Kayesha Coley

Background: Hypertrophic cardiomyopathy (HCM) is a heritable trait with marked variability in expression and outcomes. Our aims were to discover new genetic loci associated with HCM and to test the effect of a new polygenic risk score (PRS) on incidence, phenotype and outcomes stratified by genotype status. Methods: A discovery genome-wide association study (GWAS) was performed on 2284 HCM cases and 4525 controls. Two fixed-effects meta-analyses combined our discovery GWAS with single-trait and multi-trait results from a published study. Discovered loci underwent comprehensive bioinformatic analysis including functional and druggability annotations. A PRS using loci from the two meta-analyses was evaluated for association with HCM diagnosis in 411 213 individuals from UK Biobank (UKBB); imaging phenotypes in individuals without HCM; a composite endpoint (including all-cause mortality and transplantation); and sudden cardiac death (SCD) in 1756 HCM cases. PRS analyses were stratified by genotype status. Results: Three loci were found in the discovery GWAS ( BAG3 , FHOD3 and novel locus PPP1R3A ). In the meta-analyses, 70 unique loci were identified, four novel ( MYPN, YWHAE, NOS1AP and OBSCN ). Bioinformatic analyses identified NOS1AP as a candidate HCM gene. A new PRS was significantly associated with HCM diagnosis (HR=3.19, 95% CI 2.46 to 4.14 for top 5% vs lower 95%; HR=1.88, 95% CI 1.72 to 2.06 per SD increase). Significant associations were found between PRS and greater left ventricular (LV) wall thickness and higher LV ejection fraction in UKBB participants without HCM. Genotype-negative HCM cases in the top 20% of the PRS distribution had an increased risk of SCD (HR=2.72, 95% CI 1.03 to 7.17). Conclusions: We report novel HCM loci. A new PRS predicted the risk of HCM development and associated imaging characteristics in the UKBB and outcomes in an HCM cohort.

Background: Despite multiple clinical trials, disease-modifying treatments for COPD are currently limited. Since many drugs target proteins, identifying causality between proteins and lung function informs understanding of COPD pathophysiology and may suggest novel targets. We used Mendelian randomisation (MR) to prioritise proteins as potentially causal for lung function. For prioritised proteins, we explored their potential suitability as drug targets by predicting their effects on a range of clinical outcomes. Methods: We used genome-wide association study (GWAS) data on 2923 proteins (N=48 195, UK Biobank) to identify single genetic variants (cis-pQTLs) associated with protein levels (P≤5×10 ⁻⁹ , variant ≤100 kb of a transcription start site). We performed cis-pQTL-MR analyses of four spirometric traits (N=149 166, 36 independent cohorts). Sensitivity analyses included colocalisation and reverse direction MR. We report associations between cis-pQTLs for prioritised proteins and multiple clinical respiratory outcomes, and use phenome-wide analysis to explore potential adverse effects or drug repurposing opportunities. Findings: 1841 proteins had a suitable cis-pQTL. We implicated 16 proteins as potentially causal for lung function (p−5 ): six proteins have not been implicated by previous lung function GWAS or MR (DTD1, PILRA, PTPRK, TDRKH, GRHPR, NUDT5), and we provide corroborative evidence for 10 proteins. We add to the literature identifying surfactant protein D (SFTPD) as a candidate, yet predict that integrin subunit alpha V (ITGAV) inhibition could impair some lung function measures, mimicking adverse results from a recent trial. Interpretation: Our approach identifies proteins (some novel) which are potentially therapeutic targets for respiratory disease, and which warrant follow-up for utility and safety.

Background: In approximately 10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. Methods: We used electronic healthcare records (EHR) linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p≤5×10 ⁻⁶ ) signals in four independent studies (12 152 cases and 32 316 controls). Replicated signals were fine-mapped and linked to genes and pathways. Results: In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher BMI compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38 405 controls revealed 21 reproducible association signals that had previously been associated with asthma but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence ( BACH2 , D2HGDH , IL1RL1 , RPS26 , SMAD3 ). Conclusion: We present the first use of EHR in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.

Genetic predisposition and alcohol consumption are risk factors for increased blood pressure (BP), but their interactions influencing BP remain understudied. We conducted population-specific and cross-population meta-analyses of genome-wide gene-alcohol (GxAlc) interactions affecting BP in >1.1M individuals from multiple populations. We identified 46 GxAlc interaction loci for BP, including 21 from one-degree-of-freedom interaction tests (PGxAlc<5x10-8; or <0.05/Meff, Meff independent BP associations at P<10-5), and 25 from two-degree-of-freedom tests of main and interaction effects (PGxAlc<0.05/M2df, M2df independent 2df-associations at P2df<5x10-8), including 7 novel and 39 known BP loci. The 12q24 locus highlights the genetic effect of BRAP-rs11066001 on BP, being ~6 times larger in current drinkers than in non-drinkers. Gene prioritization with 46 GxAlc loci identified 15 genes with ≥3 lines of evidence (location, literature, druggability, functional/regulatory annotation, or pathway analyses). Several loci showed sex- and population-specific effects and revealed biological pathways of alcohol’s influence on BP, suggesting mechanisms underlying alcohol-induced hypertension.

Neuropathic pain is a common and debilitating symptom with limited treatment options. Genetic studies, which can provide vital evidence for drug development, have identified only 3 genome-wide significant signals for neuropathic pain traits. To address this, we performed the largest genome-wide association study (GWAS) to date of all-cause neuropathic pain and neuropathic pain subtypes. We defined all-cause neuropathic pain and 33 neuropathic pain subtypes using DeepPheWAS software in the UK Biobank, taking advantage of the longitudinal drug prescription data alongside clinical and self-reported records. We performed a GWAS of all-cause neuropathic pain (33,278 cases, 140,134 controls) as our primary analysis and GWASs of neuropathic pain subtypes as secondary analyses. We used 8 variant-to-gene criteria to identify putative causal genes. We identified 7 independent novel genome-wide associations for neuropathic pain phenotypes, which mapped to 22 novel putative causal genes. NCAM1 was the only gene identified from the primary analysis of all-cause neuropathic pain and met the most variant-to-gene criteria (4) of any identified gene. Of the 21 other genes, ASCC1, CHST3, C4A/C4B , and KCNN2 had the most compelling evidence for mechanistic involvement in neuropathic pain. We have performed the largest GWAS to date of all-cause neuropathic pain and more than doubled the number of genome-wide significant associations for neuropathic pain traits, identifying putative causal genes. There is strong evidence for the involvement of NCAM1 in neuropathic pain, which merits for further study for drug development.

Background: Chronic dry cough is a symptom of common lung conditions, can occur as a side-effect of angiotensin-converting enzyme inhibitors (ACEis), or may be unexplained. Despite the substantial health burden presented by chronic dry cough, its biological mechanisms remain unclear. We hypothesised shared genetic architecture between chronic dry cough and ACEi-induced cough and aimed to identify causal genes underlying both phenotypes. Methods: We performed multi-ancestry genome-wide association studies (GWAS) of chronic dry cough and ACEi-induced cough, and a multi-trait GWAS of both phenotypes, utilising data from five cohort studies. Chronic dry cough was defined by questionnaire responses, and ACEi-induced cough by treatment switches or clinical diagnosis in electronic health records. We mapped putative causal genes and performed phenome-wide association studies (PheWAS) of associated variants, and polygenic scores for ACEi-induced cough, to identify pleiotropic effects. Results: We found seven novel genetic association signals reaching p–8 in the multi-trait or single-trait analyses of chronic dry cough and ACEi-induced cough. The novel variants mapped to 10 novel genes, and we mapped an additional three novel genes to known risk variants, many of which implicate neurological functions ( CTNNA1 , KCNA10 , MAPKAP1 , OR4C12 , OR4C13 , SIL1 ). The polygenic-score-based PheWAS highlighted associations with an elevated risk of several clinical conditions including asthma, diabetes and multi-site chronic pain. Conclusion: Our findings provide support for neuronal dysfunction underlying cough hypersensitivity in chronic dry cough and ACEi-induced cough, and identify diseases and traits associated with genetic predisposition to cough that could inform drug target discovery.

Here we report the first genome-wide association study of foveal pit depth. In a cohort of 61,269 individuals, we identified 123 genome-wide significant loci associated with pit depth, including 47 novel associations not previously linked to macular traits. Using 12 complementary variant-to-gene mapping strategies, we prioritised 128 putative causal genes, 64 of which have not previously been implicated in foveal development. Our findings reveal previously unrecognised biological influences on foveal morphogenesis, including retinoic acid metabolism (implicating CYP26A1 for the first time in human foveal development), extracellular matrix and cytoskeletal dynamics, and retinal cell fate determination. In addition, rare-variant analysis uncovered two further gene associations, including ESYT3 , a gene not previously linked to foveal structure. Together, these results provide new insights into the genetic architecture and molecular pathways underlying human foveal development, and offer a foundation for future functional studies aimed at characterising foveal development and disease.

Introduction: The effect of coding polymorphisms of the β ₂ -adrenergic receptor gene ( ADRB2 ) on functional properties of the receptor is well established. We recently reported a genome-wide significant association between Thr164Ile and lung function, but the contribution of this variant to other traits remains unclear. Methods: To identify pleiotropic effects of ADRB2 Thr164Ile and other coding variants, we performed respiratory-focused and phenome-wide association studies in UK Biobank. In addition, we used available Olink proteomic data to characterise enriched pathways and upstream regulators of proteins associated with ADRB2 polymorphisms. Results: The minor T allele of Thr164Ile was associated with reduced lung function, but not COPD or asthma or risk of exacerbations on long-acting β-agonist treatment. It was also associated with nonrespiratory traits including increased eosinophil counts and blood lipid measurements, including increased cholesterol, reduced triglycerides and reduced apolipoprotein A. Proteins associated with Thr164Ile (p≤0.01) were enriched for various pathways, with the eosinophil-raising allele associated with reduced neutrophil degranulation, immunoregulatory interactions between lymphoid and nonlymphoid cells, tumour necrosis factor binding and DAP12 interactions, as well as activation of lipid metabolism pathways, including FXR/RXR activation and LXR/RXR activation. A gene-based analysis of rare, nonsynonymous ADRB2 variants, identified a novel association with nonrheumatic pulmonary valve disorders, but no association with lung function. Discussion: In conclusion, the lung function-lowering allele of Thr164Ile is associated with traits and proteins indicative of a role in immune and lipid metabolism pathways, suggesting potential targets for therapeutic intervention.

Background: Neuropathic pain is a common and debilitating symptom with limited treatment options. Genetic studies, which can provide vital evidence for drug development, have identified only five genome-wide significant signals for neuropathic pain traits. To address this, we performed the largest genome-wide association study (GWAS) to date of all-cause neuropathic pain and neuropathic pain subtypes. Methods: We defined all-cause neuropathic pain and 33 neuropathic pain subtypes using DeepPheWAS software in the UK Biobank, taking advantage of the longitudinal drug prescription data alongside clinical and self-reported records. We performed a GWAS of all-cause neuropathic pain (33,278 cases, 140,134 controls) as our primary analysis and GWASs of neuropathic pain subtypes as secondary analyses. We used eight variant-to-gene criteria to identify putative causal genes. Results: We identified seven independent novel genome-wide associations for neuropathic pain phenotypes which mapped to 22 novel putative causal genes. NCAM1 was the only gene identified from the primary analysis of all-cause neuropathic pain and met the most variant-to-gene criteria (four) of any identified gene. Of the 21 other genes, ASCC1, CHST3, C4A/C4B and KCNN2 had the most compelling evidence for mechanistic involvement in neuropathic pain. Discussion: We have performed the largest GWAS to date of all-cause neuropathic pain and more than doubled the number of genome-wide significant associations for neuropathic pain traits, identifying putative causal genes. There is strong evidence for the involvement of NCAM1 in neuropathic pain which merits for further study for drug development.

Introduction: Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist with the highest therapeutic efficacy of any pharmacological smoking cessation aid and a 12-month cessation rate of 26%. Genetic variation may be associated with varenicline response, but to date, no genome-wide association studies of varenicline response have been published. Methods: In this study, we investigated the genetic contribution to varenicline effectiveness using two electronic health record-derived phenotypes. We defined short-term varenicline effectiveness (SVE) and long-term varenicline effectiveness (LVE) by assessing smoking status at 3 and 12 months, respectively, after initiating varenicline treatment. In Stage 1, comprising five European cohort studies, we tested genome-wide associations with SVE (1405 cases, 2074 controls) and LVE (1576 cases, 2555 controls), defining sentinel variants (the most strongly associated variant within 1 Mb) with p-value < 5 × 10−6 to follow up in Stage 2. In Stage 2, we tested association between sentinel variants and comparable smoking cessation endpoints in varenicline randomized controlled trials. We subsequently meta-analyzed Stages 1 and 2. Results: No variants reached genome-wide significance in the meta-analysis. In Stage 1, 10 sentinel variants were associated with SVE and five with LVE at a suggestive significance threshold (p-value < 5 × 10−6); none of these sentinels were previously implicated in varenicline-aided smoking cessation or in genetic studies of smoking behavior. Conclusions: We provide initial insights into the biological underpinnings of varenicline-aided smoking cessation, through implicating genes involved in various processes, including gene expression, cilium assembly, and early-stage development. Implications: Leveraging electronic health records, we undertook the largest genetic study of varenicline-aided smoking cessation to date, and the only such study to test genome-wide associations. We showed distinct genetic variants associated (p-value < 5 × 10−6) with varenicline-aided smoking cessation which implicate diverse cellular functions, including transcriptional regulation, RNA modification, and cilium assembly. These provide insights which, if independently corroborated, will improve understanding of varenicline response. The growing availability of biobank resources with genetic and varenicline response data will provide future opportunities for larger studies using the approach we developed.