Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine

Cystic fibrosis (CF) is a monogenic autosomal recessive disease caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. CF is characterized by a high phenotypic variability present even in patients with the same genotype. This is due to the intervention of modifier genes that interact with both the CFTR gene and environmental factors. The purpose of this review is to highlight the role of non-CFTR genetic factors (modifier genes) that contribute to phenotypic variability in CF. We analyzed literature data starting with candidate gene studies and continuing with extensive studies, such as genome-wide association studies (GWAS) and whole exome sequencing (WES). The results of both types of studies revealed that the number of modifier genes in CF patients is impressive. Their identification offers a new perspective on the pathophysiological mechanisms of the disease, paving the way for the understanding of other genetic disorders. In conclusion, in the future, genetic analysis, such as GWAS and WES, should be performed routinely. A challenge for future research is to integrate their results in the process of developing new classes of drugs, with a goal to improve the prognosis, increase life expectancy, and enhance quality of life among CF patients.

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Cystic Fibrosis Disease Modifiers: Complex Genetics Defines the Phenotypic Diversity in a Monogenic Disease

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-083117-021329 ◽

2018 ◽

Vol 19 (1) ◽

pp. 201-222 ◽

Cited By ~ 23

Author(s):

Wanda K. O'Neal ◽

Michael R. Knowles

Keyword(s):

Cystic Fibrosis ◽

Phenotypic Diversity ◽

Association Studies ◽

Gene Mutations ◽

Monogenic Disease ◽

Genome Wide Association Studies ◽

Complex Genetics ◽

Genetic Components ◽

Significant Gene ◽

Gene Expression Studies

In many respects, genetic studies in cystic fibrosis (CF) serve as a paradigm for a human Mendelian genetic success story. From recognition of the condition as a heritable pathological entity to implementation of personalized treatments based on genetic findings, this multistep pathway of progress has focused on the genetic underpinnings of CF clinical disease. Along this path was the recognition that not all CFTR gene mutations produce the same disease and the recognition of the complex, multifactorial nature of CF genotype–phenotype relationships. The non- CFTR genetic components (gene modifiers) that contribute to variation in phenotype are the focus of this review. A multifaceted approach involving candidate gene studies, genome-wide association studies, and gene expression studies has revealed significant gene modifiers for multiple CF phenotypes. The bold challenges for the future are to integrate the findings into our understanding of CF pathogenesis and to use the knowledge to develop novel therapies.

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Brain imaging genomics: influences of genomic variability on the structure and function of the human brain

Medizinische Genetik ◽

10.1515/medgen-2020-2007 ◽

2020 ◽

Vol 32 (1) ◽

pp. 47-56

Author(s):

Thomas W. Mühleisen ◽

Andreas J. Forstner ◽

Per Hoffmann ◽

Sven Cichon

Keyword(s):

Brain Imaging ◽

Complex Traits ◽

Molecular Mechanisms ◽

Association Studies ◽

Phenotypic Variability ◽

Effect Sizes ◽

Future Research ◽

Environment Interaction ◽

Genome Wide Association Studies ◽

Imaging Genomics

Abstract Brain imaging genomics is an emerging discipline in which genomic and brain imaging data are integrated in order to elucidate the molecular mechanisms that underly brain phenotypes and diseases, including neuropsychiatric disorders. As with all genetic analyses of complex traits and diseases, brain imaging genomics has evolved from small, individual candidate gene investigations towards large, collaborative genome-wide association studies. Recent investigations, mostly population-based, have studied well-powered cohorts comprising tens of thousands of individuals and identified multiple robust associations of single-nucleotide polymorphisms and copy number variants with structural and functional brain phenotypes. Such systematic genomic screens of millions of genetic variants have generated initial insights into the genetic architecture of brain phenotypes and demonstrated that their etiology is polygenic in nature, involving multiple common variants with small effect sizes and rare variants with larger effect sizes. Ongoing international collaborative initiatives are now working to obtain a more complete picture of the underlying biology. As in other complex phenotypes, novel approaches – such as gene–gene interaction, gene–environment interaction, and epigenetic analyses – are being implemented in order to investigate their contribution to the observed phenotypic variability. An important consideration for future research will be the translation of brain imaging genomics findings into clinical practice.

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Genetic Basis of Mastitis Resistance in Dairy Cattle – A Review / Podstawy Genetyczne Odporności Krów Mlecznych Na Zapalenie Wymienia – Artykuł Przeglądowy

Annals of Animal Science ◽

10.2478/aoas-2013-0043 ◽

2013 ◽

Vol 13 (4) ◽

pp. 663-673 ◽

Cited By ~ 17

Author(s):

Grażyna Sender ◽

Agnieszka Korwin-Kossakowska ◽

Adrianna Pawlik ◽

Karima Galal Abdel Hameed ◽

Jolanta Oprządek

Keyword(s):

Dairy Cattle ◽

Association Studies ◽

Genetic Resistance ◽

Clinical Mastitis ◽

Future Research ◽

Complex Nature ◽

Candidate Gene Approach ◽

Genome Wide Association Studies ◽

Polygenic Control ◽

Breeding Programmes

Abstract Mastitis is one of the most important mammary gland diseases impacting lactating animals. Resistance to this disease could be improved by breeding. There are several selection methods for mastitis resistance. To improve the natural genetic resistance of cows in succeeding generations, current breeding programmes use somatic cell count and clinical mastitis cases as resistance traits. However, these methods of selection have met with limited success. This is partly due to the complex nature of the disease. The limited progress in improving udder health by conventional selection procedures requires applying information on molecular markers of mastitis susceptibility in marker-assisted selection schemes. Mastitis is under polygenic control, so there are many genes that control this trait in many loci. This review briefly describes genome-wide association studies which have been carried out to identify quantitative trait loci associated with mastitis resistance in dairy cattle worldwide. It also characterizes the candidate gene approach focus on identifying genes that are strong candidates for the mastitis resistance trait. In the conclusion of the paper we focus our attention on future research which should be conducted in the field of the resistance to mastitis.

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Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

Genes ◽

10.3390/genes12081181 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1181

Author(s):

Alessandro Maglione ◽

Miriam Zuccalà ◽

Martina Tosi ◽

Marinella Clerico ◽

Simona Rolla

Keyword(s):

Multiple Sclerosis ◽

Environmental Factors ◽

Lupus Erythematosus ◽

Gut Microbiome ◽

Complex Disease ◽

Current Knowledge ◽

Association Studies ◽

Future Research ◽

Genome Wide Association Studies ◽

Host Genetics

As a complex disease, Multiple Sclerosis (MS)’s etiology is determined by both genetic and environmental factors. In the last decade, the gut microbiome has emerged as an important environmental factor, but its interaction with host genetics is still unknown. In this review, we focus on these dual aspects of MS pathogenesis: we describe the current knowledge on genetic factors related to MS, based on genome-wide association studies, and then illustrate the interactions between the immune system, gut microbiome and central nervous system in MS, summarizing the evidence available from Experimental Autoimmune Encephalomyelitis mouse models and studies in patients. Finally, as the understanding of influence of host genetics on the gut microbiome composition in MS is in its infancy, we explore this issue based on the evidence currently available from other autoimmune diseases that share with MS the interplay of genetic with environmental factors (Inflammatory Bowel Disease, Rheumatoid Arthritis and Systemic Lupus Erythematosus), and discuss avenues for future research.

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Genetic and Epigenetic Modifiers of Alcoholic Liver Disease

International Journal of Molecular Sciences ◽

10.3390/ijms19123857 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3857 ◽

Cited By ~ 20

Author(s):

Marica Meroni ◽

Miriam Longo ◽

Raffaela Rametta ◽

Paola Dongiovanni

Keyword(s):

Liver Disease ◽

Alcohol Consumption ◽

Alcoholic Liver Disease ◽

Complex Disease ◽

Wide Spectrum ◽

Association Studies ◽

Phenotypic Variability ◽

Genome Wide Association Studies ◽

Epigenetic Factors ◽

Excessive Alcohol Consumption

Alcoholic liver disease (ALD), a disorder caused by excessive alcohol consumption is a global health issue. More than two billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders. ALD embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ALD is a complex disease where environmental, genetic, and epigenetic factors contribute to its pathogenesis and progression. The severity of alcohol-induced liver disease depends on the amount, method of usage and duration of alcohol consumption as well as on age, gender, presence of obesity, and genetic susceptibility. Genome-wide association studies and candidate gene studies have identified genetic modifiers of ALD that can be exploited as non-invasive biomarkers, but which do not completely explain the phenotypic variability. Indeed, ALD development and progression is also modulated by epigenetic factors. The premise of this review is to discuss the role of genetic variants and epigenetic modifications, with particular attention being paid to microRNAs, as pathogenic markers, risk predictors, and therapeutic targets in ALD.

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Identification of Unique Pattern of CFTR Gene Mutations in Cystic Fibrosis in an Ethnic Kashmiri Population (North India)

Journal of Genetic Syndromes & Gene Therapy ◽

10.4172/2157-7412.1000260 ◽

2015 ◽

Vol 06 (02) ◽

Cited By ~ 1

Author(s):

Arshad A Pandith

Keyword(s):

Cystic Fibrosis ◽

Gene Mutations ◽

North India ◽

Cftr Gene ◽

Unique Pattern ◽

Kashmiri Population ◽

Cftr Gene Mutations

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Four Loci Are Associated with Cardiorespiratory Fitness and Endurance Performance in Young Chinese Females

Scientific Reports ◽

10.1038/s41598-020-67045-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ying Zhao ◽

Guoyuan Huang ◽

Zuosong Chen ◽

Xiang Fan ◽

Tao Huang ◽

...

Keyword(s):

Cardiorespiratory Fitness ◽

Association Studies ◽

Endurance Performance ◽

Young Female ◽

Future Research ◽

Genome Wide Association Studies ◽

Genetic Trait ◽

Young Females ◽

Genome Wide ◽

Fixed Model

AbstractCardiorespiratory fitness (CRF) and endurance performance are characterized by a complex genetic trait with high heritability. Although research has identified many physiological and environmental correlates with CRF, the genetic architecture contributing to CRF remains unclear, especially in non-athlete population. A total of 762 Chinese young female participants were recruited and an endurance run test was used to determine CRF. We used a fixed model of genome-wide association studies (GWAS) for CRF. Genotyping was performed using the Affymetrix Axiom and illumina 1 M arrays. After quality control and imputation, a linear regression-based association analysis was conducted using a total of 5,149,327 variants. Four loci associated with CRF were identified to reach genome-wide significance (P < 5.0 × 10-8), which located in 15q21.3 (rs17240160, P = 1.73 × 10-9, GCOM1), 3q25.31 (rs819865, P = 8.56 × 10-9, GMPS), 21q22.3 (rs117828698, P = 9.59 × 10-9, COL18A1), and 17q24.2 (rs79806428, P = 3.85 × 10-8, PRKCA). These loci (GCOM1, GMPS, COL18A1 and PRKCA) associated with cardiorespiratory fitness and endurance performance in Chinese non-athlete young females. Our results suggest that these gene polymorphisms provide further genetic evidence for the polygenetic nature of cardiorespiratory endurance and be used as genetic biomarkers for future research.

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Insights into the genomics of affective disorders

Medizinische Genetik ◽

10.1515/medgen-2020-2003 ◽

2020 ◽

Vol 32 (1) ◽

pp. 9-18

Author(s):

Andreas J. Forstner ◽

Per Hoffmann ◽

Markus M. Nöthen ◽

Sven Cichon

Keyword(s):

Bipolar Disorder ◽

Major Depression ◽

Affective Disorders ◽

Association Studies ◽

Phenotypic Variability ◽

Genetic Research ◽

Autism Spectrum ◽

Risk Scores ◽

Depression Symptoms ◽

Genome Wide Association Studies

Abstract Affective disorders, or mood disorders, are a group of neuropsychiatric illnesses that are characterized by a disturbance of mood or affect. Most genetic research in this field to date has focused on bipolar disorder and major depression. Symptoms of major depression include a depressed mood, reduced energy, and a loss of interest and enjoyment. Bipolar disorder is characterized by the occurrence of (hypo)manic episodes, which generally alternate with periods of depression. Formal and molecular genetic studies have demonstrated that affective disorders are multifactorial diseases, in which both genetic and environmental factors contribute to disease development. Twin and family studies have generated heritability estimates of 58–85 % for bipolar disorder and 40 % for major depression. Large genome-wide association studies have provided important insights into the genetics of affective disorders via the identification of a number of common genetic risk factors. Based on these studies, the estimated overall contribution of common variants to the phenotypic variability (single-nucleotide polymorphism [SNP]-based heritability) is 17–23 % for bipolar disorder and 9 % for major depression. Bioinformatic analyses suggest that the associated loci and implicated genes converge into specific pathways, including calcium signaling. Research suggests that rare copy number variants make a lower contribution to the development of affective disorders than to other psychiatric diseases, such as schizophrenia or the autism spectrum disorders, which would be compatible with their less pronounced negative impact on reproduction. However, the identification of rare sequence variants remains in its infancy, as available next-generation sequencing studies have been conducted in limited samples. Future research strategies will include the enlargement of genomic data sets via innovative recruitment strategies; functional analyses of known associated loci; and the development of new, etiologically based disease models. Researchers hope that deeper insights into the biological causes of affective disorders will eventually lead to improved diagnostics and disease prediction, as well as to the development of new preventative, diagnostic, and therapeutic strategies. Pharmacogenetics and the application of polygenic risk scores represent promising initial approaches to the future translation of genomic findings into psychiatric clinical practice.

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