Biomedical subjects

Richard Packer

Publications and source records attributed to Richard Packer.

3 recordsLinked to original sources

PubMed2026

Genome-wide association study of asthma with high treatment burden and/or worse outcomes defined using electronic healthcare data in UK Biobank.

BACKGROUND: In ∼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 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 body mass index 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 electronic healthcare records 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.

Journal Article↗

PubMed2026

Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development.

Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by ≥ 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Müller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.

Journal Article↗

PubMed2025

Genome-Wide Association Study of Varenicline-Aided Smoking Cessation.

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.

Humans↗