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Gene-based association analysis of a large patient cohort identifies potential genecandidates for atypical femur fractures
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-8687-0629
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background:

Several small genetic association studies have been conducted for atypical femurfracture (AFF) without replication of results. We assessed previously implicated and novel genesassociated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES).

Methods:

We performed gene-based association analysis on 139 European AFF cases and 196 controlsmatched for bisphosphonate use. We tested all rare, protein-altering variants using both candidategene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs(uncorrected p-values < 0.01) were investigated in a Swedish whole-genome sequencing replicationstudy and assessed in 46 non-European cases.

Results:

In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-freeapproach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likelycandidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in thereplication analysis, albeit not statistically significant. Three SNPs associated with SORD expressionaccording to the GTEx portal, were in linkage disequilibrium (R2 ≥0.2) with a SNP previouslyreported in a genome-wide association study of AFF. The prevalence of carriers of variants for bothPLOD2 and SORD was higher in Asian versus European cases.

Conclusions:

While we did not identify genes enriched for damaging variants, we found suggestiveevidence of a role for XRN2, PLOD2 and SORD, which requires further investigation. Our findingsindicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The studyprovides a stepping-stone for future larger genetic studies of AFF.

National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-526953OAI: oai:DiVA.org:uu-526953DiVA, id: diva2:1853066
Available from: 2024-04-20 Created: 2024-04-20 Last updated: 2024-04-23
In thesis
1. Genomic Analysis of Adverse Drug Reactions
Open this publication in new window or tab >>Genomic Analysis of Adverse Drug Reactions
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adverse drug reactions (ADRs) pose a significant global challenge, leading to substantial costs, suffering, and even loss of life. Genetic factors can play a role in determining a patient's response to the drug treatments and predicting ADRs. While many genetic associations with ADRs have been identified, there are still numerous ADRs suspected to have genetic components.

In Paper I, the collection and curation strategies for ADR cases in the Swedegene biobank are established, presenting a cohort of 2,550 ADR-cases. Paper II presents the association between genetic variations in human leukocyte antigen (HLA) genes and the development of pancreatitis as a response to azathioprine treatment in patients with Crohn's disease. Paper III reports on an international collaboration to investigate the genetic aetiology of atypical femur fractures (AFF) during bisphosphonate treatment. The study found that previously identified genetic variants did not replicate, and --- as the cohort is the largest of its kind --- provides valuable insights into common genetic factors of AFF. Paper IV examines the genetic associations with central nervous system (CNS) toxicity as an ADR to antimicrobial drugs, identifying correlations with three genes linked to suicide and schizophrenia, although the biological connection remains unclear. Finally, Paper V presents a methodology for the experimental design of ADR studies by analysing the known protein interactions of drugs and proteins associated with ADRs. This approach aims to mitigate the impact of competing genetic correlations by identifying common protein interactions to validate the inclusion of drugs and ADRs in the study. These interactions are then ranked based on importance to the selected drugs and ADRs and used to propose genetic targets of interest. 

Overall, the findings of these studies contribute to the understanding of genetic predispositions to ADRs and provide a novel approach for data-driven experimental design for phenotype and genetic target selection.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2055
Keywords
Adverse drug reactions, Genetic association, Network biology
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-527102 (URN)978-91-513-2139-4 (ISBN)
Public defence
2024-06-13, Rosénsalen, Akademiska sjukhuset, ing. 95/96, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2024-05-21 Created: 2024-04-23 Last updated: 2024-05-21

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Ås, JoelWadelius, MiaHallberg, Pär

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