Research

11 pages, 274 KiB

Open AccessArticle

Associations between Lipid Profiles and Graves’ Orbitopathy can Be HLA-Dependent

by Magdalena Stasiak, Katarzyna Zawadzka-Starczewska, Bogusław Tymoniuk, Bartłomiej Stasiak and Andrzej Lewiński

Genes 2023, 14(6), 1209; https://doi.org/10.3390/genes14061209 - 31 May 2023

Cited by 1 | Viewed by 996

Abstract

The risk of Graves’ orbitopathy (GO) is related to the human leukocyte antigen (HLA) profile and was demonstrated to be increased in patients with elevated total cholesterol (TC) and/or low-density lipoprotein (LDL) cholesterol. We hypothesized that there were some HLA alleles that were [...] Read more.

The risk of Graves’ orbitopathy (GO) is related to the human leukocyte antigen (HLA) profile and was demonstrated to be increased in patients with elevated total cholesterol (TC) and/or low-density lipoprotein (LDL) cholesterol. We hypothesized that there were some HLA alleles that were related to both GO and TC and/or LDL levels. Therefore, the aim of the study was to compare the TC/LDL results in patients in whom GO-related HLA alleles were present to those in whom they did not occur. HLA classes were genotyped using a next-generation sequencing method in 118 patients with Graves’ disease (GD), including 63 and 55 patients with and without GO, respectively. Lipid profiles were assessed at the time of the GD diagnosis. A significant correlation between the presence of GO high-risk alleles (HLA-B*37:01 and C*03:02) and higher TC/LDL levels was found. Additionally, the presence of alleles associated with non-GO GD (HLA-C*17:01 and B*08:01), as well as alleles in linkage disequilibrium with B*08:01 (i.e., HLA-DRB1*03:01 and DQB1*02:01), was correlated with lower TC levels. These results further confirm the significance of TC/LDL in the risk of GO development and provide evidence that associations between TC/LDL and GO can be HLA-dependent. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

14 pages, 494 KiB

Open AccessArticle

Association of NEF2L2 Rs35652124 Polymorphism with Nrf2 Induction and Genotoxic Stress Biomarkers in Autism

by Lev N. Porokhovnik, Vladimir M. Pisarev, Anastasia G. Chumachenko, Julia M. Chudakova, Elizaveta S. Ershova, Natalia N. Veiko, Natalia L. Gorbachevskaya, Uliana A. Mamokhina, Alexander B. Sorokin, Anna Ya. Basova, Mikhail S. Lapshin, Vera L. Izhevskaya and Svetlana V. Kostyuk

Genes 2023, 14(3), 718; https://doi.org/10.3390/genes14030718 - 15 Mar 2023

Cited by 2 | Viewed by 1426

Abstract

Increased oxidative/genotoxic stress is known to impact the pathophysiology of ASD (autism spectrum disorder). Clinical studies, however, reported limited, heterogeneous but promising responses to treatment with antioxidant remedies. We determined whether the functional polymorphism of the Nrf2 gene, master regulator of anti-oxidant adaptive [...] Read more.

Increased oxidative/genotoxic stress is known to impact the pathophysiology of ASD (autism spectrum disorder). Clinical studies, however, reported limited, heterogeneous but promising responses to treatment with antioxidant remedies. We determined whether the functional polymorphism of the Nrf2 gene, master regulator of anti-oxidant adaptive reactions to genotoxic stress, links to the genotoxic stress responses and to an in vitro effect of a NRF2 inductor in ASD children. Oxidative stress biomarkers, adaptive responses to genotoxic/oxidative stress, levels of master antioxidant regulator Nrf2 and its active form pNrf2 before and after inducing by dimethyl fumarate (DMF), and promotor rs35652124 polymorphism of NFE2L2 gene encoding Nrf2 were studied in children with ASD (n = 179). Controls included healthy adults (n = 101). Adaptive responses to genotoxicity as indicated by H2AX and cytoprotection by NRF2 contents positively correlated in ASD children with a Spearman coefficient of R = 0.479 in T+, but not CC genotypes. ASD children with NRF2 rs35652124 CC genotype demonstrated significantly higher H2AX content (0.652 vs. 0.499 in T+) and pNrf2 induction by DMF, lowered 8-oxo-dG concentration in plasma and higher cfDNA/plasma nuclease activity ratio. Our pilot findings suggest that in ASD children the NEF2L2 rs35652124 polymorphism impacts adaptive responses that may potentially link to ASD severity. Our data warrant further studies to reveal the potential for NEF2L2 genotype-specific and age-dependent repurposing of DMF and/or other NRF2-inducing drugs. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

15 pages, 878 KiB

Open AccessArticle

CoNet: Efficient Network Regression for Survival Analysis in Transcriptome-Wide Association Studies—With Applications to Studies of Breast Cancer

by Jiayi Han, Liye Zhang, Ran Yan, Tao Ju, Xiuyuan Jin, Shukang Wang, Zhongshang Yuan and Jiadong Ji

Genes 2023, 14(3), 586; https://doi.org/10.3390/genes14030586 - 25 Feb 2023

Viewed by 1312

Abstract

Transcriptome-wide association studies (TWASs) aim to detect associations between genetically predicted gene expression and complex diseases or traits through integrating genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) mapping studies. Most current TWAS methods analyze one gene at a time, ignoring [...] Read more.

Transcriptome-wide association studies (TWASs) aim to detect associations between genetically predicted gene expression and complex diseases or traits through integrating genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) mapping studies. Most current TWAS methods analyze one gene at a time, ignoring the correlations between multiple genes. Few of the existing TWAS methods focus on survival outcomes. Here, we propose a novel method, namely a COx proportional hazards model for NEtwork regression in TWAS (CoNet), that is applicable for identifying the association between one given network and the survival time. CoNet considers the general relationship among the predicted gene expression as edges of the network and quantifies it through pointwise mutual information (PMI), which is under a two-stage TWAS. Extensive simulation studies illustrate that CoNet can not only achieve type I error calibration control in testing both the node effect and edge effect, but it can also gain more power compared with currently available methods. In addition, it demonstrates superior performance in real data application, namely utilizing the breast cancer survival data of UK Biobank. CoNet effectively accounts for network structure and can simultaneously identify the potential effecting nodes and edges that are related to survival outcomes in TWAS. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

15 pages, 7363 KiB

Open AccessArticle

Novel Variants in MPV17, PRX, GJB1, and SACS Cause Charcot–Marie–Tooth and Spastic Ataxia of Charlevoix–Saguenay Type Diseases

by Qaiser Zaman, Muhammad Abbas Khan, Kalsoom Sahar, Gauhar Rehman, Hamza Khan, Mehwish Rehman, Najumuddin, Ilyas Ahmad, Muhmmad Tariq, Osama Yousef Muthaffar, Angham Abdulrhman Abdulkareem, Fehmida Bibi, Muhammad Imran Naseer, Muhammad Shah Faisal, Naveed Wasif and Musharraf Jelani

Genes 2023, 14(2), 328; https://doi.org/10.3390/genes14020328 - 27 Jan 2023

Cited by 4 | Viewed by 2054

Abstract

Charcot–Marie–Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix–Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in MPV17 (OMIM: [...] Read more.

Charcot–Marie–Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix–Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in MPV17 (OMIM: 137960), CMT4F (OMIM: 614895) is caused by PRX (OMIM: 605725), CMTX1 (OMIM: 302800) is caused by mutations in GJB1 (OMIM: 304040), and ARSACS (OMIM: 270550) is caused by mutations in SACS (OMIM: 604490). In this study, we enrolled four families: DG-01, BD-06, MR-01, and ICP-RD11, with 16 affected individuals, for clinical and molecular diagnoses. One patient from each family was analyzed for whole exome sequencing and Sanger sequencing was done for the rest of the family members. Affected individuals of families BD-06 and MR-01 show complete CMT phenotypes and family ICP-RD11 shows ARSACS type. Family DG-01 shows complete phenotypes for both CMT and ARSACS types. The affected individuals have walking difficulties, ataxia, distal limb weakness, axonal sensorimotor neuropathies, delayed motor development, pes cavus, and speech articulations with minor variations. The WES analysis in an indexed patient of family DG-01 identified two novel variants: c.83G>T (p.Gly28Val) in MPV17 and c.4934G>C (p.Arg1645Pro) in SACS. In family ICP-RD11, a recurrent mutation that causes ARSACS, c.262C>T (p.Arg88Ter) in SACS, was identified. Another novel variant, c.231C>A (p.Arg77Ter) in PRX, which causes CMT4F, was identified in family BD-06. In family MR-01, a hemizygous missense variant c.61G>C (p.Gly21Arg) in GJB1 was identified in the indexed patient. To the best of our knowledge, there are very few reports on MPV17, SACS, PRX, and GJB1 causing CMT and ARSACS phenotypes in the Pakistani population. Our study cohort suggests that whole exome sequencing can be a useful tool in diagnosing complex multigenic and phenotypically overlapping genetic disorders such as Charcot–Marie–Tooth disease (CMT) and spastic ataxia of Charlevoix–Saguenay type. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

18 pages, 341 KiB

Open AccessArticle

Vitamin D Receptor Gene Polymorphisms Affect Osteoporosis-Related Traits and Response to Antiresorptive Therapy

by Vladimira Mondockova, Veronika Kovacova, Nina Zemanova, Martina Babikova, Monika Martiniakova, Drahomir Galbavy and Radoslav Omelka

Genes 2023, 14(1), 193; https://doi.org/10.3390/genes14010193 - 11 Jan 2023

Cited by 5 | Viewed by 1548

Abstract

The present study analyzed the effect of vitamin D receptor (VDR) gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical parameters and bone turnover markers, fracture prevalence, and response to three types of antiresorptive therapy (estrogen-progesterone, [...] Read more.

The present study analyzed the effect of vitamin D receptor (VDR) gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical parameters and bone turnover markers, fracture prevalence, and response to three types of antiresorptive therapy (estrogen-progesterone, raloxifene, and ibandronate) in 356 postmenopausal women from Slovakia. Association analysis revealed a significant effect of BsmI polymorphism on lumbar spine BMD, serum osteocalcin (OC), and β-CrossLaps levels. While ApaI and Cdx2 polymorphisms were associated with OC and alkaline phosphatase, TaqI polymorphism affected all turnover markers. ApaI, TaqI, and BsmI genotypes increased the risk of spinal, radial, or total fractures with odds ratios ranging from 2.03 to 3.17. Each of therapy types evaluated had a beneficial effect on all osteoporosis-related traits; however, the VDR gene affected only ibandronate and raloxifene treatment. ApaI/aa, TaqI/TT, and BsmI/bb genotypes showed a weaker or no response to ibandronate therapy in femoral and spinal BMD. The impact of aforementioned polymorphisms on turnover markers was also genotype dependent. On the contrary, only TaqI and BsmI polymorphisms influenced raloxifene therapy, even only in lumbar spine BMD. These results point to the potential of using the VDR gene in personalized pharmacotherapy of osteoporosis. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

8 pages, 6416 KiB

Open AccessArticle

Whole-Exome Sequencing of Pakistani Consanguineous Families Identified Pathogenic Variants in Genes of Intellectual Disability

by Maria Asif, Maryam Anayat, Faiza Tariq, Tanzeela Noureen, Ghulam Naseer Ud Din, Christian Becker, Kerstin Becker, Holger Thiele, Ehtisham ul Haq Makhdoom, Pakeeza Arzoo Shaiq, Shahid M. Baig, Peter Nürnberg, Muhammad Sajid Hussain, Ghazala Kaukab Raja and Uzma Abdullah

Genes 2023, 14(1), 48; https://doi.org/10.3390/genes14010048 - 23 Dec 2022

Cited by 4 | Viewed by 2023

Abstract

Intellectual disability (ID) is a condition of significant limitation of cognitive functioning and adaptive behavior, with 50% of etiology attributed to genetic predisposition. We recruited two consanguineous Pakistani families manifesting severe ID and developmental delay. The probands were subjected to whole exome sequencing [...] Read more.

Intellectual disability (ID) is a condition of significant limitation of cognitive functioning and adaptive behavior, with 50% of etiology attributed to genetic predisposition. We recruited two consanguineous Pakistani families manifesting severe ID and developmental delay. The probands were subjected to whole exome sequencing (WES) and variants were further prioritized based on population frequency, predicted pathogenicity and functional relevance. The WES data analysis identified homozygous pathogenic variants in genes MBOAT7 and TRAPPC9. The pathogenicity of the variants was supported by co-segregation analysis and in silico tool. The findings of this study expand mutation spectrum and provide additional evidence to the role of MBOAT7 and TRAPPC9 in causation of ID. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Graphical abstract

10 pages, 507 KiB

Open AccessArticle

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review

by Evelien Van Dijck, Sigri Beckers, Sara Diels, Tammy Huybrechts, An Verrijken, Kim Van Hoorenbeeck, Stijn Verhulst, Guy Massa, Luc Van Gaal and Wim Van Hul

Genes 2022, 13(10), 1746; https://doi.org/10.3390/genes13101746 - 27 Sep 2022

Cited by 1 | Viewed by 1571

Abstract

Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As [...] Read more.

Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 lean individuals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506) through sanger sequencing and high resulting melting curve analysis, indicating no association with obesity. Haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean), and two p.Y181H families, and showed identical haplotypes for all heterozygous carriers (p < 0.001). Likewise, state-of-the-art literature concerning the role of rare heterozygous PCSK1 variants implies them to be rarely associated with monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous variants. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

17 pages, 1027 KiB

Open AccessArticle

Clustering of Genetic Anomalies of Cilia Outer Dynein Arm and Central Apparatus in Patients with Transposition of the Great Arteries

by Marlon De Ita, Javier Gaytán-Cervantes, Bulmaro Cisneros, María Antonieta Araujo, Juan Carlos Huicochea-Montiel, Alan Cárdenas-Conejo, Charles César Lazo-Cárdenas, César Iván Ramírez-Portillo, Carina Feria-Kaiser, Leoncio Peregrino-Bejarano, Lucelli Yáñez-Gutiérrez, Carolina González-Torres and Haydeé Rosas-Vargas

Genes 2022, 13(9), 1662; https://doi.org/10.3390/genes13091662 - 16 Sep 2022

Cited by 2 | Viewed by 2164

Abstract

Transposition of the great arteries (TGA) is a congenital heart defect with a complex pathogenesis that has not been fully elucidated. In this study, we performed whole-exome sequencing (WES) in isolated TGA-diagnosed patients and analyzed genes of motile and non-motile cilia ciliogenesis and [...] Read more.

Transposition of the great arteries (TGA) is a congenital heart defect with a complex pathogenesis that has not been fully elucidated. In this study, we performed whole-exome sequencing (WES) in isolated TGA-diagnosed patients and analyzed genes of motile and non-motile cilia ciliogenesis and ciliary trafficking, as well as genes previously associated with this heart malformation. Deleterious missense and splicing variants of genes DNAH9, DNAH11, and ODAD4 of cilia outer dynein arm and central apparatus, HYDIN, were found in our TGA patients. Remarkable, there is a clustering of deleterious genetic variants in cilia genes, suggesting it could be an oligogenic disease. Our data evidence the genetic diversity and etiological complexity of TGA and point out that population allele determination and genetic aggregation studies are required to improve genetic counseling. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Graphical abstract

10 pages, 1338 KiB

Open AccessArticle

Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice

by Antonela Blazekovic, Kristina Gotovac Jercic, Sarah Meglaj, Vlasta Duranovic, Igor Prpic, Bernarda Lozic, Masa Malenica, Silvana Markovic, Lucija Lujic, Zeljka Petelin Gadze, Romana Gjergja Juraski, Nina Barišic, Ivo Baric and Fran Borovecki

Genes 2022, 13(8), 1466; https://doi.org/10.3390/genes13081466 - 17 Aug 2022

Cited by 5 | Viewed by 2420

Abstract

Epilepsy is one of the most common neurological disorders with diverse phenotypic characteristics and high genetic heterogeneity. Epilepsy often occurs in childhood, so timely diagnosis and adequate therapy are crucial for preserving quality of life and unhindered development of a child. Next-generation-sequencing (NGS)-based [...] Read more.

Epilepsy is one of the most common neurological disorders with diverse phenotypic characteristics and high genetic heterogeneity. Epilepsy often occurs in childhood, so timely diagnosis and adequate therapy are crucial for preserving quality of life and unhindered development of a child. Next-generation-sequencing (NGS)-based tools have shown potential in increasing diagnostic yield. The primary objective of this study was to evaluate the impact of genetic testing and to investigate the diagnostic utility of targeted gene panel sequencing. This retrospective cohort study included 277 patients aged 6 months to 17 years undergoing NGS with an epilepsy panel covering 142 genes. Of 118 variants detected, 38 (32.2%) were not described in the literature. We identified 64 pathogenic or likely pathogenic variants with an overall diagnostic yield of 23.1%. We showed a significantly higher diagnostic yield in patients with developmental delay (28.9%). Furthermore, we showed that patients with variants reported as pathogenic presented with seizures at a younger age, which led to the conclusion that such children should be included in genomic diagnostic procedures as soon as possible to achieve a correct diagnosis in a timely manner, potentially leading to better treatment and avoidance of unnecessary procedures. Describing and discovering the genetic background of the disease not only leads to a better understanding of the mechanisms of the disorder but also opens the possibility of more precise and individualized treatment based on stratified medicine. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

12 pages, 948 KiB

Open AccessArticle

Multi-Cell-Type Openness-Weighted Association Studies for Trait-Associated Genomic Segments Prioritization

by Shuang Song, Hongyi Sun, Jun S. Liu and Lin Hou

Genes 2022, 13(7), 1220; https://doi.org/10.3390/genes13071220 - 08 Jul 2022

Viewed by 1450

Abstract

Openness-weighted association study (OWAS) is a method that leverages the in silico prediction of chromatin accessibility to prioritize genome-wide association studies (GWAS) signals, and can provide novel insights into the roles of non-coding variants in complex diseases. A prerequisite to apply OWAS is [...] Read more.

Openness-weighted association study (OWAS) is a method that leverages the in silico prediction of chromatin accessibility to prioritize genome-wide association studies (GWAS) signals, and can provide novel insights into the roles of non-coding variants in complex diseases. A prerequisite to apply OWAS is to choose a trait-related cell type beforehand. However, for most complex traits, the trait-relevant cell types remain elusive. In addition, many complex traits involve multiple related cell types. To address these issues, we develop OWAS-joint, an efficient framework that aggregates predicted chromatin accessibility across multiple cell types, to prioritize disease-associated genomic segments. In simulation studies, we demonstrate that OWAS-joint achieves a greater statistical power compared to OWAS. Moreover, the heritability explained by OWAS-joint segments is higher than or comparable to OWAS segments. OWAS-joint segments also have high replication rates in independent replication cohorts. Applying the method to six complex human traits, we demonstrate the advantages of OWAS-joint over a single-cell-type OWAS approach. We highlight that OWAS-joint enhances the biological interpretation of disease mechanisms, especially for non-coding regions. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

17 pages, 2843 KiB

Open AccessArticle

How Variation in Risk Allele Output and Gene Interactions Shape the Genetic Architecture of Schizophrenia

by Merve Kasap and Donard S. Dwyer

Genes 2022, 13(6), 1040; https://doi.org/10.3390/genes13061040 - 10 Jun 2022

Cited by 1 | Viewed by 1613

Abstract

Schizophrenia is a highly heritable polygenic psychiatric disorder. Characterization of its genetic architecture may lead to a better understanding of the overall burden of risk variants and how they determine susceptibility to disease. A major goal of this project is to develop a [...] Read more.

Schizophrenia is a highly heritable polygenic psychiatric disorder. Characterization of its genetic architecture may lead to a better understanding of the overall burden of risk variants and how they determine susceptibility to disease. A major goal of this project is to develop a modeling approach to compare and quantify the relative effects of single nucleotide polymorphisms (SNPs), copy number variants (CNVs) and other factors. We derived a mathematical model for the various genetic contributions based on the probability of expressing a combination of risk variants at a frequency that matched disease prevalence. The model included estimated risk variant allele outputs (VAOs) adjusted for population allele frequency. We hypothesized that schizophrenia risk genes would be more interactive than random genes and we confirmed this relationship. Gene–gene interactions may cause network ripple effects that spread and amplify small individual effects of risk variants. The modeling revealed that the number of risk alleles required to achieve the threshold for susceptibility will be determined by the average functional locus output (FLO) associated with a risk allele, the risk allele frequency (RAF), the number of protective variants present and the extent of gene interactions within and between risk loci. The model can account for the quantitative impact of protective variants as well as CNVs on disease susceptibility. The fact that non-affected individuals must carry a non-trivial burden of risk alleles suggests that genetic susceptibility will inevitably reach the threshold for schizophrenia at a recurring frequency in the population. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

19 pages, 2973 KiB

Open AccessArticle

Assessment of Bidirectional Relationships between Leisure Sedentary Behaviors and Neuropsychiatric Disorders: A Two-Sample Mendelian Randomization Study

by Qian He, Adam N. Bennett, Beifang Fan, Xue Han, Jundong Liu, Kevin Chun Hei Wu, Ruixuan Huang, Juliana C. N. Chan and Kei Hang Katie Chan

Genes 2022, 13(6), 962; https://doi.org/10.3390/genes13060962 - 27 May 2022

Cited by 5 | Viewed by 3699

Abstract

(1) Background: Increasing evidence shows that sedentary behaviors are associated with neuropsychiatric disorders (NPDs) and thus may be a modifiable factor to target for the prevention of NPDs. However, the direction and causality for the relationship remain unknown; sedentary behaviors could increase or [...] Read more.

(1) Background: Increasing evidence shows that sedentary behaviors are associated with neuropsychiatric disorders (NPDs) and thus may be a modifiable factor to target for the prevention of NPDs. However, the direction and causality for the relationship remain unknown; sedentary behaviors could increase or decrease the risk of NPDs, and/or NPDs may increase or decrease engagement in sedentary behaviors. (2) Methods: This Mendelian randomization (MR) study with two samples included independent genetic variants related to sedentary behaviors (n = 408,815), Alzheimer’s disease (AD; n = 63,926), schizophrenia (SCZ; n = 105,318), and major depressive disorder (MDD; n = 500,199), which were extracted from several of the largest non-overlapping genome-wide association studies (GWASs), as instrumental variables. The summarized MR effect sizes from each instrumental variable were combined in an IVW (inverse-variance-weighted) approach, with various approaches (e.g., MR-Egger, weighted median, MR-pleiotropy residual sum and outlier), and sensitivity analyses were performed to identify and remove outliers and assess the horizontal pleiotropy. (3) Results: The MR evidence and linkage disequilibrium score regression revealed a consistent directional association between television watching and MDD (odds ratio (OR), 1.13 for MDD per one standard deviation (SD) increase in mean television watching time; 95% CI, 1.06–1.20; p = 6.80 × 10⁻⁵) and a consistent relationship between computer use and a decrease in the risk of AD (OR, 0.52 for AD per one SD increase in mean computer use time; 95% CI, 0.32–0.84; p = 8.20 × 10⁻³). In the reverse direction, MR showed a causal association between a reduced risk of SCZ and an increase in driving time (β, −0.016; 95% CI, −0.027–−0.004; p = 8.30 × 10⁻³). (4) Conclusions: Using genetic instrumental variables identified from large-scale GWASs, we found robust evidence for a causal relationship between long computer use time and a reduced risk of AD, and for a causal relationship between long television watching time and an increased risk of MDD. In reverse analyses, we found that SCZ was causally associated with reduced driving time. These findings fit in with our observations and prior knowledge as well as emphasizing the importance of distinguishing between different domains of sedentary behaviors in epidemiologic studies of NPDs. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

8 pages, 1286 KiB

Open AccessArticle

Identification of AMH and AMHR2 Variants Led to the Diagnosis of Persistent Müllerian Duct Syndrome in Three Cases

by Yang Liu, Sida Wang, Ruzhu Lan and Jun Yang

Genes 2022, 13(1), 159; https://doi.org/10.3390/genes13010159 - 17 Jan 2022

Cited by 2 | Viewed by 1922

Abstract

Persistent Müllerian duct syndrome (PMDS) is a rare autosomal recessive disorder of sexual development in males, defined by the presence of Müllerian remnants with otherwise normal sexual differentiation. Mutations in anti-Müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) [...] Read more.

Persistent Müllerian duct syndrome (PMDS) is a rare autosomal recessive disorder of sexual development in males, defined by the presence of Müllerian remnants with otherwise normal sexual differentiation. Mutations in anti-Müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) genes are the main causes of PMDS. In this study, we performed molecular genetic analysis of 11 unrelated cryptorchidism patients using whole-exome sequencing and classified the variants. Three of the 11 patients had biallelic mutations in AMH or AMHR2. Case 1 carried a homozygous 4-bp deletion; c.321_324del:p.Q109Lfs*29 in exon 1 of AMH (NM_000479 transcript), which is a frameshift mutation, leading to the loss of function of AMH. Case 2 carried compound heterozygous mutations; c.494_502del (p.I165_A168delinsT) in exon 4 and g.6147C>A of AMHR2 (NM_001164690 transcript). Case 3 carried compound heterozygous mutations; c.G1168A (p.E390K) in exon 9 and c.A1315G (p.M439V) in exon 10 of AMHR2 (NM_001164690 transcript). All three patients were admitted due to azoospermia- and oligospermia-caused infertility. They were furtherly diagnosed with PMDS, as pelvic magnetic resonance imaging revealed the presence of Müllerian remnants. Our study suggests that PMDS and genetic analysis should be considered during the differential diagnosis of cryptorchidism. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

Review

Jump to: Research, Other

11 pages, 280 KiB

Open AccessReview

Considerations of the Genetic Background of Obesity among Patients with Psoriasis

by Anna Czarnecka, Dorota Purzycka-Bohdan, Monika Zabłotna, Michał Bohdan, Roman J. Nowicki and Aneta Szczerkowska-Dobosz

Genes 2023, 14(3), 594; https://doi.org/10.3390/genes14030594 - 26 Feb 2023

Cited by 1 | Viewed by 1278

Abstract

Psoriasis comorbidities may emerge from pleiotropic mechanisms, including common proinflammatory pathways, cellular mediators or genetic predisposition. Obesity is considered to be an independent risk factor of psoriasis, which may influence the severity of the disease and its early onset, decrease patients’ quality of [...] Read more.

Psoriasis comorbidities may emerge from pleiotropic mechanisms, including common proinflammatory pathways, cellular mediators or genetic predisposition. Obesity is considered to be an independent risk factor of psoriasis, which may influence the severity of the disease and its early onset, decrease patients’ quality of life, alter response to psoriasis therapies and affect morbidity by reduced life expectancy due to cardiovascular events. Although novel approaches, including genetic techniques, have provided a wide range of new research, there are still scarce studies elaborating on the common genetic background of psoriasis and obesity. The aim of this study was to present and evaluate a possible common genetic background of psoriasis and concomitant increased body mass based on the review of the available literature. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

20 pages, 1952 KiB

Open AccessReview

Common Genetic Factors and Pathways in Alzheimer’s Disease and Ischemic Stroke: Evidences from GWAS

by Wei Dong and Yue Huang

Genes 2023, 14(2), 353; https://doi.org/10.3390/genes14020353 - 30 Jan 2023

Viewed by 2313

Abstract

Alzheimer’s disease (AD) and ischemic stroke (IS) are common neurological disorders, and the comorbidity of these two brain diseases is often seen. Although AD and IS were regarded as two distinct disease entities, in terms of different etiologies and clinical presentation, recent genome-wide [...] Read more.

Alzheimer’s disease (AD) and ischemic stroke (IS) are common neurological disorders, and the comorbidity of these two brain diseases is often seen. Although AD and IS were regarded as two distinct disease entities, in terms of different etiologies and clinical presentation, recent genome-wide association studies (GWASs) revealed that there were common risk genes between AD and IS, indicating common molecular pathways and their common pathophysiology. In this review, we summarize AD and IS risk single nucleotide polymorphisms (SNPs) and their representative genes from the GWAS Catalog database, and find thirteen common risk genes, but no common risk SNPs. Furthermore, the common molecular pathways associated with these risk gene products are summarized from the GeneCards database and clustered into inflammation and immunity, G protein-coupled receptor, and signal transduction. At least seven of these thirteen genes can be regulated by 23 microRNAs identified from the TargetScan database. Taken together, the imbalance of these molecular pathways may give rise to these two common brain disorders. This review sheds light on the pathogenesis of comorbidity of AD and IS, and provides molecular targets for disease prevention, manipulation, and brain health maintenance. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

14 pages, 1272 KiB

Open AccessReview

Research on Werner Syndrome: Trends from Past to Present and Future Prospects

by Kyoshiro Tsuge and Akira Shimamoto

Genes 2022, 13(10), 1802; https://doi.org/10.3390/genes13101802 - 06 Oct 2022

Cited by 7 | Viewed by 5789

Abstract

A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, and chromosomal instability, as well as cancer predisposition. WRN, the gene [...] Read more.

A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, and chromosomal instability, as well as cancer predisposition. WRN, the gene responsible for WS, encodes DNA helicase with a 3′ to 5′ exonuclease activity, and numerous studies have revealed that WRN helicase is involved in the maintenance of chromosome stability through actions in DNA, e.g., DNA replication, repair, recombination, and epigenetic regulation via interaction with DNA repair factors, telomere-binding proteins, histone modification enzymes, and other DNA metabolic factors. However, although these efforts have elucidated the cellular functions of the helicase in cell lines, they have not been linked to the treatment of the disease. Life expectancy has improved for WS patients over the past three decades, and it is hoped that a fundamental treatment for the disease will be developed. Disease-specific induced pluripotent stem (iPS) cells have been established, and these are expected to be used in drug discovery and regenerative medicine for WS patients. In this article, we review trends in research to date and present some perspectives on WS research with regard to the application of pluripotent stem cells. Furthermore, the elucidation of disease mechanisms and drug discovery utilizing the vast amount of scientific data accumulated to date will be discussed. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

24 pages, 1338 KiB

Open AccessReview

Epigenetic Peripheral Biomarkers for Early Diagnosis of Alzheimer’s Disease

by Chiara Villa and Andrea Stoccoro

Genes 2022, 13(8), 1308; https://doi.org/10.3390/genes13081308 - 22 Jul 2022

Cited by 10 | Viewed by 3165

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and represents the leading cause of cognitive impairment and dementia in older individuals throughout the world. The main hallmarks of AD include brain atrophy, extracellular deposition of insoluble amyloid-β (Aβ) plaques, and the intracellular aggregation [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and represents the leading cause of cognitive impairment and dementia in older individuals throughout the world. The main hallmarks of AD include brain atrophy, extracellular deposition of insoluble amyloid-β (Aβ) plaques, and the intracellular aggregation of protein tau in neurofibrillary tangles. These pathological modifications start many years prior to clinical manifestations of disease and the spectrum of AD progresses along a continuum from preclinical to clinical phases. Therefore, identifying specific biomarkers for detecting AD at early stages greatly improves clinical management. However, stable and non-invasive biomarkers are not currently available for the early detection of the disease. In the search for more reliable biomarkers, epigenetic mechanisms, able to mediate the interaction between the genome and the environment, are emerging as important players in AD pathogenesis. Herein, we discuss altered epigenetic signatures in blood as potential peripheral biomarkers for the early detection of AD in order to help diagnosis and improve therapy. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Graphical abstract

23 pages, 977 KiB

Open AccessReview

Overview of Transcriptomic Research on Type 2 Diabetes: Challenges and Perspectives

by Ziravard N. Tonyan, Yulia A. Nasykhova, Maria M. Danilova, Yury A. Barbitoff, Anton I. Changalidi, Anastasiia A. Mikhailova and Andrey S. Glotov

Genes 2022, 13(7), 1176; https://doi.org/10.3390/genes13071176 - 30 Jun 2022

Cited by 10 | Viewed by 4272

Abstract

Type 2 diabetes (T2D) is a common chronic disease whose etiology is known to have a strong genetic component. Standard genetic approaches, although allowing for the detection of a number of gene variants associated with the disease as well as differentially expressed genes, [...] Read more.

Type 2 diabetes (T2D) is a common chronic disease whose etiology is known to have a strong genetic component. Standard genetic approaches, although allowing for the detection of a number of gene variants associated with the disease as well as differentially expressed genes, cannot fully explain the hereditary factor in T2D. The explosive growth in the genomic sequencing technologies over the last decades provided an exceptional impetus for transcriptomic studies and new approaches to gene expression measurement, such as RNA-sequencing (RNA-seq) and single-cell technologies. The transcriptomic analysis has the potential to find new biomarkers to identify risk groups for developing T2D and its microvascular and macrovascular complications, which will significantly affect the strategies for early diagnosis, treatment, and preventing the development of complications. In this article, we focused on transcriptomic studies conducted using expression arrays, RNA-seq, and single-cell sequencing to highlight recent findings related to T2D and challenges associated with transcriptome experiments. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

12 pages, 658 KiB

Open AccessReview

Alzheimer’s Disease Connected Genes in the Post-Ischemic Hippocampus and Temporal Cortex

by Ryszard Pluta

Genes 2022, 13(6), 1059; https://doi.org/10.3390/genes13061059 - 14 Jun 2022

Cited by 5 | Viewed by 2182

Abstract

It is considered that brain ischemia can be causative connected to Alzheimer’s disease. In the CA1 and CA3 regions of the hippocampus and temporal cortex, genes related to Alzheimer’s disease, such as the amyloid protein precursor (APP), β-secretase (BACE1), presenilin [...] Read more.

It is considered that brain ischemia can be causative connected to Alzheimer’s disease. In the CA1 and CA3 regions of the hippocampus and temporal cortex, genes related to Alzheimer’s disease, such as the amyloid protein precursor (APP), β-secretase (BACE1), presenilin 1 (PSEN1) and 2 (PSEN2), are deregulated by ischemia. The pattern of change in the CA1 area of the hippocampus covers all genes tested, and the changes occur at all post-ischemic times. In contrast, the pattern of gene changes in the CA3 subfield is much less intense, does not occur at all post-ischemic times, and is delayed in time post-ischemia relative to the CA1 field. Conversely, the pattern of gene alterations in the temporal cortex appears immediately after ischemia, and does not occur at all post-ischemic times and does not affect all genes. Evidence therefore suggests that various forms of dysregulation of the APP, BACE1 and PSEN1 and PSEN2 genes are associated with individual neuronal cell responses in the CA1 and CA3 areas of the hippocampus and temporal cortex with reversible cerebral ischemia. Scientific data indicate that an ischemic episode of the brain is a trigger of amyloidogenic processes. From the information provided, it appears that post-ischemic brain injury additionally activates neuronal death in the hippocampus and temporal cortex in an amyloid-dependent manner. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

Other

Jump to: Research, Review

9 pages, 675 KiB

Open AccessCase Report

Whole Exome Sequencing Reveals a Novel Homozygous Variant in the Ganglioside Biosynthetic Enzyme, ST3GAL5 Gene in a Saudi Family Causing Salt and Pepper Syndrome

by Angham Abdulrhman Abdulkareem, Bader H. Shirah and Muhammad Imran Naseer

Genes 2023, 14(2), 354; https://doi.org/10.3390/genes14020354 - 30 Jan 2023

Cited by 2 | Viewed by 1349

Abstract

Salt and pepper developmental regression syndrome (SPDRS) is an autosomal recessive disorder characterized by epilepsy, profound intellectual disability, choreoathetosis, scoliosis, and dermal pigmentation along with dysmorphic facial features. GM3 synthase deficiency is due to any pathogenic mutation in the ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 5 [...] Read more.

Salt and pepper developmental regression syndrome (SPDRS) is an autosomal recessive disorder characterized by epilepsy, profound intellectual disability, choreoathetosis, scoliosis, and dermal pigmentation along with dysmorphic facial features. GM3 synthase deficiency is due to any pathogenic mutation in the ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 5 (ST3GAL5) gene, which encodes the sialyltransferase enzyme that synthesizes ganglioside GM3. In this study, the Whole Exome Sequencing (WES) results presented a novel homozygous pathogenic variant, NM_003896.3:c.221T>A (p.Val74Glu), in the exon 3 of the ST3GAL5 gene. causing SPDRS with epilepsy, short stature, speech delay, and developmental delay in all three affected members of the same Saudi family. The results of the WES sequencing were further validated using Sanger sequencing analysis. For the first time, we are reporting SPDRS in a Saudi family showing phenotypic features similar to other reported cases. This study further adds to the literature and explains the role of the ST3GAL5 gene, which plays an important role, and any pathogenic variants that may cause the GM3 synthase deficiency that leads to the disease. This study would finally enable the creation of a database of the disease that provides a base for understanding the important and critical genomic regions that will help control intellectual disability and epilepsy in Saudi patients. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Genetics of Complex Human Disease

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (20 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI