Biomedical subjects

David C Whiteman

Publications and source records attributed to David C Whiteman.

5 recordsLinked to original sources

PubMed2026

Phenotypic and genotypic risk factors for uveal melanoma in a high ambient UV radiation environment.

BACKGROUND: Most evidence regarding risk factors for uveal melanoma (UM) derives from case-control studies prone to recall bias, and its rarity has limited prospective research. To address these gaps, we applied a population-based case-control design incorporating polygenic risk scores and Mendelian randomization to explore genetic and phenotypic determinants of UM risk. METHODS: The study was conducted in Queensland, Australia. Incident UM cases diagnosed between 2011 and 2022 were recruited through specialist ocular oncology clinics. Controls were participants in the QSkin Sun and Health Study, a prospective cohort of 43,794 adults aged 40-69 at baseline (2010-2011). Demographic, phenotypic, and sun exposure factors were harmonized across studies. Polygenic risk scores were calculated for pigmentation traits and nevi characteristics using genome-wide association study datasets, and Mendelian randomization was used to assess potential causal relationships with UM risk. RESULTS: Among 485 UM cases and 43,724 controls, several phenotypic traits were strongly associated with UM risk: male sex, blue or light eye color, inability to tan, freckling, and high nevus density. A family history of cutaneous melanoma and a personal history of keratinocyte cancer were also associated with higher risk. Polygenic risk score analyses confirmed significant associations for eye color and freckling. Mendelian randomization analyses supported causal relationships between lighter eye color, freckling propensity, reduced tanning ability and UM risk. CONCLUSIONS: These findings provide genetic evidence supporting a causal role for pigmentation-related traits in UM susceptibility. IMPACT: This evidence may help refine risk assessment and inform counselling for individuals with suspicious ocular lesions.

Journal Article↗

PubMed2026

GWAS meta-analysis provides new insights into uveal melanoma risk.

OBJECTIVE: The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy controls. METHODS: Five novel UM genome-wide association studies (GWAS) were performed and included for meta-analysis with four previously published UM GWAS. A fixed-effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case-control cohorts. A follow-up transcriptome-wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma-related phenotypes were measured to elucidate UM's genetic architecture. RESULTS: We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW P value of less than 5 × 10-8. TWAS analysis indicates five potential target genes, including MOB3B, RBAK, and MTSS1, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, P = 0.01) between UM and cutaneous melanoma (CM), and a non-significant but consistent correlation with naevus count (rg = 0.25, P = 0.08). CONCLUSIONS: This meta-analysis offers new insights into the genetic architecture of UM, highlights potential therapeutic targets, and explores the genetic relationship with CM and skin pigmentation.

Humans↗

PubMed2026

Unravelling sex differences in the genetic architecture of anxiety.

BACKGROUND: Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. METHODS: Here, we report the first sex-specific meta-analysis of genome-wide association studies (GWAS) of anxiety, leveraging two of the largest biobank datasets, UK Biobank and All of Us, comprising 85,042 female cases with 196,789 controls and 36,732 male cases with 136,924 controls. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications. RESULTS: In females, 21 lead SNPs were significantly associated with anxiety, compared to five in males. Although the genetic correlation between sexes was high, it was significantly different from one, indicating partially distinct genetic architectures. In addition, both the SNP-based observed and liability-scale heritabilities (assuming a 2:1 female-to-male prevalence ratio) were significantly higher in females. Gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. Moreover, genetic correlation analyses revealed stronger associations of female anxiety with attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI), whereas male anxiety showed stronger correlations with waist-hip-ratio-adjusted BMI. CONCLUSIONS: While the overall genetic architecture of anxiety is largely shared, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analyzing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.

Female↗

PubMed2025

Genome-wide association meta-regression identifies stem cell lineage orchestration as a key driver of acne risk.

Over 85% of the population experience acne at some point in their lives, with its severity spanning a quantitative spectrum, from mild, transient outbreaks to more persistent, severe forms of the condition. Moderate to severe disease poses a substantial global burden arising from both the physical and psychological impacts of this highly visible condition. The analytical approach taken in this study aimed to address the impact of variation in the dichotomisation of acne case control status, driven by ascertainment and study design, on effect size estimates across independent genetic association studies of acne. Through a fixed intercept meta-regression framework, we combined evidence genome-wide for association with acne across studies in which case-control status had been ascertained in different settings, allowing for different severity threshold definitions. Across a combined sample of 73,997 cases and 1,103,940 controls of European, South Asian and African American ancestry we identify genetic variation at 165 genomic loci that influence acne risk. There is evidence for both shared and ancestry specific components to the genetic susceptibility to acne and for sex differences in the magnitude of effect of risk alleles at three loci. We observe that common genetic variation explains 13.4% of acne heritability on the liability scale. Consistent with the hypothesis that genetic risk primarily operates at the level of individual pilosebaceous units, a polygenic score derived from this case-control study of acne susceptibility is associated with both self-reported and clinically assessed acne severity in adolescence, further strengthening the link between genetic risk and disease severity. Prioritisation of causal genes at the identified acne risk loci, provides genetic validation of the targets of established and emerging acne therapies, including retinoid treatments. The identified acne risk loci are enriched for genes encoding downstream effectors of RXRA signalling, including SOX9 and components of the WNT and p53 pathways. Illustrating that the control of stem cell lineage plasticity and cellular fate are important mechanisms through which genetic variation influences acne susceptibility within the pilosebaceous unit.

Journal Article↗

PubMed2025

Cost-Effectiveness Analysis of 3D Total-Body Photography for People at High Risk of Melanoma.

IMPORTANCE: Greater use of novel digital technologies could be associated with improved health outcomes and save health care costs by detecting smaller melanomas earlier (needing less treatment) or benign tumors (needing no treatment). OBJECTIVE: To compare costs and health effects of 3-dimensional (3D) total-body photography (TBP) and sequential digital dermoscopy imaging (SDDI) vs usual care for early detection of melanoma. DESIGN, SETTING, AND PARTICIPANTS: This prespecified cost-effectiveness analysis using randomized clinical trial (n = 309) data with 2 years of follow-up was conducted at a research hospital in Brisbane, Australia, and took a health system perspective. It included adults 18 years or older at high risk of developing a primary or subsequent melanoma. INTERVENTION: The intervention group received usual care plus clinical skin examinations by junior clinicians at baseline and 6, 12, 18, and 24 months with 3D TBP-SDDI reviewed by a teledermatologist. The control group continued to receive usual care and completed online surveys every 6 months. MAIN OUTCOMES AND MEASURES: Government health care costs, patient out-of-pocket costs, numbers of benign and malignant skin tumor excisions, and quality-adjusted life-years. Skin biopsy, excisions, pathology, and their costs were collected using administrative claims data. Quality of life was collected using the EuroQol-5D-5L. RESULTS: The trial included 314 participants (mean [SD] age, 51.6 [12.8] years; 194 female individuals [62%]) who completed all of the study procedures (158 in the intervention and 156 in the control groups). Compared with controls, intervention group participants had fewer melanoma excisions, more keratinocyte carcinomas and benign excisions, and more biopsy specimens. Over 24 months, mean per-person costs (analyzed in Australian dollars and converted to US$) for the intervention group were $1708 (95% CI, $1455-$1961) vs $763 (95% CI, $655-$870) for controls, an incremental cost of $945 (95% CI, $738-$1157) to provide the intervention. Total quality-adjusted life-years per person were similar for the intervention (1.84; 95% CI, 1.82-1.86) and control groups (1.84; 95% CI, 1.83-1.86). The incremental cost per additional malignant skin tumor excised was $40 (95% CI, $34-$48). CONCLUSIONS AND RELEVANCE: Over 2 years of the trial, the 3D TBP-SDDI model by junior clinicians and teledermatologist review generated higher costs and detected similar numbers of malignant tumors than usual care in a high-risk melanoma cohort. Cost-effectiveness is a necessary but not sufficient consideration for implementation. Other benefits of 3D TBP-SDDI may arise once artificial intelligence clinician support systems are integrated, and more research is needed to understand factors associated with costs and whether there are other benefits of 3D TBP-SDDI.

Adult↗