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Application of Genome-Wide Association Studies in Rare Diseases Research
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Application of Genome-Wide Association Studies in Rare Diseases Research

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (25 April 2026) | Viewed by 4820

Special Issue Editors

Dr. Menglu Liang

E-Mail Website
Guest Editor
Department of Epidemiology and Biostatistics, School of Public Health, University of Maryland, College Park, MD 20742, USA
Interests: Bayesian hierarchical model; dynamic prediction; environmental health; statistical learning; prediction model
Prof. Dr. Andrzej Ciechanowicz

E-Mail Website
Guest Editor
Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
Interests: genetic polymorphism; association analysis; molecular cardiology; molecular nephrology; pharmacogenetics; monogenic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genome-wide association studies (GWASs) have revolutionized our understanding of genetic contributions to complex traits and diseases. While GWASs have been widely applied to common diseases, their application in rare disease research presents unique challenges and opportunities. Rare diseases collectively affect millions worldwide but individually have low prevalence, making traditional GWAS approaches difficult to implement due to limited sample sizes and statistical power.

This Special Issue aims to highlight innovative methodological approaches and applications of GWASs in rare disease contexts. We welcome original research articles and reviews addressing novel statistical frameworks, meta-analytic approaches, integration of multi-omics data, and innovative study designs that overcome sample size limitations. This Special Issue will showcase advances in polygenic risk scores for rare conditions, cross-ancestry GWAS applications, and gene–gene interaction (epistasis) and gene–environment interaction findings that may have outsized effects in rare disease etiology. We particularly encourage submissions exploring how environmental factors may modify genetic risk in rare diseases and methodological advances for detecting epistatic effects despite limited sample sizes. Contributions demonstrating successful translation of GWAS findings into clinical applications for rare disease diagnosis, prognosis, and treatment are also highly welcomed.

I look forward to receiving your contributions.

Dr. Menglu Liang
Prof. Dr. Andrzej Ciechanowicz
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • rare disease genetics
  • statistical methods
  • genomic association
  • small sample inference
  • polygenic risk scores
  • cross-ancestry GWAS
  • gene–gene interaction
  • gene–environment interaction
  • disease biomarkers
  • precision medicine

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Published Papers (4 papers)

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Research

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13 pages, 694 KB  
Article
Assessing Genetic Risk for Physical Activity and Its Interaction with Diet in Predicting Activity Levels and Weight Loss in the iMPROVE Study
by Maria Kafyra, Panagiotis Symianakis, Ioanna Panagiota Kalafati, Panagiotis Moulos and George V. Dedoussis
Genes 2026, 17(2), 155; https://doi.org/10.3390/genes17020155 - 29 Jan 2026
Viewed by 799
Abstract
Background: Physical activity (PA) and weight regulation are influenced by both genetic and lifestyle factors. This study aimed to evaluate the predictive value of Polygenic Risk Scores (PRSs) for PA and weight outcomes, and their interaction with dietary habits. Methods: Baseline phenotypic data [...] Read more.
Background: Physical activity (PA) and weight regulation are influenced by both genetic and lifestyle factors. This study aimed to evaluate the predictive value of Polygenic Risk Scores (PRSs) for PA and weight outcomes, and their interaction with dietary habits. Methods: Baseline phenotypic data from 202 participants enrolled in the iMPROVE study were analyzed. The sample included 59 men and 143 women, aged 19–65 years. Based on baseline Body Mass Index (BMI), 75 participants were classified as having overweight and 126 as having obesity. Polygenic risk scores (PRSs) were calculated for 197 participants with available genetic data. PA was operationalized as metabolic equivalent of task minutes per week (MET-mins/week), derived from self-reported activity questionnaires. Weight-related outcomes included log-transformed weight loss from baseline to month 3 and change in BMI post-intervention. Interactions with diet were examined using both the randomized intervention dietary groups and previously extracted dietary patterns from the iMPROVE cohort. Correlation analyses and linear regression models were used to assess the main effects of PRSs and dietary patterns, as well as gene–diet interactions. Results: The measured PA PGS002254 presented a nominal significant interaction with diet group for weight loss post-intervention (B = 7.57, SE = 3.57 × 100, p = 0.04; R2 = 0.06). Similarly, the sedentary behavior PGS001923 presented a significant interaction with the “High in unsaturated fats and fruit juice consumption” pattern for baseline MET-mins/week (B = 1.51 × 103, SE = 4.135 × 102, p = 0.001; R2 = 0.091). Conclusions: Genetic predisposition influences short-term activity and weight outcomes, with dietary patterns moderating these effects. However, the multifactorial nature of lifestyle behaviors is being underscored by the modest variance explained. Full article
(This article belongs to the Special Issue Application of Genome-Wide Association Studies in Rare Diseases Research)
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21 pages, 1990 KB  
Article
Statistical Genetics of DMD Gene Mutations in a Kazakhstan Cohort: MLPA/NGS Variant Validation and Genotype–Phenotype Modelling
by Aizhan Moldakaryzova, Dias Dautov, Saken Khaidarov, Saniya Ossikbayeva and Dilyara Kaidarova
Genes 2026, 17(1), 20; https://doi.org/10.3390/genes17010020 - 26 Dec 2025
Viewed by 844
Abstract
Background: Duchenne muscular dystrophy (DMD) results from pathogenic variants in the DMD gene, one of the most significant and most mutation-prone genes in the human genome. Although global mutation registries are well developed, genetic data from Central Asian populations remain extremely limited, [...] Read more.
Background: Duchenne muscular dystrophy (DMD) results from pathogenic variants in the DMD gene, one of the most significant and most mutation-prone genes in the human genome. Although global mutation registries are well developed, genetic data from Central Asian populations remain extremely limited, leaving essential gaps in regional epidemiology and in the understanding of genotype–phenotype patterns. Methods: We conducted a retrospective analysis of patients with genetically confirmed dystrophinopathy in Kazakhstan. Variants were identified using multiplex ligation-dependent probe amplification (MLPA) for exon-level copy number alterations and next-generation sequencing (NGS) with Sanger confirmation for sequence-level changes. All variants were classified under ACMG guidelines. Statistical modelling incorporated mutation-class grouping, exon-hotspot mapping, reading-frame status, CPK stratification, chi-squared association testing, Spearman correlations, Kaplan–Meier ambulation survival curves, and multivariable logistic and Cox regression. Results: multi-exon deletions were the predominant mutation class, with a marked concentration within the canonical hotspot spanning exons 44–55. Recurrent deletions affecting exons 46–50 and 45–50 appeared in several unrelated patients. NGS confirmed severe protein-truncating variants, including p. Lys1049* and p. Ser861Ilefs*7. Phenotypic severity followed a consistent hierarchy: hotspot-associated deletions and early truncating variants showed the earliest loss of ambulation, whereas splice-site variants and duplications demonstrated the mildest courses. CPK levels correlated with the extent of genomic involvement, though extreme elevations did not consistently predict early functional decline. Regression models identified hotspot localization and out-of-frame effect as independent predictors of ambulation loss. Conclusions: This study provides the first statistically modelled characterisation of DMD gene mutations in Kazakhstan. While the mutational landscape largely mirrors global patterns, notable variability in clinical severity suggests the presence of population-specific modifiers. Integrating comprehensive molecular diagnostics with statistical-genetics approaches enhances prognostic accuracy and supports the development of mutation-targeted therapeutic strategies in Central Asia. Full article
(This article belongs to the Special Issue Application of Genome-Wide Association Studies in Rare Diseases Research)
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21 pages, 5191 KB  
Article
Identification of a Novel CLPX Variant in a Mixed-Breed Dog with Anemia and Spinocerebellar Ataxia
by Bianca S. de Cecco, Jeanna M. Blake, Namju J. Kim, Madeline C. Coffey, Andrea N. Johnston, Andrew D. Miller, Kari J. Ekenstedt and Jeongha Lee
Genes 2025, 16(11), 1359; https://doi.org/10.3390/genes16111359 - 10 Nov 2025
Viewed by 1008
Abstract
Background/Objectives: Spinocerebellar ataxia (SCA), or hereditary ataxia, is a progressive neurodegenerative disorder primarily affecting motor control and voluntary muscle coordination due to cerebellar or spinocerebellar dysfunction. While numerous genetic variants have been linked to SCA in both humans and dogs, some cases remain [...] Read more.
Background/Objectives: Spinocerebellar ataxia (SCA), or hereditary ataxia, is a progressive neurodegenerative disorder primarily affecting motor control and voluntary muscle coordination due to cerebellar or spinocerebellar dysfunction. While numerous genetic variants have been linked to SCA in both humans and dogs, some cases remain genetically unexplained. This study aimed to describe the clinical and pathological phenotype, and to identify the genetic basis, of an atypical form of SCA observed in a mixed-breed dog presenting with additional clinical signs beyond classic SCA. Methods: Clinical and postmortem examinations were performed to document neurological and systemic pathology. Whole-genome sequencing (WGS) was conducted on the affected dog, and variant filtering was carried out using a control cohort of over 700 unaffected dog genomes to identify candidate variants. Results: In addition to classical SCA features, the affected dog exhibited retinal and optic nerve degeneration and severe, non-regenerative anemia. WGS did not reveal any known SCA-associated variants. Variant filtering identified a novel homozygous 4-base-pair frameshift deletion in CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X) [XM_038580726.1:c.1723_1726del; chr30:g.29943285_29943288del]. This variant is predicted to cause a frameshift and premature stop codon within 17 amino acids, truncating approximately 6.64% of the protein. Conclusions: This is the first report associating a CLPX variant with SCA in any species. Given the gene’s high evolutionary conservation and known role in mitochondrial protein homeostasis, this finding may have implications for understanding CLPX-related neurodegeneration and anemia in both veterinary and human medicine. Full article
(This article belongs to the Special Issue Application of Genome-Wide Association Studies in Rare Diseases Research)
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Review

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22 pages, 1034 KB  
Review
The Utility of Genome-Wide Association Studies in Inherited Arrhythmias and Cardiomyopathies
by Saif Dababneh, Arya Ardehali, Jasleen Badesha and Zachary Laksman
Genes 2025, 16(12), 1448; https://doi.org/10.3390/genes16121448 - 3 Dec 2025
Cited by 3 | Viewed by 1124
Abstract
Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given [...] Read more.
Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as SCN5A for Brugada syndrome, and MYH7 and MYBPC3 for hypertrophic cardiomyopathy, which have revolutionized diagnosis, risk stratification, and medical management. Nonetheless, issues such as variable expressivity and penetrance, low yield of genetic testing, and relative lack of disease-modifying therapies remain significant hurdles for clinical management. The revolution of genome-wide association studies GWASs has transformed our understanding of inherited arrhythmias and cardiomyopathies, shifting the view of these disorders from a monogenic Mendelian inheritance towards a more complex, often polygenic inheritance with nuanced interplay between genetics and environment. Moreover, GWASs have enabled the quantification of polygenic predisposition to disease using polygenic risk scores, which are often complementary to and independent of monogenic risk. In this review, we highlight how GWASs have transformed the field of inherited arrhythmias and cardiomyopathies, with a particular focus on the polygenic risk scores developed and their clinical utility for the four disorders which have been impacted by GWASs—hypertrophic cardiomyopathy, dilated cardiomyopathy, Brugada syndrome, and long QT syndrome. Full article
(This article belongs to the Special Issue Application of Genome-Wide Association Studies in Rare Diseases Research)
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