleotide polymorphisms with r(2) > 0.9: rs3768080 A allele associated with reduced count, P = 6.5 × 10(-8); and rs10754833 T allele associated with reduced count, P = 1.5 × 10(-7)). We further determined that the rs10754833 [T] was associated with a decreased melanoma risk in 2368 melanoma cases and 7432 controls [for CT genotype: odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.75-0.99, P = 0.04; for TT genotype: OR = 0.84, 95% CI = 0.71-0.98, P = 0.03]. Expression level of the NID1 locus was 2-fold higher for the rs10754833 T allele carriers than that with the CC genotype (P = 0.017) in the 87 HapMap CEU cell lines. The NID1 gene is a biologically plausible locus for nevogenesis and melanoma development, with decreased expression levels of NID1 in benign nevi (P = 3.5 × 10(-6)) and in primary melanoma (P = 4.6 × 10(-4)) compared with the normal skin.

Figure 1.

The QQ plot of observed versus expected −log₁₀(P) values for each study of the discovery set and combined set.

Figure 2.

Regional association plot in the 400 kb neighborhood of NID1. The left-hand Y-axis shows the association P-value of individual SNPs in the discovery set, which is plotted as −log₁₀(P) against chromosomal base-pair position. The right-hand Y-axis shows the recombination rate estimated from the HapMap CEU population. Genotyped SNPs are plotted as diamonds, and imputed as circles in grey. Blue highlights the SNPs of rs3768080 and rs10754833; bright red indicates high LD (r² ≥ 0.8) with rs3768080; orange moderate LD (r² ≥ 0.5 but <0.8); yellow weak LD (r² ≥ 0.2 but <0.5); and white no LD (r² < 0.2). The genomic coordinate is in NCBI35/hg17.

Figure 3.

The NID1 expression in normal skin, benign nevi and primary melanoma. Total RNA isolated from 45 primary melanomas, 18 benign skin nevi and 7 normal skin tissue specimens was analyzed on an Affymetrix Hu133A microarray. The data set was downloaded from NCBI GEO, accession number GSE3189 (9). The box part represents the central 50% of the data or the interquartile range. The lower edge of the box plot is the first quartile or 25th percentile. The upper edge of the box plot is the third quartile or 75th percentile. The line in the box is the median value. The ends of the vertical lines extend to a maximum of 1.5 times the inter-quartile range. The points plot the outliers.

Figure 4.

NID1 expression by the rs10754833 genotype. Based on the transcript expression profiling data of 87 HapMap CEU cell lines (NCBI GEO database, accession GSE7792) (12), the expression level of NID1 locus was 2-fold higher for the rs10754833 T allele carriers compared with that with the CC genotype (P = 0.017) (data not available for rs3768080). The Y-axis is the expression intensity of NID1. The box represents the central 50% of the data or the interquartile range. The lower edge of the box plot is the first quartile or 25th percentile. The upper edge of the box plot is the third quartile or 75th percentile. The line in the box is the median value. The ends of the vertical lines extend to a maximum of 1.5 times the inter-quartile range. The points plot the outliers.