Phenome-wide identification of therapeutic genetic targets, leveraging knowledge graphs, graph neural networks, and UK Biobank data.

The ongoing expansion of human genomic datasets propels therapeutic target identification; however, extracting gene-disease associations from gene annotations remains challenging. Here, we introduce Mantis-ML 2.0, a framework integrating AstraZeneca's Biological Insights Knowledge Graph and numerous tabular datasets, to assess gene-disease probabilities throughout the phenome. We use graph neural networks, capturing the graph's holistic structure, and train them on hundreds of balanced datasets via a robust semi-supervised learning framework to provide gene-disease probabilities across the human exome. Mantis-ML 2.0 incorporates natural language processing to automate disease-relevant feature selection for thousands of diseases. The enhanced models demonstrate a 6.9% average classification power boost, achieving a median receiver operating characteristic (ROC) area under curve (AUC) score of 0.90 across 5220 diseases from Human Phenotype Ontology, OpenTargets, and Genomics England. Notably, Mantis-ML 2.0 prioritizes associations from an independent UK Biobank phenome-wide association study (PheWAS), providing a stronger form of triaging and mitigating against underpowered PheWAS associations. Results are exposed through an interactive web resource.

Symptom severity and trajectories among adolescent and young adult patients with cancer.

BACKGROUND: Patients with cancer experience significant symptom burden. We investigated symptom severity in adolescents and young adults (18- to 39-year-olds) during the year following a cancer diagnosis and made comparisons with older adult (those older than 40 years of age) patients with cancer. METHODS: All Albertan residents diagnosed with a first primary neoplasm at 18 years of age or older between April 1, 2018, and December 31, 2019, and who completed at least 1 electronic patient-reported outcome questionnaire were included. Symptom severity was assessed using the Edmonton Symptom Assessment System-revised. Descriptive statistics, multivariable logistic modeling, and mixed logistic regression modeling were used to describe symptom severity, identify risk factors, and assess symptom trajectories, respectively. RESULTS: In total, 473 and 322 adolescents and young adults completed a patient-reported outcomes questionnaire at diagnosis and 1 year after diagnosis, respectively. Adolescent and young adult patients with cancer reported high levels of tiredness, poor well-being, and anxiety. Important risk factors included metastatic disease, female sex, treatment types received, and age at diagnosis. Symptom severity varied by clinical tumor group, with those diagnosed with sarcoma having the worst scores for all symptoms at diagnosis and patients with intrathoracic or endocrine tumors having the worst scores for all symptoms at 1 year after diagnosis. Statistically significant differences in symptom severity over the 1-year period were observed between adolescents and young adults and older adults-specifically, the odds of having moderate to severe symptoms were statistically significantly greater among adolescents and young adults with respect to pain, tiredness, nausea, depression, anxiety, and poor well-being (all P < .01). CONCLUSIONS: A substantial proportion of adolescents and young adults experience moderate to severe symptoms during the year following diagnosis. Modifying existing supportive services and developing interventions based on the needs of adolescent and young adult patients with cancer could aid symptom control.

Rare variant associations with plasma protein levels in the UK Biobank.

Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets1-4. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype-protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort5. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene-protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1 and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13 and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.

The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings.

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.

Alberta Childhood Cancer Survivorship Research Program.

Adverse outcomes after childhood cancer have been assessed in a range of settings, but most existing studies are historical and ascertain outcomes only after 5-year survival. Here, we describe the Alberta Childhood Cancer Survivorship Research Program and its foundational retrospective, population-based cohort of Albertan residents diagnosed with a first primary neoplasm between the ages of 0 and 17 years from 1 January 2001 to 31 December 2018. The cohort was established in collaboration with the Alberta Cancer Registry and Cancer in Young People in Canada program and has been linked to existing administrative health databases and patient-reported outcome questionnaires. The cohort comprised 2580 survivors of childhood cancer, 1379 (53.4%) of whom were 5-year survivors. Approximately 48% of the cohort was female, 47% of the cohort was diagnosed between 0 and 4 years of age, and the most frequent diagnoses were leukemias (25.4%), central nervous system tumors (24.0%), and lymphomas (14.9%). Detailed treatment information was available for 1741 survivors (67.5%), with manual abstraction ongoing for those with missing data. By the study exit date, the median time since diagnosis was 5.5 years overall and 10.4 years for 5-year survivors. During the follow-up time, 82 subsequent primary cancers were diagnosed, 20,355 inpatient and 555,425 ambulatory/outpatient events occurred, 606,773 claims were reported, and 437 survivors died. The results from this research program seek to inform and improve clinical care and reduce cancer-related sequelae via tertiary prevention strategies.

GYY4137, a hydrogen sulfide donor, protects against endothelial dysfunction in porcine coronary arteries exposed to myeloperoxidase and hypochlorous acid.

BACKGROUND AND AIMS: Myeloperoxidase (MPO) and its principal reaction product hypochlorous acid (HOCl) are part of the innate immune response but are also associated with endothelial dysfunction, thought to involve a reduction in nitric oxide (NO) bioavailability. We aimed to investigate the effect of MPO and HOCl on vasorelaxation of coronary arteries and to assess directly the involvement of NO. In addition, we hypothesised that the slow release hydrogen sulfide (H2S) donor GYY4137 would salvage coronary artery endothelial function in the presence of MPO and HOCl. METHODS AND RESULTS: Contractility of porcine coronary artery segments was measured using isometric tension recording. Incubation with MPO (50 ng/ml) plus hydrogen peroxide (H2O2) (30 µM; substrate for MPO) impaired endothelium-dependent vasorelaxation to bradykinin in coronary arteries. HOCl (10-500 µM) also impaired endothelium-dependent relaxations. There was no effect of MPO plus H2O2, or HOCl, on endothelium-independent relaxations to 5'-N-ethylcarboxamidoadenosine and sodium nitroprusside. L-NAME (300 µM), a NO synthase inhibitor, attenuated bradykinin relaxations, leaving L-NAME-resistant relaxations to bradykinin mediated by endothelium-dependent hyperpolarization. In the presence of L-NAME, MPO plus H2O2 largely failed to impair endothelium-dependent relaxations to bradykinin. Similarly, HOCl failed to inhibit endothelium-dependent relaxations to bradykinin in the presence of L-NAME. GYY4137 (1-100 µM) protected endothelium-dependent relaxations to bradykinin from dysfunction caused by MPO plus H2O2, and HOCl, with no effect alone on bradykinin relaxation responses. The specific MPO inhibitor aminobenzoic acid hydrazide (ABAH) (1 and 10 µM) also protected against MPO plus H2O2-induced endothelial dysfunction (at 10 µM ABAH), but was less potent than GYY4137. CONCLUSIONS: MPO plus H2O2, and HOCl, impair coronary artery endothelium-dependent vasorelaxation via inhibition of NO. GYY4137 protects against endothelial dysfunction in arteries exposed to MPO plus H2O2, and HOCl. H2S donors such as GYY4137 are possible therapeutic options to control excessive MPO activity in cardiovascular diseases.

Improvement in patient-reported pain among patients with metastatic cancer and its association with opioid prescribing.

PURPOSE: Opioids are a mainstay of cancer pain management; however, patients with metastatic cancer are often excluded from studies, leading to a lack of evidence on whether increased prescribing (dosage and/or duration) results in improved outcomes for this population. This study aimed to investigate whether increased opioid prescribing is associated with an improvement in patient-reported pain among patients with metastatic cancer. PATIENTS AND METHODS: A retrospective cohort of all adult patients diagnosed with stage IV cancers, who completed at least two patient-reported outcomes (PROs) within 30 days of each other, was identified from administrative data. Opioid prescriptions were categorized by dosage level and number of prescription days. Multivariable logistic regression was used to investigate the association between opioid prescribing and clinically important improvement in pain score (≥ 1 point change on the Edmonton Symptom Assessment System). RESULTS: A total of 2169 patients were included, 770 (35.5%) of whom had active opioid prescription between PROs, with an average daily dosage of 86.1 mg of oral morphine equivalent. Active prescription was associated with improvement in pain (OR = 2.17, P < 0.001). However, among patients with active prescription, neither dosage nor number of prescription days was significantly associated with pain improvement. CONCLUSION: Opioid prescription is important for treating cancer-related pain; however, increased dosage or duration may not be leading to greater improvements in pain. Patients with metastatic cancer who are receiving increased opioid prescribing may have difficult-to-treat pain and may benefit from multidisciplinary pain management strategies to supplement opioid prescription and improve outcomes.

Plasma hPG80 (Circulating Progastrin) as a Novel Prognostic Biomarker for early-stage breast cancer in a breast cancer cohort.

BACKGROUND: Recurrence and metastases are still frequent outcomes after initial tumour control in women diagnosed with breast cancer. Although therapies are selected based on tumour characteristics measured at baseline, prognostic biomarkers can identify those at risk of poor outcomes. Circulating progastrin or hPG80 was found to be associated with survival outcomes in renal and hepatocellular carcinomas and was a plausible prognostic biomarker for breast cancer. METHODS: Women with incident breast cancers from Calgary, Alberta, Canada enrolled in the Breast to Bone (B2B) study between 2010 to 2016 and provided blood samples prior to any treatment initiation. Plasma from these baseline samples were analysed for circulating progastrin or hPG80. Participant characteristics as well as tumour ones were evaluated for their association with hPG80 and survival outcomes (time to recurrence, recurrence - free survival, breast cancer specific survival and overall survival) in Cox proportional hazards regression models. RESULTS: The 464 participants with measurable hPG80 in this study had an average age of 57.03 years (standard deviation of 11.17 years) and were predominantly diagnosed with Stage I (52.2%) and Stage II (40.1%) disease. A total of 50 recurrences and 50 deaths were recorded as of June 2022. In Cox PH regression models adjusted for chemotherapy, radiation therapy, cancer stage and age at diagnosis, log hPG80 (pmol/L) significantly increased the risks for recurrence (Hazard Ratio (HR) = 1.330, 95% Confidence Interval (CI) = (0.995 - 1.777, p = 0.054)), recurrence-free survival (HR = 1.399, 95% CI = (1.106 - 1.770), p = 0.005) and overall survival (HR = 1.385, 95% CI = (1.046 - 1.834), = 0.023) but not for breast cancer specific survival (HR = 1.015, 95% CI = (0.684 - 1.505), p = 0.942). CONCLUSIONS: hPG80 levels measured at diagnosis were significantly associated with the risk of recurrence or death from any cause in women with breast cancer. Since the recurrence rates of breast cancer are still relatively high amongst women diagnosed at an early stage, identifying women at high risk of recurrence at their time of diagnosis is important. hPG80 is a promising new prognostic biomarker that could improve the identification of women at higher risk of poor outcomes.

Genetic Determinants of the Interventricular Septum Are Linked to Ventricular Septal Defects and Hypertrophic Cardiomyopathy.

BACKGROUND: A large proportion of genetic risk remains unexplained for structural heart disease involving the interventricular septum (IVS) including hypertrophic cardiomyopathy and ventricular septal defects. This study sought to develop a reproducible proxy of IVS structure from standard medical imaging, discover novel genetic determinants of IVS structure, and relate these loci to diseases of the IVS, hypertrophic cardiomyopathy, and ventricular septal defect. METHODS: We estimated the cross-sectional area of the IVS from the 4-chamber view of cardiac magnetic resonance imaging in 32 219 individuals from the UK Biobank which was used as the basis of genome wide association studies and Mendelian randomization. RESULTS: Measures of IVS cross-sectional area at diastole were a strong proxy for the 3-dimensional volume of the IVS (Pearson r=0.814, P=0.004), and correlated with anthropometric measures, blood pressure, and diagnostic codes related to cardiovascular physiology. Seven loci with clear genomic consequence and relevance to cardiovascular biology were uncovered by genome wide association studies, most notably a single nucleotide polymorphism in an intron of CDKN1A (rs2376620; ß, 7.7 mm2 [95% CI, 5.8-11.0]; P=6.0×10-10), and a common inversion incorporating KANSL1 predicted to disrupt local chromatin structure (ß, 8.4 mm2 [95% CI, 6.3-10.9]; P=4.2×10-14). Mendelian randomization suggested that inheritance of larger IVS cross-sectional area at diastole was strongly associated with hypertrophic cardiomyopathy risk (pIVW=4.6×10-10) while inheritance of smaller IVS cross-sectional area at diastole was associated with risk for ventricular septal defect (pIVW=0.007). CONCLUSIONS: Automated estimates of cross-sectional area of the IVS supports discovery of novel loci related to cardiac development and Mendelian disease. Inheritance of genetic liability for either small or large IVS, appears to confer risk for ventricular septal defect or hypertrophic cardiomyopathy, respectively. These data suggest that a proportion of risk for structural and congenital heart disease can be localized to the common genetic determinants of size and shape of cardiovascular anatomy.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Effects of protein-coding variants on blood metabolite measurements and clinical biomarkers in the UK Biobank.

Genome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements-including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers-using 412,393 exome sequences from four genetically diverse ancestries in the UKB. Gene-level collapsing analyses were conducted to evaluate a diverse range of rare-variant architectures for the metabolic blood measurements. Altogether, we identified significant associations (p < 1 × 10-8) for 205 distinct genes that involved 1,968 significant relationships for the Nightingale blood metabolite measurements and 331 for the clinical blood biomarkers. These include associations for rare non-synonymous variants in PLIN1 and CREB3L3 with lipid metabolite measurements and SYT7 with creatinine, among others, which may not only provide insights into novel biology but also deepen our understanding of established disease mechanisms. Of the study-wide significant clinical biomarker associations, 40% were not previously detected on analyzing coding variants in a GWAS in the same cohort, reinforcing the importance of studying rare variation to fully understand the genetic architecture of metabolic blood measurements.

Association between Presurgical Weight Status and Urinary and Sexual Function in Prostate Cancer Patients Treated by Radical Prostatectomy: A Prospective Cohort Study.

OBJECTIVE: To prospectively examine the influence of weight status on urinary and sexual function in clinically localized prostate cancer patients treated by radical prostatectomy (RP). METHODS: The Prostatectomy, Incontinence and Erectile dysfunction study recruited patients at 2 US institutions between 2011 and 2014. At baseline, height and weight were measured, and urinary and sexual function were collected by the modified Expanded Prostate Cancer Index Composite-50. This index was repeated at the 5-week, 6-month, and 12-month postsurgical assessments and compared to baseline using linear generalized estimating equations. Logistic equations were used to evaluate the likelihood of functional recovery at the 6- and 12-month assessments. RESULT: Presurgery, nonobese patients (68.8% of 407 patients) had similar urinary function as those with obesity (P = .217), but better sexual function (P = .006). One year after surgery, 50.5% and 28.9% patients had recovered to baseline levels for urinary and sexual function, respectively. Recovery was not, however, uniform by obesity. Compared to those with obesity, nonobese patients had better urinary function at the 6- (P < .001) and 12-month postsurgical assessments (P = .011) and were more likely to recover their function by the 6-month assessment (OR = 2.55, 95% CI = 1.36-4.76). For sexual function, nonobese patients had better function at the 6- (P = .028) and 12-month (P = .051) assessments, but a similar likelihood of recovery 1-year postsurgery. CONCLUSION: Nonobese prostate cancer patients had better and likely earlier recovery in urinary function postsurgery, and better sexual function both pre- and postsurgery. These findings support the potential for tailored presurgical counseling about RP side-effects and prehabilitation to improve these side-effects.

Genome-Wide Analysis of Left Ventricular Maximum Wall Thickness in the UK Biobank Cohort Reveals a Shared Genetic Background With Hypertrophic Cardiomyopathy.

BACKGROUND: Left ventricular maximum wall thickness (LVMWT) is an important biomarker of left ventricular hypertrophy and provides diagnostic and prognostic information in hypertrophic cardiomyopathy (HCM). Limited information is available on the genetic determinants of LVMWT. METHODS: We performed a genome-wide association study of LVMWT measured from the cardiovascular magnetic resonance examinations of 42 176 European individuals. We evaluated the genetic relationship between LVMWT and HCM by performing pairwise analysis using the data from the Hypertrophic Cardiomyopathy Registry in which the controls were randomly selected from UK Biobank individuals not included in the cardiovascular magnetic resonance sub-study. RESULTS: Twenty-one genetic loci were discovered at P<5×10-8. Several novel candidate genes were identified including PROX1, PXN, and PTK2, with known functional roles in myocardial growth and sarcomere organization. The LVMWT genetic risk score is predictive of HCM in the Hypertrophic Cardiomyopathy Registry (odds ratio per SD: 1.18 [95% CI, 1.13-1.23]) with pairwise analyses demonstrating a moderate genetic correlation (rg=0.53) and substantial loci overlap (19/21). CONCLUSIONS: Our findings provide novel insights into the genetic underpinning of LVMWT and highlight its shared genetic background with HCM, supporting future endeavours to elucidate the genetic etiology of HCM.

Trends in the Incidence of Cancer Among Adolescent and Young Adults in Alberta, 1983-2017: A Population-Based Study Using Cancer Registry Data.

Purpose: To describe the cancer incidence burden and trends among adolescent and young adults (AYAs) in Alberta, Canada over a 35-year period. Methods: We obtained data from the Alberta Cancer Registry on all first primary cancers, excluding non-melanoma skin cancer, diagnosed at ages 15-39 years among residents in Alberta from 1983 to 2017. Cancers were classified by using Barr's AYA cancer classification system. Age-standardized incidence rates (ASIR) and the average annual percentage change (AAPC) in incidence rates were calculated. Statistically significant changes in the AAPC during the study period were assessed using Joinpoint regression. Results: Overall, 23,652 incident cases of AYA cancer were diagnosed in Alberta. Females accounted for ∼60% of the diagnoses. AYA cancer increased significantly over the study period overall (AAPC: 0.5%; 95%CI: 0.3%-0.7%), for each sex (AAPCmale: 0.7%; 95%CI: 0.4%-0.9%; AAPCfemale: 0.4%; 95%CI: 0.2%-0.6%), and among male and female 20-39 year-olds. Although statistically significant increases were observed in 11 out of 29 cancer sites for at least a portion of the study period, with significant AAPCs ranging from 0.8% (95%CI: 0.01%-1.5%) to 6.6% (95%CI: 4.6%-8.5%), the main driver was thyroid cancer (AAPC: 3.7%; 95%CI: 3.2%-4.2%). Statistically significant decreases were observed for six cancer sites, with AAPCs ranging from -6.4% (95%CI: -8.7% to -4.1%) to -1.1% (95%CI: -1.8% to -0.5%). Conclusions: There is a growing cancer burden among AYAs in Alberta, which is driven primarily by thyroid cancer and early-onset cancers in males. These results highlight the need for etiological studies and tertiary strategies to prevent and mitigate morbidity and mortality in the AYA population.

Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes.

We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in MAP3K15 were 30% less likely to develop diabetes (P = 5.7 × 10-10) and had lower glycosylated hemoglobin (ß = -0.14 SD units, P = 1.1 × 10-24). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study (P < 0.05)Moreover, the protective effect of MAP3K15 variants was stronger in individuals who did not carry the Latino-enriched SLC16A11 risk haplotype (P = 6.0 × 10-4). Separately, we identified a Finnish-enriched MAP3K15 protein-truncating variant associated with decreased odds of both type 1 and type 2 diabetes (P < 0.05) in FinnGen. No adverse phenotypes were associated with protein-truncating MAP3K15 variants in the UKB, supporting this gene as a therapeutic target for diabetes.

DrugnomeAI is an ensemble machine-learning framework for predicting druggability of candidate drug targets.

The druggability of targets is a crucial consideration in drug target selection. Here, we adopt a stochastic semi-supervised ML framework to develop DrugnomeAI, which estimates the druggability likelihood for every protein-coding gene in the human exome. DrugnomeAI integrates gene-level properties from 15 sources resulting in 324 features. The tool generates exome-wide predictions based on labelled sets of known drug targets (median AUC: 0.97), highlighting features from protein-protein interaction networks as top predictors. DrugnomeAI provides generic as well as specialised models stratified by disease type or drug therapeutic modality. The top-ranking DrugnomeAI genes were significantly enriched for genes previously selected for clinical development programs (p value < 1 × 10-308) and for genes achieving genome-wide significance in phenome-wide association studies of 450 K UK Biobank exomes for binary (p value = 1.7 × 10-5) and quantitative traits (p value = 1.6 × 10-7). We accompany our method with a web application ( http://drugnomeai.public.cgr.astrazeneca.com ) to visualise the druggability predictions and the key features that define gene druggability, per disease type and modality.

Cancer-driving mutations are enriched in genic regions intolerant to germline variation.

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic subregions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. We hypothesized that cancer-driving mutations might be enriched in genic subregions that are depleted of germline variation relative to somatic variation. We introduce a new metric, OncMTR (oncology missense tolerance ratio), which uses 125,748 exomes in the Genome Aggregation Database (gnomAD) to identify these genic subregions. We demonstrate that OncMTR can significantly predict driver mutations implicated in hematologic malignancies. Divergent OncMTR regions were enriched for cancer-relevant protein domains, and overlaying OncMTR scores on protein structures identified functionally important protein residues. Last, we performed a rare variant, gene-based collapsing analysis on an independent set of 394,694 exomes from the UK Biobank and find that OncMTR markedly improves genetic signals for hematologic malignancies.

Further Studies on the [1,2]-Wittig Rearrangement of 2-(2-Benzyloxy)aryloxazolines.

The behaviour of 14 ortho-functionalised 2-aryloxazolines (11 of them prepared and characterised for the first time) with butyllithium has been examined. Significant limitations to the Wittig rearrangement of such systems are revealed. In terms of asymmetric Wittig rearrangement, good diastereoselectivity is obtained with a valine-derived 4-isopropyl oxazoline, but this is compromised by racemisation upon hydrolysis. More encouraging selectivity is achieved in the Wittig rearrangement of an acyclic phenylalanine-derived ortho-benzyloxy benzamide.