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BMC Genetics Feb 2017Recent advances in the development of sequencing technologies provide researchers with unprecedented possibilities for genetic analyses. In this review, we will discuss... (Review)
Review
Recent advances in the development of sequencing technologies provide researchers with unprecedented possibilities for genetic analyses. In this review, we will discuss the history of genetic studies and the progress driven by next-generation sequencing (NGS), using complex inflammatory bowel diseases as an example. We focus on the opportunities, but also challenges that researchers are facing when working with NGS data to unravel the genetic causes underlying diseases.
Topics: Disease; Exome; Genomics; High-Throughput Nucleotide Sequencing; Humans; Sequence Analysis, DNA
PubMed: 28193154
DOI: 10.1186/s12863-017-0479-5 -
Current Protocols in Human Genetics Dec 2019Genome-wide variation data with millions of genetic markers have become commonplace. However, the potential for interpretation and application of these data for clinical... (Review)
Review
Genome-wide variation data with millions of genetic markers have become commonplace. However, the potential for interpretation and application of these data for clinical assessment of outcomes of interest, and prediction of disease risk, is currently not fully realized. Many common complex diseases now have numerous, well-established risk loci and likely harbor many genetic determinants with effects too small to be detected at genome-wide levels of statistical significance. A simple and intuitive approach for converting genetic data to a predictive measure of disease susceptibility is to aggregate the effects of these loci into a single measure, the genetic risk score. Here, we describe some common methods and software packages for calculating genetic risk scores and polygenic risk scores, with focus on studies of common complex diseases. We review the basic information needed, as well as important considerations for constructing genetic risk scores, including specific requirements for phenotypic and genetic data, and limitations in their application. © 2019 by John Wiley & Sons, Inc.
Topics: Disease; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Multifactorial Inheritance; Phenotype; Risk Factors; Software
PubMed: 31765077
DOI: 10.1002/cphg.95 -
EMBO Reports Aug 2015Recent research has established clear connections between G-quadruplexes and human disease. Features of quadruplex structures that promote genomic instability have been... (Review)
Review
Recent research has established clear connections between G-quadruplexes and human disease. Features of quadruplex structures that promote genomic instability have been determined. Quadruplexes have been identified as transcriptional, translational and epigenetic regulatory targets of factors associated with human genetic disease. An expandable GGGGCC motif that can adopt a G4 structure, located in the previously obscure C9ORF72 locus, has been shown to contribute to two well-recognized neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This review focuses on these advances, which further dispel the view that genomic biology is limited to the confines of the canonical B-form DNA duplex, and show how quadruplexes contribute spatial and temporal dimensionalities to linear sequence information. This recent progress also has clear practical ramifications, as prevention, diagnosis, and treatment of disease depend on understanding the underlying mechanisms.
Topics: Animals; DNA; Disease; G-Quadruplexes; Genome, Human; Genomic Instability; Humans; Neoplasms; Nervous System Diseases
PubMed: 26150098
DOI: 10.15252/embr.201540607 -
Nature Medicine Jun 2023Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the...
Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the associations of alcohol consumption with 207 diseases in the 12-year China Kadoorie Biobank of >512,000 adults (41% men), including 168,050 genotyped for ALDH2- rs671 and ADH1B- rs1229984 , with >1.1 million ICD-10 coded hospitalized events. At baseline, 33% of men drank alcohol regularly. Among men, alcohol intake was positively associated with 61 diseases, including 33 not defined by the World Health Organization as alcohol-related, such as cataract (n = 2,028; hazard ratio 1.21; 95% confidence interval 1.09-1.33, per 280 g per week) and gout (n = 402; 1.57, 1.33-1.86). Genotype-predicted mean alcohol intake was positively associated with established (n = 28,564; 1.14, 1.09-1.20) and new alcohol-associated (n = 16,138; 1.06, 1.01-1.12) diseases, and with specific diseases such as liver cirrhosis (n = 499; 2.30, 1.58-3.35), stroke (n = 12,176; 1.38, 1.27-1.49) and gout (n = 338; 2.33, 1.49-3.62), but not ischemic heart disease (n = 8,408; 1.04, 0.94-1.14). Among women, 2% drank alcohol resulting in low power to assess associations of self-reported alcohol intake with disease risks, but genetic findings in women suggested the excess male risks were not due to pleiotropic genotypic effects. Among Chinese men, alcohol consumption increased multiple disease risks, highlighting the need to strengthen preventive measures to reduce alcohol intake.
Topics: Adult; Female; Humans; Male; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; East Asian People; Ethanol; Genotype; Gout; Risk Factors; Disease; China
PubMed: 37291211
DOI: 10.1038/s41591-023-02383-8 -
Cells Sep 2021Almost 25 years have passed since a mutation of a formin gene, , was identified as being responsible for a human inherited disorder: a form of sensorineural hearing... (Review)
Review
Almost 25 years have passed since a mutation of a formin gene, , was identified as being responsible for a human inherited disorder: a form of sensorineural hearing loss. Since then, our knowledge of the links between formins and disease has deepened considerably. Mutations of and six other formin genes (, , , , and ) have been identified as the genetic cause of a variety of inherited human disorders, including intellectual disability, renal disease, peripheral neuropathy, thrombocytopenia, primary ovarian insufficiency, hearing loss and cardiomyopathy. In addition, alterations in formin genes have been associated with a variety of pathological conditions, including developmental defects affecting the heart, nervous system and kidney, aging-related diseases, and cancer. This review summarizes the most recent discoveries about the involvement of formin alterations in monogenic disorders and other human pathological conditions, especially cancer, with which they have been associated. In vitro results and experiments in modified animal models are discussed. Finally, we outline the directions for future research in this field.
Topics: Disease; Female; Formins; Humans; Male
PubMed: 34685534
DOI: 10.3390/cells10102554 -
Nature Genetics May 2018Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the 'no...
Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the 'no horizontal pleiotropy' assumption can cause severe bias in MR. We developed the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that the MR-PRESSO test is best suited when horizontal pleiotropy occurs in <50% of instruments. Next we applied the MR-PRESSO test, along with several other MR tests, to complex traits and diseases and found that horizontal pleiotropy (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from -131% to 201%; (iii) induced false-positive causal relationships in up to 10% of relationships; and (iv) could be corrected in some but not all instances.
Topics: Disease; Genetic Pleiotropy; Genetic Predisposition to Disease; Genetic Variation; Humans
PubMed: 29686387
DOI: 10.1038/s41588-018-0099-7 -
AMA Journal of Ethics Dec 2019This image of a silhouetted figure looking out over a body of water at sunset aims to promote reflection about patients' feelings of sadness, despair, helplessness, and...
This image of a silhouetted figure looking out over a body of water at sunset aims to promote reflection about patients' feelings of sadness, despair, helplessness, and uncertainty upon being diagnosed.
Topics: Disease; Emotions; Humans; Medicine in the Arts; Sadness
PubMed: 31876476
DOI: 10.1001/amajethics.2019.1103 -
Essays in Biochemistry Dec 2018This article gives the reader an insight into the role of biochemistry in some of the current global health and disease problems. It surveys the biochemical causes of... (Review)
Review
This article gives the reader an insight into the role of biochemistry in some of the current global health and disease problems. It surveys the biochemical causes of disease in an accessible and succinct form while also bringing in aspects of pharmacology, cell biology, pathology and physiology which are closely aligned with biochemistry. The discussion of the selected diseases highlights exciting new developments and illuminates key biochemical pathways and commonalities. The article includes coverage of diabetes, atherosclerosis, cancer, microorganisms and disease, nutrition, liver disease and Alzheimer's disease, but does not attempt to be comprehensive in its coverage of disease, since this is beyond its remit and scope. Consequently there are many fascinating biochemical aspects of diseases, both common and rare, that are not addressed here that can be explored in the further reading cited. Techniques and biochemical procedures for studying disease are not covered in detail here, but these can be found readily in a range of biochemical methods sources.
Topics: Biochemical Phenomena; Disease; Humans
PubMed: 30509933
DOI: 10.1042/EBC20170054 -
Science (New York, N.Y.) Apr 2023Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern...
Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.
Topics: Animals; Humans; Biological Evolution; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomics; Molecular Sequence Annotation; Polymorphism, Single Nucleotide; Disease
PubMed: 37104612
DOI: 10.1126/science.abn2937 -
Cold Spring Harbor Perspectives in... Feb 2016Genetic causes for human disorders are being discovered at an unprecedented pace. A growing subclass of disease-causing mutations involves changes in the epigenome or in... (Review)
Review
Genetic causes for human disorders are being discovered at an unprecedented pace. A growing subclass of disease-causing mutations involves changes in the epigenome or in the abundance and activity of proteins that regulate chromatin structure. This article focuses on research that has uncovered human diseases that stem from such epigenetic deregulation. Disease may be caused by direct changes in epigenetic marks, such as DNA methylation, commonly found to affect imprinted gene regulation. Also described are disease-causing genetic mutations in epigenetic modifiers that either affect chromatin in trans or have a cis effect in altering chromatin configuration.
Topics: Disease; Epigenesis, Genetic; Humans
PubMed: 26834142
DOI: 10.1101/cshperspect.a019497