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

Hongmei Nan,Eric B Rimm,Christopher I Amos,Yiqing Song,Jeffrey E Lee,Abrar A Qureshi,Qingyi Wei,Jiali Han,Gary Curhan,Constance Chen,Mousheng Xu,Peter Kraft,Li-E Wang,Frank B Hu,Mingfeng Zhang,David J Hunter,Qun Guo,Jiangwen Zhang

doi:10.1093/hmg/ddr154

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.

Highlights

The number of melanocytic nevi occurring in sun-exposed sites is a wellknown risk factor for melanoma [1,2]
We further evaluated the association of rs3768080 and rs10754833 with melanoma risk among 2389 cases and 7527 controls, including 585 melanoma cases and 6500 controls nested within the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts as set 1, and a case– control study of 1804 melanoma cases and 1027 controls from the MD Anderson Cancer Center as set 2
We identified a novel susceptibility locus to mole count, nidogen 1 (NID1)

Summary

Introduction

The number of melanocytic nevi (moles) occurring in sun-exposed sites (e.g. on the extensor forearms) is a wellknown risk factor for melanoma [1,2]. As a presumed precursor to melanoma, nevi occur when melanocytes cluster, forming nests at the dermo-epidermal junction. Both benign and dysplastic nevi are characterized by disruption of the epidermal melanin transfer system through which each melanocyte transfers melanin-containing melanosomes to the suprabasal keratinocytes via dendrites [3]. Among different types of nevi (most of which are benign), melanocytic dysplastic nevi are believed to confer a higher risk for melanoma [4]. A recent genome-wide association study (GWAS) using 1524 healthy adult female twins from the TwinsUK registry identified genetic variants at 9p21 and 22q13 associated with the development of melanocytic nevi [7]. To identify additional genetic variants conferring development of

Methods

Results

Conclusion