Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

Genome-Wide Association Shows that Pigmentation Genes Play a Role in Skin Aging.

Loss of fine skin patterning is a sign of both aging and photoaging. Studies investigating the genetic contribution to skin patterning offer an opportunity to better understand a trait that influences both physical appearance and risk of keratinocyte skin cancer. We undertook a meta-analysis of genome-wide association studies of a measure of skin pattern (microtopography score) damage in 1,671 twin pairs and 1,745 singletons (N = 5,087) drawn from three independent cohorts. We identified that rs185146 near SLC45A2 is associated with a skin aging trait at genome-wide significance (P = 4.1 × 10-9); to our knowledge this is previously unreported. We also confirm previously identified loci, rs12203592 near IRF4 (P = 8.8 × 10-13) and rs4268748 near MC1R (P = 1.2 × 10-15). At all three loci we highlight putative functionally relevant SNPs. There are a number of red hair/low pigmentation alleles of MC1R; we found that together these MC1R alleles explained 4.1% of variance in skin pattern damage. We also show that skin aging and reported experience of sunburns was proportional to the degree of penetrance for red hair of alleles of MC1R. Our work has uncovered genetic contributions to skin aging and confirmed previous findings, showing that pigmentation is a critical determinant of skin aging.

Positive Association Between Vitamin D Serum Levels and Naevus Counts.

Lower vitamin D serum levels are linked to increased melanoma risk and poorer survival. Naevus counts are associated with both melanoma risk and survival and to leucocyte telomere length. Vitamin D is also linked to telomere biology with higher levels of vitamin D in individuals with longer leucocyte telomere length despite adjusting for age. Using the TwinsUK data, we explored the association between naevus count, leucocyte telomere length and vitamin D serum levels. Increasing vitamin D levels were associated with increasing naevus count: serum levels were 73.3 nmol/l in individuals with less than 50 naevi compared to 78.8 nmol/l in individuals with more than 50 naevi (p?=?0.002). In the final regression model, using naevus count as a continuous variable, vitamin D remained associated with higher naevus counts despite adjustment for age, weight, height, season of sampling and twin relatedness (p?=?0.02). Further adjustment for leucocyte telomere length, decreased the magnitude of the association but it remained significant so leucocyte telomere length is not the sole driver of this association. Having large numbers of naevi is associated with higher vitamin D serum levels.

Genetic epidemiology of melanoma.

The field of melanoma genetics is moving at great pace with new platforms to investigate single nucleotide polymorphism, genome sequencing, gene expression, and methylation. Melanoma incidence is still rising mainly because of screening campaigns, which has increased the number of reported melanomas. However, mortality due to melanoma is not decreasing. Many cutaneous phenotypic risk factors have been linked to melanoma, but the association with UV radiation is very complex. The level of vitamin D affects both the risk of melanoma and prognosis, but more studies are needed. The genetics of melanoma involves genes involved in pigmentation and naevi, as well as genes involved in the cell cycle and senescence, which have been identified via genome-wide association studies over the last 10 years. One area of research highly relevant to melanoma is telomere biology with further links to reduced senescence. At the somatic level, new gene pathways are being explored with many new therapeutic targets, and boosting immune responses against the tumour appears to offer the best long-term outcome.

What Is New in Melanoma Genetics and Treatment?

New therapies for advanced melanoma have led to major advances, which, for the first time, showed improved survival for patients with this very challenging neoplasm. These new treatments are based on gene-targeted therapies or stimulation of immune responses. However, these treatments are not without challenges in terms of resistance and toxicity. Physicians should be aware of these side effects as prompt treatment may save lives. Melanoma genetics is also unravelling new genetic risk factors involving telomere genes as well as new gene pathways at the somatic level which may soon become therapeutic targets. It is also shedding new light onto the pathology of this tumour with links to neural diseases and longevity.

The Prevalence of Peyronie's Disease in the United States: A Population-Based Study.

Peyronie's disease (PD) is a connective tissue disorder which can result in penile deformity. The prevalence of diagnosed PD in the United States (US) has been estimated to be 0.5% in adult males, but there is limited additional information comparing definitive and probable PD cases. We conducted a population-based survey to assess PD prevalence using a convenience-sample of adult men participating in the ResearchNow general population panel. Respondents were categorized according to PD status (definitive, probable, no PD) and segmented by US geographic region, education, and income levels. Of the 7,711 respondents, 57 (0.7%) had definitive PD while 850 (11.0%) had probable PD. Using univariate logistic regression modeling, older age (18-24 vs 24+) (OR = 0.721; 95% CI = 0.570,0.913), Midwest/Northeast/West geographic region (South vs Midwest/Northeast/West) (OR = 0.747; 95% CI = 0.646,0.864), and higher income level (<25K vs 25K+) (OR = 0.820; 95% CI = 0.673,0.997) were each significantly associated with reduced odds of having a definitive/probable PD diagnosis compared with no PD diagnosis. When all three variables were entered in a stepwise multivariable logistic regression, only age (OR = 0.642; 95% CI = 0.497, 0.828) and region (OR = 0.752; 95% CI = 0.647, 0.872) remained significant. This study is the first to report PD prevalence by geographic region and income, and it advocates that the prevalence of PD in the US may be higher than previously cited. Further, given the large discrepancy between definitive PD cases diagnosed by a physician and probable cases not diagnosed by a physician, much more needs to be done to raise awareness of this disease.

Pathway-based factor analysis of gene expression data produces highly heritable phenotypes that associate with age.

Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 "pathway phenotypes" that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold ([Formula: see text]). These phenotypes are more heritable ([Formula: see text]) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors.

Mitochondrial DNA heteroplasmy in diabetes and normal adults: role of acquired and inherited mutational patterns in twins.

Heteroplasmy, the mixture of mitochondrial genomes (mtDNA), varies among individuals and cells. Heteroplasmy levels alter the penetrance of pathological mtDNA mutations, and the susceptibility to age-related diseases such as Parkinson's disease. Although mitochondrial dysfunction occurs in age-related type 2 diabetes mellitus (T2DM), the involvement of heteroplasmy in diabetes is unclear. We hypothesized that the heteroplasmic mutational (HM) pattern may change in T2DM. To test this, we used next-generation sequencing, i.e. massive parallel sequencing (MPS), along with PCR-cloning-Sanger sequencing to analyze HM in blood and skeletal muscle DNA samples from monozygotic (MZ) twins either concordant or discordant for T2DM. Great variability was identified in the repertoires and amounts of HMs among individuals, with a tendency towards more mutations in skeletal muscle than in blood. Whereas many HMs were unique, many were either shared among twin pairs or among tissues of the same individual, regardless of their prevalence. This suggested a heritable influence on even low abundance HMs. We found no clear differences between T2DM and controls. However, we found ~5-fold increase of HMs in non-coding sequences implying the influence of negative selection (P < 0.001). This negative selection was evident both in moderate to highly abundant heteroplasmy (>5% of the molecules per sample) and in low abundance heteroplasmy (<5% of the molecules). Although our study found no evidence supporting the involvement of HMs in the etiology of T2DM, the twin study found clear evidence of a heritable influence on the accumulation of HMs as well as the signatures of selection in heteroplasmic mutations.

IRF4 variants have age-specific effects on nevus count and predispose to melanoma.

High melanocytic nevus count is a strong predictor of melanoma risk. A GWAS of nevus count in Australian adolescent twins identified an association of nevus count with the interferon regulatory factor 4 gene (IRF4 [p = 6 x 10(-9)]). There was a strong genotype-by-age interaction, which was replicated in independent UK samples of adolescents and adults. The rs12203592(*)T allele was associated with high nevus counts and high freckling scores in adolescents, but with low nevus counts and high freckling scores in adults. The rs12203592(*)T increased counts of flat (compound and junctional) nevi in Australian adolescent twins, but decreased counts of raised (intradermal) nevi. In combined analysis of melanoma case-control data from Australia, the UK, and Sweden, the rs12203592(*)C allele was associated with melanoma (odds ratio [OR] 1.15, p = 4 x 10(-3)), most significantly on the trunk (OR = 1.33, p = 2.5 x 10(-5)). The melanoma association was corroborated in a GWAS performed by the GenoMEL consortium for an adjacent SNP, rs872071 (rs872071(*)T: OR 1.14, p = 0.0035; excluding Australian, the UK, and Swedish samples typed at rs12203592: OR 1.08, p = 0.08).