目前尚不清楚种系遗传因素对原位黑色素瘤风险的影响是否与侵袭性黑色素瘤风险不同。为了确定原位黑色素瘤和侵袭性黑色素瘤的风险差异是否可遗传。对原位黑色素瘤与侵袭性黑色素瘤进行了三项全基因组关联研究荟萃分析。使用 4 个基于人群的遗传队列（英国生物银行、FinnGen 队列、QSkin 阳光与健康研究以及昆士兰黑色素瘤研究：环境和遗传关联（Q-MEGA）。黑色素瘤状态是使用癌症登记数据中的国际疾病统计分类和相关健康问题代码确定的。收集1987年至2022年的数据，分析2022年9月至2023年6月的数据。原位和侵袭性皮肤黑色素瘤。为了测试原位和侵袭性黑色素瘤是否具有独立的可遗传成分，计算了单核苷酸变异的遗传效应估计值（ SNV；以前的单核苷酸多态性）遍及每个黑色素瘤的基因组。然后，估计基于 SNV 的遗传力，评估黑色素瘤亚型之间的遗传相关性，并针对 Q-MEGA 参与者的原位与侵袭状态生成多基因风险评分 (PRS)。总共 6 个全基因组显着位点与确定了原位黑色素瘤和 18 个侵袭性黑色素瘤位点。两种分类之间观察到很强的遗传相关性（遗传 r = 0.96；95% CI，0.76-1.15）。值得注意的是，与侵袭性黑色素瘤相比，IRF4、KLF4和HULC附近的位点对原位黑色素瘤的影响显着更大，而与原位黑色素瘤相比，MC1R对侵袭性黑色素瘤的影响显着更大。两者的遗传力估计值一致，原位黑色素瘤遗传率为 6.7%（95% CI，4.1-9.3），侵袭性黑色素瘤遗传率为 4.9%（95% CI，2.8-7.2）。最后，通过比较侵袭性黑色素瘤与原位黑色素瘤遗传风险得出的 PRS，在患有侵袭性黑色素瘤的参与者中平均显着较高（PRS 每增加 1-SD，优势比为 1.43；95% CI，1.16-1.77）。原位黑色素瘤和侵袭性黑色素瘤之间有很多共同的遗传结构。尽管黑色素瘤分类之间的遗传力估计无法区分，但 PRS 表明种系遗传学可能会影响一个人是否患有原位黑色素瘤或侵袭性黑色素瘤。 PRS 可能有助于根据侵袭性黑色素瘤风险对人群进行分层，为未来的筛查计划提供信息，而不会加剧当前黑色素瘤过度诊断的负担。

It is unknown whether germline genetic factors influence in situ melanoma risk differently than invasive melanoma risk.To determine whether differences in risk of in situ melanoma and invasive melanoma are heritable.Three genome-wide association study meta-analyses were conducted of in situ melanoma vs controls, invasive melanoma vs controls, and in situ vs invasive melanoma (case-case) using 4 population-based genetic cohorts: the UK Biobank, the FinnGen cohort, the QSkin Sun and Health Study, and the Queensland Study of Melanoma: Environmental and Genetic Associations (Q-MEGA). Melanoma status was determined using International Statistical Classification of Diseases and Related Health Problems codes from cancer registry data. Data were collected from 1987 to 2022, and data were analyzed from September 2022 to June 2023.In situ and invasive cutaneous melanoma.To test whether in situ and invasive melanoma have independent heritable components, genetic effect estimates were calculated for single-nucleotide variants (SNV; formerly single-nucleotide polymorphisms) throughout the genome for each melanoma. Then, SNV-based heritability was estimated, the genetic correlation between melanoma subtypes was assessed, and polygenic risk scores (PRS) were generated for in situ vs invasive status in Q-MEGA participants.A total of 6 genome-wide significant loci associated with in situ melanoma and 18 loci with invasive melanoma were identified. A strong genetic correlation (genetic r = 0.96; 95% CI, 0.76-1.15) was observed between the 2 classifications. Notably, loci near IRF4, KLF4, and HULC had significantly larger effects for in situ melanoma compared with invasive melanoma, while MC1R had a significantly larger effect on invasive melanoma compared with in situ melanoma. Heritability estimates were consistent for both, with in situ melanoma heritability of 6.7% (95% CI, 4.1-9.3) and invasive melanoma heritability of 4.9% (95% CI, 2.8-7.2). Finally, a PRS, derived from comparing invasive melanoma with in situ melanoma genetic risk, was on average significantly higher in participants with invasive melanoma (odds ratio per 1-SD increase in PRS, 1.43; 95% CI, 1.16-1.77).There is much shared genetic architecture between in situ melanoma and invasive melanoma. Despite indistinguishable heritability estimates between the melanoma classifications, PRS suggest germline genetics may influence whether a person gets in situ melanoma or invasive melanoma. PRS could potentially help stratify populations based on invasive melanoma risk, informing future screening programs without exacerbating the current burden of melanoma overdiagnosis.