David C. Whiteman

JAMA dermatology • March 26, 2025

H Soyer, Dilki Jayasinghe, Astrid Rodriguez Acevedo, Louisa Collins, Liam Caffery, David Whiteman, Brigid Betz Stablein, Sonya Osborne, Anna Finnane, Caitlin Horsham, Clare Primiero, Leonard Gray, Monika Janda

Three-dimensional (3D) total-body photography (TBP) can support clinicians in monitoring and identifying changes to skin lesions in patients at high risk of melanoma. To assess clinical outcomes between patients at high risk of melanoma receiving usual clinical care compared with those receiving usual care plus 3D TBP and sequential digital dermoscopy imaging (SDDI) every 6 months via teledermatology. This randomized clinical trial was conducted at a research hospital in Brisbane, Australia, from April 2018 to October 2021, with adult patients (≥18 years) at high risk of developing a primary or subsequent melanoma. Data analysis was conducted from March 2022 to June 2024. Usual care plus 3D-TBP in person and SDDI via teledermatology at baseline, 6, 12, 18, and 24 months. The control group continued usual care and completed online surveys every 6 months. Number and rates of excisions and/or biopsies of lesions suggestive of melanoma, and results of histopathologic testing. The analysis included 314 participants (mean [SD] age, 51.6 [12.8] years; 194 females [62%]) who completed all of the study procedures (158 in the intervention and 156 in the control). In all, 1527 excisions (905 intervention and 622 in the control) were performed among 226 participants (122 intervention and 104 controls), with 67 (4%) histopathologically confirmed as melanoma and 402 (26%) as keratinocyte cancer (KC). The mean (SD) number of lesions of any type excised per person was significantly higher in the intervention (5.73 [6.77]; 95% CI, 4.66-6.79) compared to the control group (3.99 [5.72]; 95% CI, 3.08-4.89; P = .02). Fewer melanomas were detected among the intervention group compared with the control (24 [35%] vs 43 [64%], respectively), and therefore, a lower incidence rate: 2.03 (95% CI, 1.30-3.02) vs 3.62 (95% CI, 2.62-4.88), respectively. After 1 year of follow-up, the intervention had a lower, but not statistically significant, rate of melanoma per person: 0.08 (95% CI, 0.03-0.13) compared with 0.16 (95% CI, 0.08-0.25) in the control; an average of 0.86 (95% CI, 0.55-1.16) vs 0.42 (95% CI, 0.24-0.59) KCs per person; and 2.01 (95% CI, 1.50-2.51) vs 1.39 (95% CI, 0.98-1.82) excisions or biopsies per person, respectively. The results of this randomized clinical trial indicate that the addition of 3D-TPB and SDDI to usual care in a teledermatology setting without AI (artificial intelligence) increased the number and rate of skin excisions and biopsies performed. Further studies are required to compare teledermatology to usual care rather than adding it, and to study whether the use of AI can improve the teledermatology outcomes. Larger studies in multiple settings with a greater number of teledermatologists are needed. This study shows that conducting clinical trials in this setting is feasible. anzctr.org.au Identifier: ACTRN12618000267257.

MedRxiv : The Preprint Server For Health Sciences • July 16, 2025

Jessye Maxwell, Brittany Mitchell, Xinyi Duharpur, Luba Pardo, Willemijn C A Witkam, Nick Dand, Meike Bartels, Michael Betti, Dorret Boomsma, Xianjun Dong, Zachary Gerring, Sarah Finer, Jouke Hottenga, George Hripcsak, Laura Huilaja, Kristian Hveem, Benjamin Jacobs, Mart Kals, James Kaufman Cook, Johannes Kettunen, Atlas Khan, Külli Kingo, Krzysztof Kiryluk, Mari Løset, Gerton Lunter, Michelle Lupton, Josine Min, Nicholas Martin, Sarah Medland, Dorien Neijzen, Tamar E Nijsten, Tiit Nikopensius, Catherine Olsen, Lynn Petukhova, Anu Reigo, Miguel Rentería, Rossella Rispoli, Jake Saklatvala, Eeva Sliz, Kaisa Tasanen Määttä, Laurent Thomas, Richard Trembath, Mariliis Vaht, David Van Heel, Chunhua Weng, David Whiteman, Jonathan Barker, Catherine Smith, Michael Simpson

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.

MedRxiv : The Preprint Server For Health Sciences • July 16, 2025

Tracey Van Der Veen, Markos Tesfaye, Jessica Mei Yang, Toni Boltz, Friederike David, Shane Crinion, Maria Koromina, Till F Andlauer, Tim Bigdeli, Brandon Coombes, Tiffany Greenwood, Georgia Panagiotaropoulou, Nadine Parker, Heejong Sung, Nicholas Bass, Jonathan R Coleman, José Guzman Parra, Janos Kalman, Caroline Mcgrouther, Brittany Mitchell, Aaditya Rangan, Katie Scott, Alexey Shadrin, Daniel Smith, Annabel Vreeker, Kristina Adorjan, Diego Albani, Silvia Alemany, Ney Alliey Rodriguez, Anastasia Antoniou, Michael Bauer, Eva Beins, Marco Boks, Rosa Bosch, Ben Brumpton, Nathalie Brunkhorst Kanaan, Monika Budde, William Byerley, Judit Cabana Domínguez, Murray Cairns, Bernardo Carpiniello, Miquel Casas, Pablo Cervantes, Chris Chatzinakos, Toni-kim Clarke, Isabelle Claus, Cristiana Cruceanu, Alfredo Cuellar Barboza, Piotr Czerski, Konstantinos Dafnas, Anders Dale, Nina Dalkner, J Depaulo, Franziska Degenhardt, Srdjan Djurovic, Valentina Escott Price, Ayman Fanous, Frederike Fellendorf, I Ferrier, Liz Forty, Josef Frank, Oleksandr Frei, Nelson Freimer, Julie Garnham, Ian Gizer, Scott Gordon, Katherine Gordon Smith, Tim Hahn, L Marian, Arvid Harder, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Ian Hickie, Per Hoffmann, Peter Holmans, Stéphane Jamain, Lina Jonsson, James Kennedy, Sarah Kittel Schneider, James Knowles, Elise Koch, Manolis Kogevinas, Thorsten Kranz, Steven Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Penelope Lind, Susanne Lucae, Martin Lundberg, Donald Macintyre, Wolfgang Maier, Adam Maihofer, Dolores Malaspina, Mirko Manchia, Eirini Maratou, Lina Martinsson, Melvin Mcinnis, James Mckay, Helena Medeiros, Andreas Meyer Lindenberg, Vincent Millischer, Derek Morris, Paraskevi Moutsatsou, Thomas Mühleisen, Claire 'donovan, Catherine Olsen, Sergi Papiol, Antonio Pardiñas, Amy Perry, Andrea Pfennig, Claudia Pisanu, James Potash, Digby Quested, Mark Rapaport, Eline Regeer, John Rice, Margarita Rivera, Eva Schulte, Fanny Senner, Paul Shilling, Lisa Sindermann, Lea Sirignano, Dan Siskind, Claire Slaney, Olav Smeland, Janet Sobell, Maria Artigas, Dan Stein, Frederike Stein, Beata Swiatkowska, Jackson Thorp, Claudio Toma, Leonardo Tondo, Paul Tooney, Marquis Vawter, Helmut Vedder, James T Walters, Stephanie Witt, Allan Young, Peter Zandi, Lea Zillich, Bernhard Baune, Frank Bellivier, Susanne Bengesser, Wade Berrettini, Joanna Biernacka, Douglas Blackwood, Michael Boehnke, Gerome Breen, Vaughan Carr, Stanley Catts, Sven Cichon, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Tõnu Esko, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice Fullerton, Micha Gawlik, Elliot Gershon, Fernando Goes, Melissa Green, Joanna Hauser, Frans Henskens, Jens Hjerling Leffler, Ian Jones, Lisa Jones, René Kahn, John Kelsoe, Tilo Kircher, George Kirov, Nene Kobayashi, Mikael Landén, Marion Leboyer, Melanie Lenger, Qingqin Li, Jolanta Lissowska, Carmel Loughland, Jurjen Luykx, Nicholas Martin, Carol Mathews, Fermin Mayoral, Susan Mcelroy, Andrew Mcintosh, Sarah Medland, Ingrid Melle, Philip Mitchell, Gunnar Morken, Richard Myers, Chiara Möser, Bertram Müller Myhsok, Benjamin Neale, Caroline Nievergelt, John Nurnberger, Markus Nöthen, Michael O'donovan, Ketil Oedegaard, Tomas Olsson, Michael Owen, Sara Paciga, Christos Pantelis, Carlos Pato, Michele Pato, George Patrinos, Joanna Pawlak, Roy Perlis, Josep Ramos Quiroga, Andreas Reif, Eva Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy Rouleau, Ulrich Schall, Martin Schalling, Peter Schofield, Thomas Schulze, Laura Scott, Rodney Scott, Alessandro Serretti, Jordan Smoller, Alessio Squassina, Eli Stahl, Eystein Stordal, Fabian Streit, Patrick Sullivan, Gustavo Turecki, Arne Vaaler, Eduard Vieta, John Vincent, Irwin Waldman, Cynthia Weickert, Thomas Weickert, David Whiteman, Martin Alda, Roel Ophoff, Kevin O'connell, Niamh Mullins, Andreas Forstner, Maria Grigoroiu Serbanescu, Howard Edenberg, Francis Mcmahon, Ole Andreassen, Arianna Di Florio, Andrew Mcquillin

The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures. This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for. The primary outcomes were the genetic dimensions underlying BD heterogeneity, differentiated by single nucleotide polymorphism (SNP)-heritability (h 2 SNP ), genetic correlations, genomic loci ( P ≤5×10 -8 ), and functional, cell-type, and gene-expression pathway analyses. We identified four genetically-informed dimensions of BD: Severe Illness, Core Mania, Externalizing/Impulsive Comorbidity, and Internalizing/Affective Comorbidity. The analyses yielded up to 181 subphenotype-associated loci, 53 of which are novel. The Severe Illness Dimension was characterized by a unique neuro-immune signature (a protective association with HLA-DMB , P =2.50×10 -273 ) evident only when leveraging SCZ genetic data. The Internalizing/Affective dimension was associated with neurodevelopmental genes (e.g., DCC ). Notably, the rapid-cycling subphenotype showed a unique signature of strong negative selection, a finding not observed in other subphenotypes. The clinical heterogeneity of bipolar disorder appears to be defined by a complex and multi-layered genetic architecture. The presented findings provide an empirical framework that may advance psychiatric nosology beyond its current diagnostic boundaries. These results may also inform future research to identify targets for personalized interventions. The delineation of these genetically-informed dimensions offers specific, biologically-grounded hypotheses for subsequent therapeutic discovery. Establishing such a framework is an essential step toward refining diagnostic criteria and developing more effective, personalized treatments. This work lays the foundation for a transition from a uniform treatment model to the paradigm of precision psychiatry. Question: What are the distinct genetic architectures underlying the clinical heterogeneity of bipolar disorder?Findings: In this genetic study of 23,819 bipolar disorder (BD) cases and 163,839 controls, clinical heterogeneity mapped onto four genetically-informed dimensions. A severe illness dimension was defined by a neuro-immune signature ( HLA-DMB ) shared with schizophrenia. An affective comorbidity dimension was distinguished by neurodevelopmental pathways involving axonal guidance ( DCC ). Notably, the rapid-cycling phenotype showed evidence of purifying selection, suggesting influence by rare, highly penetrant alleles. Meaning: These findings provide a data-driven biological framework for bipolar disorder, guiding future research toward patient stratification and targeted therapeutics.

JAMA Dermatology • July 09, 2025

Catherine Olsen, Maja Shalit, Nirmala Pandeya, Rachel Neale, G J M Shanika Jayasinghe, Matthew Law, David Whiteman

No prospective epidemiologic studies have investigated genetic vs environmental factors on the risks of nevus-associated melanoma (NAM) and de novo melanoma. To determine whether the risk factor profile differs for nevus-associated and de novo invasive melanoma, and whether the associations differ according to sex. This population-based prospective cohort study (the QSkin Study) conducted in Queensland, Australia, included participants aged 40 to 69 years at baseline. Participants were recruited in 2011 and followed up until December 2022. All analyses were conducted between October 2024 and January 2025. Self-reported information from the baseline survey on phenotypic factors (hair color, tanning ability, nevus density, family history), sun exposure-related factors (sunburns, history of skin cancers and actinic lesions), and polygenic risk scores for melanoma and nevus development was collected. The primary outcome was incident invasive melanoma (nevus-associated and de novo). A total of 17 752 males and 21 049 females were included and 859 were analyzed. During a median (IQR) follow-up of 11.4 (11.2-11.7) years, 209 participants developed an invasive nevus-associated melanoma (129 in males and 80 in females) and 650 developed an invasive de novo melanoma (362 in males and 288 in females). Many of the known phenotypic and sun exposure-related risk factors for melanoma were similarly associated with nevus-associated and de novo melanoma, but high nevus density and high genetic propensity for melanoma development had significantly higher hazard ratios (HRs) for NAM than de novo melanoma (HR for many moles vs no moles, 6.86 [95% CI, 3.82-12.33] vs 3.21 [95% CI, 2.23-4.63]; P = .001; HR for melanoma polygenic risk score tertile 3 vs tertile 1, 6.46 [95% CI, 3.42-12.20) vs 2.98 [95% CI, 2.21-4.02]; P = .006). No significant differences in the risk factor profile for NAM were found for sex, but the HR for older age was significantly higher among males with de novo melanoma than in females. The site distribution of NAM differed for males and females, occurring mostly commonly on the trunk in males and on the limbs in females. Results of this study identified distinct risk factor profiles for NAM and de novo melanomas, particularly polygenic risk and nevus propensity. Males and females tended to develop NAM on different body sites, which may have implications for early detection strategies.

MedRxiv : The Preprint Server For Health Sciences • June 04, 2025

Samantha White, Maizy Brasher, Jack Pattee, Wei Zhou, Sinéad Chapman, Yon Jee, Caitlin Bell, Taylor Jamil, Martin Barrio, Jibril Hirbo, Nancy Cox, Peter Straub, Shinichi Namba, Emily Bertucci Richter, Lindsay Guare, Ahmed Edrismohammed, Sam Morris, Ashley Mulford, Haoyu Zhang, Brian Fennessy, Martin Tobin, Jing Chen, Alexander Williams, Catherine John, David Van Heel, Rohini Mathur, Sarah Finer, Marta Moksnes, Ben Brumpton, Bjørn Åsvold, Raitis Peculis, Vita Rovite, Ilze Konrade, Ying Wang, Kristy Crooks, Sameer Chavan, Matthew Fisher, Nicholas Rafaels, Meng Lin, Jonathan Shortt, Alan Sanders, David Whiteman, Stuart Macgregor, Sarah Medland, Unnur Thorsteinsdóttir, Kári Stefánsson, Tugce Karaderi, Kathleen Egan, Therese Bocklage, Hilary Mccrary, Greg Riedlingeer, Bodour Salhia, Craig Shriver, Minh Phan, Janice Farlow, Stephen Edge, Varinder Kaur, Michelle Churchman, Robert Rounbehler, Pamela Brock, Matthew Ringel, Milton Pividori, Rebecca Schweppe, Christopher Raeburn, Robin Walters, Zhengming Chen, Liming Li, Koichi Matsuda, Yukinori Okada, Sebastian Zoellner, Anurag Verma, Michael Preuss, Eimear Kenny, Audrey Hendricks, Lauren Fishbein, Peter Kraft, Mark Daly, Benjamin Neale, Christopher Gignoux, Nikita Pozdeyev

Thyroid diseases are common and highly heritable. Under the Global Biobank Meta-analysis Initiative, we performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer, benign nodular goiter, Graves' disease, lymphocytic thyroiditis, and primary hypothyroidism. We analyzed genetic association data from ~2.9 million genomes and identified 235 known and 501 novel independent variants significantly linked to thyroid diseases. We discovered genetic correlations between thyroid cancer, benign nodular goiter, and autoimmune thyroid diseases (r 2 =0.21-0.97). Telomere maintenance genes contribute to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair, and DNA damage response genes are predominantly associated with thyroid cancer. We proposed a paradigm explaining genetic predisposition to benign and malignant thyroid nodules. We evaluated thyroid cancer polygenic risk scores (PRS) for clinical applications in thyroid cancer diagnosis. We found PRS associations with thyroid cancer risk features: multifocality, lymph node metastases, and extranodal extension.