rs10739221 (LINC01505): melanoma susceptibility

What the research says The studies associated with this variant investigate two phenotypes - cutaneous melanoma susceptibility and age at menarche - through large-scale genome-wide association studies (GWAS); a multitrait GWAS analysis (MTAG), a method that combines multiple GWAS datasets while accounting for sample overlap and incomplete genetic correlation, identified 74 genome-wide independent loci for melanoma, 55 of which were replicated in independent cohorts including Melanoma Institute Australia and 23andMe [Study 1]. A meta-analysis in up to 182,416 women of European descent found 123 independent signals at 106 genomic loci for age at menarche (the age at first menstrual period), collectively explaining 2.71% of the variance in pubertal timing, with 90 of 106 loci also showing consistent directional associations with pubertal stage in both sexes [Study 2]. Two additional melanoma GWAS studies spanning 15,990 cases and 26,409 controls (multi-national meta-analysis) and 6,628 cases and 287,591 controls (two-stage analysis) characterize the broader genetic landscape of melanoma susceptibility within which this locus region appears [Study 3, Study 4].

Reported associations

• Cutaneous melanoma: GWAS and MTAG analyses implicate this genomic region in melanoma susceptibility; MTAG leveraged genetic correlations between melanoma and autoimmune traits to uncover loci not detectable by melanoma GWAS alone, identifying 19 novel loci beyond those found in the input melanoma GWAS [Study 1]
• Age at menarche (pubertal timing): Studied in 182,416 women across 57 cohorts; 123 independent signals were identified at 106 loci, with the top 123 SNPs jointly explaining 2.71% of variance versus 1.31% for the 42 previously known signals, indicating a highly polygenic architecture [Study 2]
• Pubertal timing across sexes: 86 of 106 menarche loci showed consistent directional associations with Tanner stage in girls and 72 of 106 in boys, suggesting many menarche loci regulate pubertal timing broadly rather than in a female-specific manner [Study 2]
• Metabolic and cardiovascular co-association: Age at menarche loci showed substantial overlap with genes implicated in body mass index, type 2 diabetes, cardiovascular disease, and breast cancer, reflecting shared polygenic architecture between pubertal timing and metabolic traits [Study 2]
• Autoimmune trait co-localization with melanoma: MTAG revealed that melanoma shares genetic architecture with autoimmune traits; exploiting this correlation uncovered novel melanoma loci including ones near LPP and AP4B1, which have also been associated with autoimmune conditions [Study 1]

Evidence quality The studies span large, well-powered sample sizes: the melanoma meta-analysis included 15,990 cases and 26,409 controls across European, Australian, and U.S. populations, reached the conventional genome-wide significance threshold of P < 5×10-8 for reported loci, and demonstrated minimal population stratification inflation (λ1000 = 1.002) [Study 3]; the age at menarche meta-analysis included up to 182,416 women with binomial sign-test directional validation in an independent sample of 8,689 women at P = 2.2×10-15 [Study 2]. Melanoma loci identified through MTAG were replicated in two independent cohorts with a Bonferroni-corrected threshold (P < 0.05/74) [Study 1]. However, the specific association statistics for rs10739221 - including its odds ratio, p-value, and confidence interval - are not enumerated in the provided study excerpts, which limits precise characterization of this variant's individual effect size. LINC01505 encodes a long intergenic non-coding RNA (a RNA transcript that does not produce protein but may regulate nearby gene expression); the functional mechanism connecting it to melanoma susceptibility or pubertal timing has not been established in these studies. All associations are observational, derived from common variant analyses conducted predominantly in European-ancestry populations, and should be considered preliminary until mechanistic and cross-ancestry replication is achieved.

Study sources

1. Liyanage UE et al., The Journal of Investigative Dermatology, 2022 - multitrait GWAS meta-analysis of cutaneous melanoma integrating autoimmune trait genetic correlations
2. Authors not reported, Journal not reported - meta-analysis of age at menarche, 123 independent signals at 106 genomic loci in up to 182,416 women
3. Authors not reported, Journal not reported - two-stage genome-wide meta-analysis of cutaneous malignant melanoma identifying five novel susceptibility loci, 15,990 cases and 26,409 controls
4. Authors not reported, Journal not reported - two-stage GWAS of melanoma, 6,628 cases and 287,591 controls, novel locus near BASP1