Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Environmental plastics in the context of UV radiation, climate change, and the Montreal Protocol.

There are close links between solar UV radiation, climate change, and plastic pollution. UV-driven weathering is a key process leading to the degradation of plastics in the environment but also the formation of potentially harmful plastic fragments such as micro- and nanoplastic particles. Estimates of the environmental persistence of plastic pollution, and the formation of fragments, will need to take in account plastic dispersal around the globe, as well as projected UV radiation levels and climate change factors.

International patterns and trends in the incidence of melanoma and cutaneous squamous cell carcinoma, 1989-2020.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) and melanoma have different associations with sun exposure. OBJECTIVES: To compare trends in the incidence rates of cSCC and melanoma, to provide insight into changing patterns of exposure to ultraviolet radiation (UVR). METHODS: We compared trends in the incidence of cSCC and melanoma in seven susceptible populations residing at mid-to-high latitudes: Finland, Norway, Sweden, Denmark, Scotland, the Netherlands and Tasmania (Australia). We fitted Joinpoint models to describe trends in age-standardized incidence rates for melanoma and cSCC and calculated the average annual percentage rate of change for the period 1989-2020 (1989-2018 for Tasmania). We calculated the incident rate ratio (IRR) as the ratio of the age-standardized rates (European Standard Population) for cSCC to melanoma and conducted age-period-cohort modelling to compare age, period and cohort effects. RESULTS: The ratio of cSCC-to-melanoma incidence increased with proximity to the equator and over time. In the most recent time period, the incidence of cSCC was higher than the incidence of melanoma for men and women in all seven populations. While the ratio of cSCC-to-melanoma incidence was higher for men vs. women, in most countries the cSCC-to-melanoma IRR increased over time to a greater extent in women than in men. Melanoma incidence was higher among younger people and cSCC incidence was higher among older people; the age at which the incidence of cSCC overtook the incidence of melanoma was progressively younger with proximity to the equator. CONCLUSIONS: Despite concerted international efforts to preserve the ozone layer over the past four decades resulting in significant reductions in surface ultraviolet B at mid-latitudes, the incidence of skin cancer, particularly cSCC, continues to rise in those regions. Our findings are consistent with a stronger association with age-associated cumulative sun exposure for cSCC vs. melanoma and suggest that women are currently receiving greater UV radiation exposure than in the past.

Plastics in the environment in the context of UV radiation, climate change and the Montreal Protocol: UNEP Environmental Effects Assessment Panel, Update 2023.

This Assessment Update by the Environmental Effects Assessment Panel (EEAP) of the United Nations Environment Programme (UNEP) considers the interactive effects of solar UV radiation, global warming, and other weathering factors on plastics. The Assessment illustrates the significance of solar UV radiation in decreasing the durability of plastic materials, degradation of plastic debris, formation of micro- and nanoplastic particles and accompanying leaching of potential toxic compounds. Micro- and nanoplastics have been found in all ecosystems, the atmosphere, and in humans. While the potential biological risks are not yet well-established, the widespread and increasing occurrence of plastic pollution is reason for continuing research and monitoring. Plastic debris persists after its intended life in soils, water bodies and the atmosphere as well as in living organisms. To counteract accumulation of plastics in the environment, the lifetime of novel plastics or plastic alternatives should better match the functional life of products, with eventual breakdown releasing harmless substances to the environment.

Age group-specific changes in keratinocyte cancer treatment rates in Australia, 2012-2021: a retrospective cohort study based on MBS claims data.

OBJECTIVES: To examine recent changes in the numbers of Medicare-subsidised keratinocyte cancer excisions, particularly for younger people exposed to primary prevention campaigns since the early 1980s. STUDY DESIGN: Retrospective cohort study; analysis of administrative data. SETTING, PARTICIPANTS: Analysis of Medicare Benefits Schedule (MBS) claims data for procedures related to the diagnosis and treatment of keratinocyte cancer in Australia, 2012-2021. MAIN OUTCOME MEASURES: Age-standardised rates for MBS-subsidised claims for first surgical squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) excisions, Mohs surgery, surgical excisions of benign lesions, skin biopsies, and cryotherapy or serial curettage of premalignant and malignant lesions, overall, and by sex, state/territory, and age group; average annual percentage change in rate for time intervals determined by joinpoint regression. RESULTS: In men, the age-standardised rate of BCC/SCC excisions increased by 1.9% (95% confidence interval [CI], 1.4-2.4%) per year during 2012-2019 (from 2931 to 3371 per 100 000 men) and then declined by 3.8% (95% CI, 0.5-7.0%) per year during 2019-2021 (to 3152 per 100 000). In women, the age-standardised rate increased by 2.2% (95% CI, 1.7-2.8%) per year during 2012-2019 (from 1798 to 2093 per 100 000 women); the decline to 1967 excisions per 100 000 women in 2021 was not statistically significant. BCC/SCC excision rates declined for men under 55 years of age (by 1.0-3.4% per year) and women under 45 years of age (by 1.7-2.3% per year). Age-standardised biopsy rates increased during 2012-2021 in all age groups (by 2.8-6.9% per year). CONCLUSIONS: Rates of MBS-subsidised treatment for keratinocyte cancers increased during 2012-2019, but BCC/SCC treatment rates declined among younger Australians, who have probably been exposed to less sunlight than earlier generations because of public health interventions and population-wide lifestyle changes related to technology use.

Oral human papillomavirus (HPV) infection and HPV vaccination in an Australian cohort.

Human papillomavirus (HPV)-related oropharyngeal cancer (OPC) is increasing in incidence, yet very little is known about oral HPV infection in the general population. In this Australian-based study we assess oral HPV prevalence according to HPV vaccination status. Participants of the Oral Diversity Study were Australian residents, aged 18 to 70 years, who filled out a questionnaire about lifestyle and sexual behaviour, and donated a saliva sample in 2020 to 2021. We obtained permission to access HPV vaccination status through record linkage with the Australian Immunisation Register. Saliva samples were DNA extracted, DNA quality checked and analysed for HPV. We recruited 1023 participants to the Oral Diversity Study. Nine hundred twenty-one returned a saliva sample for analysis, 911 passed the DNA quality check and were included in the study. The oral HPV prevalence was 7.2%, and was strongly associated with sexual behaviours. We identified 27 different HPV types; 53% of participants carried high-risk HPV types, with no difference between the vaccinated and the unvaccinated groups (53% both, P = .979). Two hundred thirty participants (26%) were HPV vaccinated. The oral prevalence of the nine HPV types included in the nonavalent HPV vaccine was significantly lower in the vaccinated participants compared to the unvaccinated (0.9% vs 3.4%; P = .022). These findings suggest that a sizeable minority of Australian residents harbour oral HPV infections, and many of these are high-risk subtypes. We found some evidence that HPV vaccination resulted in lower prevalence of oral HPV infections of vaccine-specific types. Larger surveys are required to confirm these findings.

Does genetic risk modify the effect of skin screening on melanoma detection rates?

BACKGROUND: Skin screening is associated with higher melanoma detection rates, a potential indicator of overdiagnosis, but it remains possible that this effect is due to confounding by genetic risk. OBJECTIVES: To compare melanoma incidence among screened vs. unscreened participants within tertiles of genetic risk. METHODS: We investigated melanoma incidence in the QSkin study, a prospective cohort study which for this analysis comprised 15 283 participants aged 40-69 years with genotype data and no prior history of melanoma. We calculated a polygenic score (PGS) for melanoma. We first calculated the age-standardized rate (ASR) of melanoma within PGS tertiles, and then measured the association between skin examination and melanoma detection by calculating the hazard ratio (HR) and 95% confidence interval (95% CI), overall and within PGS tertiles. RESULTS: Melanoma incidence increased with PGS (ASR per 100 000 per year): tertile 1 = 442; tertile 2 = 519; tertile 3 = 871. We found that the HRs for all melanomas (i.e. in situ and invasive) associated with skin examination differed slightly across PGS tertiles [age- and sex-adjusted tertile 1 HR 1.88 (95% CI 1.26-2.81); tertile 2 HR 1.70 (95% CI 1.20-2.41); tertile 3 HR 1.96 (95% CI 1.43-2.70); fully adjusted tertile 1 HR 1.14 (95% CI 0.74-1.75); tertile 2 HR 1.21 (95% CI 0.82-1.78); tertile 3 HR 1.41 (95% CI 1.00-1.98)], but these differences were not statistically significant. HRs for in situ melanoma associated with skin examination were similar across PGS tertiles. For invasive melanomas, the point estimates appeared to be highest in PGS tertile 3 in both the minimally adjusted (age, sex) and fully adjusted models; however, these apparent differences were also not statistically significant. CONCLUSIONS: Genetic risk predicts subsequent melanoma incidence, and is weakly associated with screening behaviour, but it does not explain the higher rate of melanoma detection between screened and unscreened people.

The MC1R r allele does not increase melanoma risk in MITF E318K carriers.

BACKGROUND: Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored. OBJECTIVES: To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals. MATERIALS AND METHODS: Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank). RESULTS: The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals. CONCLUSIONS: RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals.

Health care service use by people diagnosed with invasive melanoma in Queensland: a benefit incidence analysis.

OBJECTIVE: To quantify differences, by residential remoteness and socio-economic status, in health care service use by people diagnosed with invasive melanoma in Queensland. DESIGN: Benefit incidence analysis of CancerCostMod data, comprising Queensland Cancer Registry data linked with Queensland Hospital Admitted Patient Data Collection (QHAPDC), Medicare Benefits Schedule (MBS), and Pharmaceutical Benefits Scheme (PBS) data. SETTING, PARTICIPANTS: Adults (18 years or older) newly diagnosed with invasive melanoma in Queensland during 1 July 2011 - 31 June 2015 and alive three years after diagnosis. MAIN OUTCOME MEASURES: Concentration curves and indices quantifying differences by residential postcode-based remoteness (Australian Statistical Geography Standard - Remoteness Area) and socio-economic disadvantage (Index of Relative Socioeconomic Disadvantage) in hospital admissions (overall and by type) and use of MBS (overall and by type) and PBS services during the three years following diagnosis of invasive melanoma. RESULTS: A total of 13 145 adults diagnosed with invasive melanoma during 2011-15 were alive three years after the diagnosis. Public hospital admissions were more frequent for people living in areas of greater socio-economic disadvantage (concentration index, -0.15; 95% confidence interval [CI], -0.19 to -0.12) or outside major cities (concentration index, -0.10; 95% CI, -0.13 to -0.06); private hospital admissions (concentration index, 0.11; 95% CI, 0.07-0.15) and specialist consultations (concentration index, 0.08; 95% CI, 0.07-0.10) were more frequent in areas of lesser disadvantage and in major cities (private hospital admissions: 0.10; 95% CI, 0.06-0.13; specialist services: 0.07; 95% CI, 0.06-0.09). Differences in other melanoma health care service use by residential remoteness and socio-economic disadvantage were not statistically significant. CONCLUSIONS: Variation in health care service use by Queenslanders with primary diagnoses of invasive melanoma by residential socio-economic disadvantage and remoteness were generally minor. Our analysis suggests that access to health care for people with melanoma is fairly equitable in Queensland.

The diagnosis and initial management of melanoma in Australia: findings from the prospective, population-based QSkin study.

OBJECTIVES: To determine the proportions of newly diagnosed melanomas treated by different medical specialist types, to describe the types of excisions performed, and to investigate factors associated with treating practitioner specialty and excision type. DESIGN, SETTING: Prospective cohort study; analysis of linked data: baseline surveys, hospital, pathology, Queensland Cancer Register, and Medical Benefits Schedule databases. PARTICIPANTS: Random sample of 43 764 Queensland residents aged 40-69 years recruited during 2011, with initial diagnoses of in situ or invasive melanoma diagnosed to 31 December 2019. MAIN OUTCOME MEASURES: Treating practitioner type and treatment modality for first incident melanoma; second and subsequent treatment events for the primary melanoma. RESULTS: During a median follow-up of 8.4 years (interquartile range, 8.3-8.8 years), 1683 eligible participants (720 women, 963 men) developed at least one primary melanoma (in situ melanoma, 1125; invasive melanoma, 558), 1296 of which (77.1%) were initially managed in primary care; 248 were diagnosed by dermatologists (14.8%), 83 by plastic surgeons (4.9%), 43 by general surgeons (2.6%), and ten by other specialists (0.6%). The most frequent initial procedures leading to histologically confirmed melanoma diagnosis were first excision (854, 50.7%), shave biopsy (549, 32.6%), and punch biopsy (178, 10.6%); 1339 melanomas (79.6%) required two procedures, 187 (11.1%) three. Larger proportions of melanomas diagnosed by dermatologists (87%) or plastic surgeons (71%) were in people living in urban areas than of those diagnosed in primary care (63%); larger proportions of melanomas diagnosed by dermatologists or plastic surgeons than of those diagnosed in primary care were in people with university degrees (45%, 42% v 23%) or upper quartile clinical risk scores (63%, 59% v 47%). CONCLUSIONS: Most incident melanomas in Queensland are diagnosed in primary care, and nearly half are initially managed by partial excision (shave or punch biopsy). Second or third, wider excisions are undertaken in about 90% of cases.

GWAS of Dizygotic Twinning in an Enlarged Australian Sample of Mothers of DZ Twins.

Female fertility is a complex trait with age-specific changes in spontaneous dizygotic (DZ) twinning and fertility. To elucidate factors regulating female fertility and infertility, we conducted a genome-wide association study (GWAS) on mothers of spontaneous DZ twins (MoDZT) versus controls (3273 cases, 24,009 controls). This is a follow-up study to the Australia/New Zealand (ANZ) component of that previously reported (Mbarek et al., 2016), with a sample size almost twice that of the entire discovery sample meta-analysed in the previous article (and five times the ANZ contribution to that), resulting from newly available additional genotyping and representing a significant increase in power. We compare analyses with and without male controls and show unequivocally that it is better to include male controls who have been screened for recent family history, than to use only female controls. Results from the SNP based GWAS identified four genomewide significant signals, including one novel region, ZFPM1 (Zinc Finger Protein, FOG Family Member 1), on chromosome 16. Previous signals near FSHB (Follicle Stimulating Hormone beta subunit) and SMAD3 (SMAD Family Member 3) were also replicated (Mbarek et al., 2016). We also ran the GWAS with a dominance model that identified a further locus ADRB2 on chr 5. These results have been contributed to the International Twinning Genetics Consortium for inclusion in the next GWAS meta-analysis (Mbarek et al., in press).

Patterns and cost of care according to keratinocyte cancer risk stratification in a volunteer population screening clinic: Real-world data from the TRoPICS study.

BACKGROUND: Risk prediction tools have been developed for keratinocyte cancers (KCs) to effectively categorize individuals with different levels of skin cancer burden. Few have been clinically validated nor routinely used in clinical settings. OBJECTIVES: To assess whether risk prediction tool categories associate with interventions including chemoprophylaxis for skin cancer, and health-care costs in a dermatologist-run screening clinic. METHODS: Adult participants who presented to a walk-in screening facility were invited to participate. A self-completed KC risk prediction tool was used to classify participants into one of the five risk categories. Participants subsequently underwent full skin examination by a dermatologist. Dermatological interventions and skin cancer-related medical prescriptions were documented. Total health-care costs, both to the health-care system and patients were evaluated. RESULTS: Of the 507 participants recruited, 5-fluorouracil cream and nicotinamide were more frequently prescribed in the higher risk groups as chemoprophylaxis (p < 0.005). A significant association with high predicted risk was also observed in the use of cryotherapy and curettage and cautery (p < 0.05). The average health-care costs associated with a skin check visit increased from $90 ± 37 (standard deviation) in the lowest risk group to $149 ± 97 in the highest risk group (p < 0.0001). CONCLUSIONS: We observed a positive association between higher predicted risk of skin cancer and the prescription of chemoprophylaxis and health-care costs involved with opportunistic community skin cancer screening. A clinical use of risk stratification may be to provide an opportunity for clinicians to discuss skin cancer prevention and chemoprophylaxis with individual patients.

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis.

OBJECTIVE: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. DESIGN: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). RESULTS: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. CONCLUSION: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Genetically determined cutaneous nevi and risk of cancer.

Numerous epidemiologic studies have reported positive associations between higher nevus counts and internal cancers. Whether this association represents a true relationship or is due to bias or confounding by factors associated with both nevus counts and cancer remains unclear. We used germline genetic variants for nevus count to test whether this phenotypic trait is a risk-marker for cancer. We calculated polygenic risk scores (PRS) for nevus counts using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 17 427). The association between the nevus PRS and each cancer site was assessed using logistic regression adjusted for the effects of age, sex and the first five principal components. In both cohorts, those in the highest nevus PRS quartile had higher risks of melanoma than those in the lowest quartile (UK Biobank odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.29-1.55; QSkin OR 1.58, 95% CI: 1.29-1.94). We also observed increases in risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with higher nevus PRS quartiles (BCC UK Biobank OR 1.38, 95% CI: 1.33-1.44; QSkin OR 1.20, 95% CI: 1.05-1.38 and SCC UK Biobank OR 1.41, 95% CI: 1.28-1.55; QSkin OR 1.44, 95% CI: 1.19-1.77). We found no consistent evidence that nevus count PRS were associated with risks of developing internal cancers. We infer that associations between nevus counts and internal cancers reported in earlier observational studies arose because of unmeasured confounding or other biases.

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting.

BACKGROUND: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. OBJECTIVE: To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. METHODS: We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10-8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. RESULTS: Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61-2.71, P = 2.08 × 10-8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77-3.21, P = 1.07 × 10-8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83-0.94, P = 6.93 × 10-5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78-0.90). CONCLUSION: We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.

The effect of screening on melanoma incidence and biopsy rates.

BACKGROUND: Cutaneous melanomas are common cancers in white-skinned populations, and early detection is promoted as a means of reducing morbidity and mortality. There is concern that increased skin screening is leading to overdiagnosis of indolent melanomas with low risk of lethality. The extent of melanoma overdiagnosis associated with screening is unknown. OBJECTIVES: To estimate possible overdiagnosis by comparing subsequent melanoma incidence and biopsy rates among people subjected to skin screening those who were not. METHODS: We recruited 43 762 residents of Queensland, Australia, aged 40-69 years, with no prior history of melanoma, selected at random from a population register in 2010. At baseline, participants completed a comprehensive melanoma risk factor survey and were asked if their skin had been examined by a doctor in the 3 years prior to baseline. We calculated incidence and relative risk of histologically confirmed melanoma (invasive and in situ) in years 2-7 of follow-up, obtained through linkage to the cancer registry. In secondary analyses, we measured biopsy rates in years 2-6 of follow-up. We used propensity score analysis to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: In total, 28 155 participants underwent skin screening prior to baseline. We observed 967 first-incident melanomas (381 invasive) during 197 191 person-years of follow-up. Those screened had higher rates of melanoma (aHR 1·29, 95% CI 1·02-1·63) and subsequent skin biopses (aHR 1·85, 95% CI 1·69-2·04) than unscreened participants. The higher risk associated with skin screening was evident for in situ melanoma (aHR 1·45, 95% CI 1·09-1·92) but not invasive melanoma (aHR 1·05, 95% CI 0·72-1·54). In secondary analyses, where screening was defined as having a skin biopsy in the first year after baseline, we observed significantly increased risks of melanoma (aHR 1·53, 95% CI 1·23-1·89) and subsequent biopsies (aHR 2·64, 95% CI 2·46-2·84) relative to those who did not have a biopsy. CONCLUSIONS: People who undergo skin screening subsequently experience higher rates of biopsies and melanoma (especially in situ melanoma), even after adjusting for all known risk factors, consistent with overdiagnosis. What is already known about this topic? Cutaneous melanomas are common cancers in white-skinned populations for which early detection is promoted as a means of reducing morbidity and mortality. There is concern that increased surveillance is leading to the overdiagnosis of indolent melanomas that are not destined to be lethal. The extent of melanoma overdiagnosis associated with surveillance is not known. What does this study add? People subjected to skin examinations by a doctor or who undergo skin biopsies subsequently have higher numbers of biopsies and higher rates of melanoma than people not subjected to either, even after adjusting for all known risk factors. These findings suggest that heightened surveillance leads to a proportion of melanomas being diagnosed that otherwise may not have come to clinical attention.

Perinatal depression is associated with a higher polygenic risk for major depressive disorder than non-perinatal depression.

BACKGROUND: Distinctions between major depressive disorder (MDD) and perinatal depression (PND) reflect varying views of PND, from a unique etiological subtype of MDD to an MDD episode that happens to coincide with childbirth. This case-control study investigated genetic differences between PND and MDD outside the perinatal period (non-perinatal depression or NPD). METHODS: We conducted a genome-wide association study using PND cases (Edinburgh Postnatal Depression Scale score ≥ 13) from the Australian Genetics of Depression Study 2018 data (n = 3804) and screened controls (n = 6134). Results of gene-set enrichment analysis were compared with those of women with non-PND. For six psychiatric disorders/traits, genetic correlations with PND were evaluated, and logistic regression analysis reported polygenic score (PGS) association with both PND and NPD. RESULTS: Genes differentially expressed in ovarian tissue were significantly enriched (stdBeta = 0.07, p = 3.3e-04), but were not found to be associated with NPD. The genetic correlation between PND and MDD was 0.93 (SE = 0.07; p = 3.5e-38). Compared with controls, PGS for MDD are higher for PND cases (odds ratio [OR] = 1.8, confidence interval [CI] = [1.7-1.8], p = 9.5e-140) than for NPD cases (OR = 1.6, CI = [1.5-1.7], p = 1.2e-49). Highest risk is for those reporting both antenatal and postnatal depression, irrespective of prior MDD history. CONCLUSIONS: PND has a high genetic overlap with MDD, but points of distinction focus on differential expression in ovarian tissue and higher MDD PGS, particularly for women experiencing both antenatal and postpartum PND.

Predicting obesity and smoking using medication data: A machine-learning approach.

PURPOSE: Administrative health datasets are widely used in public health research but often lack information about common confounders. We aimed to develop and validate machine learning (ML)-based models using medication data from Australia's Pharmaceutical Benefits Scheme (PBS) database to predict obesity and smoking. METHODS: We used data from the D-Health Trial (N = 18 000) and the QSkin Study (N = 43 794). Smoking history, and height and weight were self-reported at study entry. Linkage to the PBS dataset captured 5 years of medication data after cohort entry. We used age, sex, and medication use, classified using anatomical therapeutic classification codes, as potential predictors of smoking (current or quit <10 years ago; never or quit ≥10 years ago) and obesity (obese; non-obese). We trained gradient-boosted machine learning models using data for the first 80% of participants enrolled; models were validated using the remaining 20%. We assessed model performance overall and by sex and age, and compared models generated using 3 and 5 years of PBS data. RESULTS: Based on the validation dataset using 3 years of PBS data, the area under the receiver operating characteristic curve was 0.70 (95% confidence interval [CI] 0.68-0.71) for predicting obesity and 0.71 (95% CI 0.70-0.72) for predicting smoking. Models performed better in women than in men. Using 5 years of PBS data resulted in marginal improvement. CONCLUSIONS: Medication data in combination with age and sex can be used to predict obesity and smoking. These models may be of value to researchers using data collected for administrative purposes.

Combined analysis of keratinocyte cancers identifies novel genome-wide loci.

The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5-1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

Out-of-pocket medical expenses compared across five years for patients with one of five common cancers in Australia.

BACKGROUND: Patient medical out-of-pocket expenses are thought to be rising worldwide yet data describing trends over time is scant. We evaluated trends of out-of-pocket expenses for patients in Australia with one of five major cancers in the first-year after diagnosis. METHODS: Participants from the QSKIN Sun and Health prospective cohort Study with a histologically confirmed breast, colorectal, lung, melanoma, or prostate cancer diagnosed between 2011 and 2015 were included (n = 1965). Medicare claims data on out-of-pocket expenses were analysed using a two-part model adjusted for year of diagnosis, health insurance status, age and education level. Fisher price and quantity indexes were also calculated to assess prices and volumes separately. RESULTS: On average, patients with cancer diagnosed in 2015 spent 70% more out-of-pocket on direct medical expenses than those diagnosed in 2011. Out-of-pocket expenses increased significantly for patients with breast cancer (mean AU$2513 in 2011 to AU$6802 in 2015). Out-of-pocket expenses were higher overall for individuals with private health insurance. For prostate cancer, expenses increased for those without private health insurance over time (mean AU$1586 in 2011 to AU$4748 in 2014) and remained stable for those with private health insurance (AU$4397 in 2011 to AU$5623 in 2015). There were progressive increases in prices and quantities of medical services for patients with melanoma, breast and lung cancer. For all cancers, prices increased for medicines and doctor attendances but fluctuated for other medical services. CONCLUSION: Out-of-pocket expenses for patients with cancer have increased substantially over time. Such increases were more pronounced for women with breast cancer and those without private health insurance. Increased out-of-pocket expenses arose from both higher prices and higher volumes of health services but differ by cancer type. Further efforts to monitor patient out-of-pocket costs and prevent health inequities are required.