Genes & Health (G&H) is a biomedical study of adult British Pakistani and Bangladeshi research volunteers enriched for autozygosity. Here we performed whole-exome sequencing in 44,028 G&H participants, establishing a large publicly available South Asian exome resource linked to longitudinal electronic health records. We performed exome-wide association analyses for 645 electronic health record-derived traits under additive and recessive models, and meta-analyses of 33 cardiometabolic traits with UK Biobank, finding more than 100 novel gene-phenotype associations. We identified 2,991 genes with rare biallelic predicted loss-of-function ('knockout') genotypes, 546 of which had not been previously reported. We show that drugs targeting genes with knockouts in adults are associated with a 2.2-fold higher likelihood of progressing beyond phase 1 clinical trials. We further illustrate how phenotypic profiles associated with knockout genotypes can enhance efficacy and safety assessment of drug targets and aid in the interpretation of variants with ambiguous clinical significance in autosomal recessive disease genes.

Comorbid cardiovascular disease (including coronary artery disease [CAD] and stroke) is a major source of morbidity and mortality in people with psoriasis. A recent Mendelian randomization (MR) study has provided supportive evidence that lifetime risk of CAD is causally implicated in psoriasis development, independent of adiposity (Patricket al Nat Commun. 2022). However, it is currently unclear whether lifetime risk of stroke influences psoriasis risk. A two-sample MR approach was undertaken to evaluate the putative causal effect of stroke on psoriasis risk. Instrumental variables comprised genetic variants with genome-wide significant effects on the risk of stroke and CAD, derived from genome-wide association meta-analysis studies (including 67,162 stroke cases; 454,000 controls). The effects of these instrumental variables on psoriasis risk were evaluated in a meta-analysis of genome-wide association studies of psoriasis risk (36,466 cases; 458,078 controls). Inverse-variance weighted (IVW) MR estimates confirmed previous findings of a causal role of CAD on psoriasis (p=0.02). IVW and weighted median estimates supported a strong causal effect of stroke on psoriasis risk (IVW OR 1.29 [1.08-1.57], p=0.006). Dissection of the stroke instrumental variable by exclusion of seven genetic variants that also have genome-wide significant effects on CAD risk indicates that the effect is independent of observed CAD risk (IVW OR 1.32 [1.10-1.59], p=0.003). In the reverse direction, weak causal effects of psoriasis on CAD (p=0.05) and stroke (p=0.04) were also observed. Our data are consistent with lifetime risk of stroke increasing psoriasis risk. This supports the notion that the pathways influencing cardiovascular disease risk contribute to the casual biological pathways of psoriasis. Future work should focus on distinguishing potential confounding effects of adiposity and circulating lipids on this causal relationship.

Identification of prognostic indicators for severe psoriasis may enable earlier intervention, limit disease progression and reduce cumulative impact on quality of life. Psoriasis severity has different components, with different measures and proxies, and can vary over time. To facilitate a coordinated analytical approach within a large European consortium(BIOMAP), we assessed the data available across a range of population- and registry-based datasets. Preferred severity definitions were established by an inter-disciplinary expert group according to published literature and previous consensus work. We next evaluated the association of epidemiological and genetic risk factors with psoriasis severity. In population-based datasets, severe psoriasis was defined by use of systemic medication (self-reported or linked prescription data) or secondary care (via linked hospital inpatient data). In UK Biobank, individuals with severe psoriasis (N=878) were more likely to have known risk factors relative to non-severe psoriasis (N=5,901) including male sex (OR=1.18; 95%CI: 1.03-1.37), earlier onset (OR=1.78; 95%CI: 1.53-2.05), higher smoking frequency (OR=1.09; 95%CI: 1.03-1.16) and higher BMI (OR=1.23; 95%CI: 1.15-1.31). We observed no genetic association with severity at HLA-C*06:02, but severe cases exhibited a higher polygenic risk score of established non-HLA psoriasis susceptibility variants (OR=1.23; 95%CI: 1.14-1.32). Genetic and epidemiological associations were largely replicated in a disease-only registry-based dataset (BSTOP; N=4,151) using maximum PASI to measure severity. We have developed a framework enabling future research into disease severity, and shown that individuals exhibiting increased genetic risk for psoriasis are more likely to develop severe disease. Wider application of our approach will facilitate meta-analyses to reveal specific severity-associated genetic loci.

To investigate a potential causal role of natural variation in endogenous testosterone levels in the development of acne, we performed a two-sample sex-stratified Mendelian randomisation (MR) study. Instrumental variables comprised genetic variants with genome-wide significant effects on total testosterone (TT), free testosterone (FT) and steroid hormone binding globulin (SHBG) levels in male and female participants in UK Biobank. The effects of these instrumental variables on acne were derived from sex-stratified genome-wide association studies of acne comprising 3,173 female cases and 2,426 male cases. Inverse-variance weighted MR estimates did not support a causal role for testosterone traits on acne risk in males (ORTT = 1.00 (0.85-1.18), pTT = 0.98; ORFT = 1.02 (0.79-1.31), pFT = 0.87; ORSHBG = 0.91 (0.70-1.18), pSHBG = 0.47). In females, genetic variants associated with increased levels of total testosterone and free testosterone conferred a proportional increase in acne risk (ORTT = 1.79 (1.38-2.32), pTT = 1.0x10-5; ORFT = 2.30 (1.53-3.45), pFT = 5.8x10-5). Whereas genetic variants associated with increased SHBG conferred a proportional decrease in acne risk (ORSHBG = 0.68 (0.50-0.93), pSHBG = 0.016). Dissection of the instrumental variable sets indicated that the MR effect in females is driven by variants with effects specific to total and free testosterone, and independent of SHBG levels (OR = 2.29 (1.46-3.58), p = 2.8x10-4). Our data are consistent with endogenous, SHBG-independent, testosterone levels contributing to the casual biological pathways of female acne. The discordant effect of variation in endogenous testosterone levels in males and females is suggestive of a pathophysiological sexual dimorphism in severe acne and motivates further sex-stratified investigations.

Acne vulgaris is a highly heritable and common skin disorder. Acne lesions primarily impact facial skin and severely inflamed lesions may leave permanent scars that have been associated with long-term psychosocial consequences. Individuals with severe acne have been reported to have elevated rates of depression, anxiety, suicidal ideation and other mental health disorders. Nonetheless, the shared biology between these disorders and the direction of causality remains unclear. We used summary statistics from the largest available genome-wide association studies to date, to examine the genetic overlap between acne and seven mental health disorders. Next, we applied Generalised Summary-data-based Mendelian Randomisation to test for evidence of possible causal relationships between acne and each mental disorder. Increased risk of acne was significantly genetically correlated with increased risk of depression, anxiety, schizophrenia and bipolar disorder – with the largest genetic correlation occurring with bipolar disorder (rg = 0.18; P=6.7e-05) – and an acne genetic risk score significantly predicted a reported history of depression, anxiety and bipolar disorder (P<0.001). We also observed a causal relationship between increased risk of acne and increased risk of depression (OR=1.04 [95% CI 1.02-1.07]). Here, we show evidence of shared genetic pathways that jointly influence risk for acne and several mental health disorders, suggesting that the co-morbidity between these disorders may be genetically mediated, and provide evidence of the direction of causation. Future work will consist of further interrogation of these results, particularly through the exploration of regional genomic overlap and underlying pathway analysis. These results provide novel insight into the relationships and underlying mechanisms between acne and mental health disorders which may improve our ability to diagnose, prevent or manage such conditions.

Acne vulgaris is a highly heritable skin disorder that primarily impacts facial skin. Severely inflamed lesions may leave permanent scars that have been associated with long-term psychosocial consequences. Current treatments are limited in their efficacy and tolerance and there is a substantial unmet medical need. Improved understanding of the pathogenic mechanisms of acne is critical for the development of novel therapies that could replace or supplement existing approaches. Here, we perform the largest GWAS meta-analysis to date comprising 20,165 individuals with acne from nine independent cohorts from Australia, Finland, Norway, the Netherlands, the UK and the USA; a four-fold increase in cases on the previous largest acne meta-analysis. We identify 29 novel genome-wide significant loci and replicate 14 of the 17 previously identified risk loci, bringing the total number of reported acne risk loci to 46. Using fine-mapping and eQTL colocalisation approaches we identify putative causal genes at several novel acne susceptibility loci that have previously been implicated in Mendelian hair and skin disorders, including ectodermal dysplasia, mandibulofacial dysostosis and pustular psoriasis. We identify shared genetic aetiology between acne, hormone levels, hormone-sensitive cancers and psychiatric traits. Finally, we show that a polygenic risk score calculated from our results explains up to 5.6% of the variance in acne liability in an independent cohort.

The identification of robust endotypes???disease subgroups of clinical relevance???is fundamental to stratified medicine. We hypothesized that HLA-C*06:02 status, the major genetic determinant of psoriasis, defines a psoriasis endotype of clinical relevance. Using two United Kingdom-based cross-sectional datasets???an observational severe-psoriasis study (Biomarkers of Systemic Treatment Outcomes in Psoriasis; n = 3,767) and a large population-based bioresource (UK Biobank, including n = 5,519 individuals with psoriasis)???we compared demographic, environmental, and clinical variables of interest in HLA-C*06:02-positive (one or two copies of the HLA-C*06:02 allele) with those in HLA-C*06:02-negative (no copies) individuals of European ancestry. We used multivariable regression analyses to account for mediation effects established a priori. We confirm previous observations that HLA-C*06:02-positive status is associated with earlier age of psoriasis onset and extend findings to reveal an association with disease expressivity in females (Biomarkers of Systemic Treatment Outcomes in Psoriasis: P = 2.7 x 10-14, UK Biobank: P = 1.0 x 10-8). We also show HLA-C*06:02-negative status to be associated with characteristic clinical features (large plaque disease, OR for HLA-C*06:02 = 0.73, P = 7.4 x 10-4; nail involvement, OR = 0.70, P = 2.4 x 10-6); higher central adiposity (Biomarkers of Systemic Treatment Outcomes in Psoriasis: waist circumference difference of 2.0 cm, P = 8.4 x 10-4; UK Biobank: waist circumference difference of 1.4 cm, P = 1.5 x 10-4), especially in women; and a higher prevalence of other cardiometabolic comorbidities. These findings extend the clinical phenotype delineated by HLA-C*06:02 and highlight its potential as an important biomarker to consider in future multimarker stratified medicine approaches.

Targeted biologic therapies can elicit an undesirable host immune response characterised by the development of anti-drug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is the TNF inhibitor adalimumab. This genome-wide association study aimed to identify genetic predictors of developing ADA in psoriasis patients on their first course of adalimumab. Within the BSTOP bioresource, 784 psoriasis patients had ADA data 6-36 months after starting adalimumab (discovery cohort), 232 patients had ADA data <6 months after starting adalimumab (early ADA cohort), and 716 patients had only clinical data available (clinical outcome cohort). We genotyped and imputed 10,917,604 SNPs genome-wide and performed HLA imputation. We tested for association between genetic variation and development of ADA (logistic regression), as well as treatment failure (stopping adalimumab due to ineffectiveness [Cox proportional hazards]). We observed a genome-wide association with ADA within the Major Histocompatibility Complex (rs9268628, OR 3.44, 95% CI 2.21-5.36, p=4.93 x10-8) that mapped to the presence of tryptophan at position 9 (OR 0.34, 95% CI 0.25-0.45, p=1.76x10-12) and lysine at position 71 (OR 0.39, 95% CI 0.28-0.55, p=5.77x10-8) within the HLA-DRB1 peptide-binding groove, explaining 20% of ADA heritability. The protective effect of these residues on early ADA development was also observed in the second cohort of 232 patients. Underscoring their clinical relevance, these HLA-DRB1 residues were protective against treatment failure in the third cohort of 716 patients (HR 0.73, 95% CI 0.57-0.94, p=0.013). We suggest that pre-treatment HLA-DRB1 typing could direct clinical decision-making in terms of biologic selection and immunosuppressant co-therapy. Our findings also provide fundamental insight into the mechanisms by which amino acids within MHC Class II subunits play a critical role in selection of drug antigens displayed to the T-cell receptor, thereby determining the immune response to biologics.

Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in the F13A1 gene encoding factor XIII subunit A (FXIII-A), a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has an allele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, the treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation, and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and α4β1 integrins, more prominently for Lys679Met FXIII-A than the wild type. In addition, both the α4β1 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine-Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may lead to a conformational change in the FXIII-A protein that enhances α4-integrin binding and provides insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

RESULTS FROM THE PHASE 3, RANDOMIZED, DOUBLE-BLIND, VEHICLECONTROLLED ESSENCE TRIAL OF THE TOPICAL INVESTIGATIONAL DRUG SD-101 IN PATIENTSWITHEPIDERMOLYSIS BULLOSA: OVERALL RESULTS AND KEY SUBGROUP ANALYSES C. Kowalewski, M. Nikolic, D. Murrell, J. Browning, A. Paller, C. Bodemer, H. Ott, D. Kiritsi, A. Reha, J. Barth, H. Lagast Medical University of Warsaw, Warsaw, Poland, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia, University of New South Wales, Sydney, Australia, Texas Dermatology and Laser Specialists, San Antonio, USA, Northwestern University Feinberg School of Medicine, Chicago, USA, The University Hospital Necker Enfants Malades, Paris, France, Children’s Hospital Auf der Bult, Hanover, Germany, Medical Center-University of Freiburg, Freiburg, Germany and Amicus Therapeutics, Inc., Cranbury, USA

BG01 Novel ADAR mutations in two cases of dyschromatosis symmetrica hereditaria S. O’Sullivan, S.M. Lwin, L. Liu, J. Lai-Cheong, J.A. McGrath and J.E. Mellerio St. John’s Institute of Dermatology, King’s College, Guy’s and St. Thomas’ Hospital, London, U.K.; Viapath, St Thomas’ Hospital, London, U.K. and King Edward VII Hospital, Windsor, U.K. Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant disorder characterized by hyperand hypopigmentation predominantly affecting the dorsa of the distal extremities. It results from loss-of-function mutations in the ADAR gene that encodes the enzyme responsible for doublestrand breakage of RNA through deamination of adenosines. Case 1, a 6-year-old boy of Chinese ethnicity, had depigmentation affecting the dorsa of the hands, feet, arms and knees from age 18 months within which he developed progressive darker freckling. Facial hypopigmentation with freckling on the cheeks and forehead was present along with Blaschkolinear hypopigmentation of the left scapula and anterior chest. The skin texture, nails, hair, sweating and dermatoglyphics were normal. No family members were affected. Sanger sequencing revealed a novel heterozygous ADAR mutation not present in his parents, suggesting de novo occurrence. This single nucleotide transversion, c.1601+ 1G>T, within the consensus region of a donor splice site, is predicted to compromise splicing, potentially resulting in haploinsufficiency and is therefore highly likely to be pathogenic. Case 2, a 30-year-old man of Estonian origin, had skin dyspigmentation from age 5 years. Initially, his hands had darker, blotchy pigmentation and sun-induced hand swelling, reduced sweating and corneal opacification. Examination revealed mottled hyperand hypopigmentation, reduced dermatoglyphics, general xerosis with lichenification around the ankles and mild dental anomalies. There were no oral mucosal changes, hair or nail abnormalities. His features suggested Naegeli–Franceschetti–Jadassohn syndrome; however, KRT14 gene screening was negative. The proband had a persistently borderline low vitamin B12 (43 pmol L ); however, dyspigmentation did not improve with vitamin B12 supplementation. Subsequently, whole exome sequencing of his DNA identified a new heterozygous splice site mutation in ADAR, c.15+ 10G>T which in silico modelling suggests is pathogenic, supporting a diagnosis of DSH. ADAR mutations in DSH are mainly reported in the Asian population. ADAR enzymes are involved in regulation of the immune system with both cellular and viral editing capacities. The exact mechanism of ADAR1 in causing pigmentary changes seen in DSH is not yet fully known. Autosomal recessive ADAR mutations can cause Aicardi–Goutieres syndrome although the clinical features in skin and brain are related to inflammation arising from autoimmunity. Additionally, other cutaneous dyspigmentation diseases, including dyschromatosis universalis hereditaria, reticulate acropigmentation of Kitamura and Dowling–Degos disease, result from mutations in different, distinct genes indicating that multiple cellular mechanisms can give rise to similar cutaneous pigmentary phenotypes.