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Exploring the Genetics and Genomics of Complex Diseases
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Exploring the Genetics and Genomics of Complex Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 20 June 2025 | Viewed by 3453

Special Issue Editor

Dr. Keeley Brookes

E-Mail Website
Guest Editor
Department of Biosciences, School of Science & Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
Interests: complex diseases; Alzheimer’s disease; genomics; transcriptomics; genetics

Special Issue Information

Dear Colleagues,

Complex diseases are caused by a combination of genetics, lifestyle, and environmental risk factors, many of which are still being elucidated. With many complex diseases estimated to have a significant contribution from genetics, the identification of DNA variants of interest from large sequencing efforts and genome-wide association studies have increased our understanding and extended molecular work to biological pathways outside that of initial disease impact. Our understanding of the mechanisms operating at these variants is aided not only by molecular studies but also by the application of bioinformatics and machine-learning approaches to large data sets.

In this special issue of IJMS entitled “Exploring the Genetics and Genomics of Complex Diseases” a broad range of complex diseases and their genetic and genomic aetiology and/or modifiers are explored. It will include a selection of original research articles, current review articles, and communications examining key genetic underpinnings of disease.

Authors of studies from all complex diseases are welcome to contribute, with all areas of genetics, transcriptomics, epigenetics, genomics, and gene-environmental interplay are welcome to contribute.

Dr. Keeley Brookes
Guest Editor

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 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • complex disease
  • genetics
  • polymorphisms
  • genomics
  • transcriptome
  • epigenetics
  • gene-environment interplay

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Published Papers (4 papers)

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Research

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12 pages, 400 KiB  
Article
A Large Multicenter Brazilian Case-Control Study Exploring Genetic Variations in Interferon Regulatory Factor 6 and the Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate
by Renato Assis Machado, Daniella Reis Barbosa Martelli, Silvia Regina de Almeida Reis, Luiz Evaristo Ricci Volpato, Rafaela Scariot, Juliana Feltrin-Souza, Ana Lúcia Carrinho Ayroza Rangel, Brazilian Oral Cleft Group, Hercílio Martelli-Júnior and Ricardo D. Coletta
Int. J. Mol. Sci. 2025, 26(7), 3441; https://doi.org/10.3390/ijms26073441 - 7 Apr 2025
Viewed by 358
Abstract
Nonsyndromic cleft lip with or without cleft palate (NSCL ± P) is strongly associated with both environmental and genetic risk factors, but its genetic underpinnings remain partially known. While variants in interferon regulatory factor 6 (IRF6) are linked to NSCL ± P risk [...] Read more.
Nonsyndromic cleft lip with or without cleft palate (NSCL ± P) is strongly associated with both environmental and genetic risk factors, but its genetic underpinnings remain partially known. While variants in interferon regulatory factor 6 (IRF6) are linked to NSCL ± P risk in populations from Asia and Europe, studies on the highly admixed Brazilian population are scarce and have produced ambiguous results. This study aimed to investigate the contribution of IRF6 variants to the risk of NSCL ± P. Five tag-single nucleotide polymorphisms (rs599021, rs2073485, rs2235375, rs7552506, and rs642961) were analyzed in a large multicenter cohort composed of 1006 patients with NSCL ± P and 942 healthy controls. Statistical analyses involved multiple logistic regression tests consideration the tri-hybrid genetic origin of the Brazilian population, under a Bonferroni p value correcting for multiple comparisons. The A allele (OR: 1.43, 95% CI: 1.22–1.67, p < 0.0001) and AA genotype (OR: 2.04, 95% CI: 1.46–2.86, p < 0.0001) frequencies of rs642961 were significantly associated with NSCL ± P risk. Stratified analyses indicated that the variant is associated with susceptibility to both nonsyndromic cleft lip only (NSCLO) and nonsyndromic cleft lip and palate (NSCLP). However, the association with NSCLO was primarily observed in patients with high African ancestry, whereas the association with NSCLP was predominantly seen in patients with high European ancestry. No significant associations were found for the other investigated variants. Our results support the notion that the IRF6 rs642961 variant represents a marker of susceptibility to NSCL ± P in the Brazilian population, and that genetic ancestry composition plays a central role in the association with the cleft type. Full article
(This article belongs to the Special Issue Exploring the Genetics and Genomics of Complex Diseases)
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16 pages, 1448 KiB  
Article
Longitudinal Analysis of Placental IRS1 DNA Methylation and Childhood Obesity
by Ariadna Gómez-Vilarrubla, Maria Niubó-Pallàs, Berta Mas-Parés, Alexandra Bonmatí-Santané, Jose-Maria Martínez-Calcerrada, Beatriz López, Aaron Peñas-Cruz, Francis de Zegher, Lourdes Ibáñez, Abel López-Bermejo and Judit Bassols
Int. J. Mol. Sci. 2025, 26(7), 3141; https://doi.org/10.3390/ijms26073141 - 28 Mar 2025
Viewed by 225
Abstract
Accumulating evidence suggests that the predisposition to metabolic diseases is established in utero through epigenomic modifications. However, it remains unclear whether childhood obesity results from preexisting epigenomic alterations or whether obesity itself induces changes in the epigenome. This study aimed to identify DNA [...] Read more.
Accumulating evidence suggests that the predisposition to metabolic diseases is established in utero through epigenomic modifications. However, it remains unclear whether childhood obesity results from preexisting epigenomic alterations or whether obesity itself induces changes in the epigenome. This study aimed to identify DNA methylation marks in the placenta associated with obesity-related outcomes in children at age 6 and to assess these marks in blood samples at age 6 and whether they correlate with obesity-related outcomes at that time. Using an epigenome-wide DNA methylation microarray on 24 placental samples, we identified differentially methylated CpGs (DMCs) associated with offspring BMI-SDS at 6 years. Individual DMCs were validated in 147 additional placental and leukocyte samples from children at 6 years of age. The methylation and/or gene expression of IRS1 in both placenta and offspring leukocytes were significantly associated with various metabolic risk parameters at age 6 (all p ≤ 0.05). Logistic regression models (LRM) and machine learning (ML) models indicated that IRS1 methylation in the placenta could strongly predict offspring obesity. Our results suggest that IRS1 may serve as a potential biomarker for the prediction of obesity and metabolic risk in children. Full article
(This article belongs to the Special Issue Exploring the Genetics and Genomics of Complex Diseases)
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12 pages, 2301 KiB  
Article
OAS1: A Protective Mechanism for Alzheimer’s Disease? An Exploration of Data and Possible Mechanisms
by Richard J. Elsworthy, Alex Pearce, Farnoush Masoudzadeh, Klaudia Koska, Honey Lodhiya, Gargi Meher, Jodelle Adjej and Keeley J. Brookes
Int. J. Mol. Sci. 2025, 26(2), 524; https://doi.org/10.3390/ijms26020524 - 9 Jan 2025
Viewed by 1114
Abstract
The immune system and neuroinflammation are now well established in the aetiology of neurodegeneration. Previous studies of transcriptomic and gene association studies have highlighted the potential of the 2′–5′ oligoadenylate synthetase 1 (OAS1) to play a role in Alzheimer’s disease. OAS1 is a [...] Read more.
The immune system and neuroinflammation are now well established in the aetiology of neurodegeneration. Previous studies of transcriptomic and gene association studies have highlighted the potential of the 2′–5′ oligoadenylate synthetase 1 (OAS1) to play a role in Alzheimer’s disease. OAS1 is a viral response gene, interferon-induced, dsRNA activated enzyme, which binds RNase L to degrade dsRNA, and has been associated with COVID-19 response. This study explores whether a viral defence gene could play a vital role in neurodegeneration pathology. The genotyping of five SNPs across the OAS1 locus was conducted in the Brains for Dementia Research (BDR) Cohort for association with AD. RNA-sequencing data were explored for differences in OAS1 gene expression between phenotypes and genotypes. Finally, levels of dsRNA were measured in control cell lines, prior to and after exposure to amyloid oligomers and in cells harbouring a dementia-relevant mutation. No association of any of the OAS1 SNPs investigated were associated with the AD phenotype in the BDR cohort. However, gene expression data supported the previous observation that the minor allele haplotype was associated with higher levels of the OAS1 gene expression and the presence of an alternative transcript. Further to this, the presence of endogenous dsRNA was found to increase with exposure to amyloid oligomers and in the cell line with a dementia-relevant mutation. The data presented here suggest further exploration of the OAS1 gene in relation to dementia is warranted. Investigations of whether carriers of the protective OAS1 haplotype lower dsRNA presence and in turn lower inflammation and cell death are required to support the role of the gene as a moderator of neurodegeneration. Full article
(This article belongs to the Special Issue Exploring the Genetics and Genomics of Complex Diseases)
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Review

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19 pages, 2193 KiB  
Review
Genetic Background of Macular Telangiectasia Type 2
by Ajda Kunčič, Mojca Urbančič, Darja Dobovšek Divjak, Petra Hudler and Nataša Debeljak
Int. J. Mol. Sci. 2025, 26(2), 684; https://doi.org/10.3390/ijms26020684 - 15 Jan 2025
Viewed by 1020
Abstract
Macular telangiectasia type 2 (MacTel) is a slowly progressive macular disorder that is often diagnosed late due to the gradual onset of vision loss. Recent advances in diagnostic techniques have facilitated earlier detection and have shown that MacTel is more common than initially [...] Read more.
Macular telangiectasia type 2 (MacTel) is a slowly progressive macular disorder that is often diagnosed late due to the gradual onset of vision loss. Recent advances in diagnostic techniques have facilitated earlier detection and have shown that MacTel is more common than initially thought. The disease is genetically complex, and multiple variants contribute incrementally to the overall risk. The familial occurrence of the disease prompted the investigation of the genetic background of MacTel. To better understand the molecular milieu of the disease, a literature review of the clinical reports and publications investigating the genetic factors of MacTel was performed. To date, disease-associated variants have been found in genes involved in amino acid (glycine/serine) metabolism and transport, urea cycle, lipid metabolism, and retinal vasculature and thickness. Variants in genes implicated in sphingolipid metabolism and fatty acid/steroid/retinol metabolism have been found in patients with neurological disorders who also have MacTel. Retinal metabolism involves complex biochemical processes that are essential for maintaining the high energy requirements of the retina. Genetic alterations can disrupt key metabolic pathways, leading to retinal cell degradation and the subsequent vision loss that characterizes several retinal disorders, including MacTel. This review article summarizes genetic findings that may allow MacTel to be further investigated as an inherited retinal disorder. Full article
(This article belongs to the Special Issue Exploring the Genetics and Genomics of Complex Diseases)
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