Zhong Kaiyin, Verkouteren Joris A C, Jacobs Leonie C, Uitterlinden Andre G, Hofman Albert, Liu Fan, Nijsten Tamar, Kayser Manfred
Department of Genetic Identification, Erasmus Medical Center University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Dermatology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
J Invest Dermatol. 2017 Jan;137(1):77-84. doi: 10.1016/j.jid.2016.09.007. Epub 2016 Sep 16.
Actinic keratosis (AK) is a skin disease frequently found in European elderly, and it represents the precursor of cutaneous squamous cell carcinoma. Our recent genome-wide association study highlighted DNA variants in two pigmentation genes, IRF4 and MC1R, that confer AK risk in Europeans. Here, we performed a genome-wide search for relaxed forms of compound heterozygosity in association with AK using our recently developed software CollapsABEL. In a discovery dataset of 3,193 Dutch Europeans, a total of 15 genetic loci showed genome-wide significant association with AK (P < 1.25 × 10). Of those, three loci (6p21.2, 6p12.2, and 6q13) were confirmed in a replication dataset that included 624 additional Dutch Europeans (P < 0.05). These replicated loci harbored six genes (KCNK5/KCNK17, PAQR8/GSTA2, and KCNQ5/KHDC1), none of them known to be involved in pigmentation. A candidate compound heterozygosity analysis for 12 pigmentation loci highlighted SLC24A4 at 14q32.12 as showing significant association with AK (P = 8.83 × 10). The four significantly AK-associated compound heterozygosity single-nucleotide polymorphism pairs together explained 4.37% of the total AK variation, which was 2.62 times greater than the two top-associated individual single nucleotide polymorphisms together (1.67%) identified in the previous conventional genome-wide association study. In conclusion, CollapsABEL showed compound heterozygosity in non-pigmentation- and pigmentation-related loci conferring genetic risk of AK.
光化性角化病（AK）是一种在欧洲老年人中常见的皮肤病，它是皮肤鳞状细胞癌的前驱病变。我们最近的全基因组关联研究强调了两个色素沉着基因IRF4和MC1R中的DNA变异，这些变异赋予欧洲人患AK的风险。在这里，我们使用我们最近开发的软件CollapsABEL对与AK相关的复合杂合性的松弛形式进行了全基因组搜索。在一个由3193名荷兰欧洲人组成的发现数据集中，共有15个基因位点显示出与AK的全基因组显著关联（P < 1.25 × 10）。其中，三个位点（6p21.2、6p12.2和6q13）在一个包含另外624名荷兰欧洲人的复制数据集中得到了证实（P < 0.05）。这些复制的位点包含六个基因（KCNK5/KCNK17、PAQR8/GSTA2和KCNQ5/KHDC1），其中没有一个已知与色素沉着有关。对12个色素沉着位点的候选复合杂合性分析突出显示14q32.12处的SLC24A4与AK有显著关联（P = 8.83 × 10）。这四对与AK显著相关的复合杂合性单核苷酸多态性共同解释了AK总变异的4.37%，这比之前传统全基因组关联研究中确定的两个最相关的单个单核苷酸多态性共同解释的变异（1.67%）大2.62倍。总之，CollapsABEL显示非色素沉着相关和色素沉着相关位点的复合杂合性赋予了AK的遗传风险。
