Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
180,480
result(s) for
"Genetic disorders"
Sort by:
From gene to therapy : understanding human disease through genetics
This Colloquium Lecture provides an overview of the progress made in molecular medicine applying genetics and genomics to the understanding, diagnosis, and treatment of human diseases. Specifically, the methods for identifying genes involved in human diseases are described. Examples from 10 genes and diseases will be provided, drawing on the author's research. Topics include examples from simple Mendelian diseases, such as cystic fibrosis, inherited cancers, oncogenes activated by chromosomal translocations, host genes involved in infectious disease, genes identified via genomewide association studies, pathogens causing cancer, and gene families contributing to multiple diseases. For each example, historical details will be provided as background for readers to understand the context and process of the discoveries, technologies explained, and current understanding and treatment implications detailed.
Book
Assessing the Causal Effects of Human Serum Metabolites on 5 Major Psychiatric Disorders
Psychiatric disorders are the leading cause of disability worldwide while the pathogenesis remains unclear. Genome-wide association studies (GWASs) have made great achievements in detecting disease-related genetic variants. However, functional information on the underlying biological processes is often lacking. Current reports propose the use of metabolic traits as functional intermediate phenotypes (the so-called genetically determined metabotypes or GDMs) to reveal the biological mechanisms of genetics in human diseases. Here we conducted a two-sample Mendelian randomization analysis that uses GDMs to assess the causal effects of 486 human serum metabolites on 5 major psychiatric disorders, which respectively were schizophrenia (SCZ), major depression (MDD), bipolar disorder (BIP), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Using genetic variants as proxies, our study has identified 137 metabolites linked to the risk of psychiatric disorders, including 2-methoxyacetaminophen sulfate, which affects SCZ (P = 1.7 × 10–5) and 1-docosahexaenoylglycerophosphocholine, which affects ADHD (P = 5.6 × 10–5). Fourteen significant metabolic pathways involved in the 5 psychiatric disorders assessed were also detected, such as glycine, serine, and threonine metabolism for SCZ (P = .0238), Aminoacyl-tRNA biosynthesis for both MDD (P = .0144) and ADHD (P = .0029). Our study provided novel insights into integrating metabolomics with genomics in order to understand the mechanisms underlying the pathogenesis of human diseases.
Journal Article
Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls
Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders.
We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia.
Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50.
Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.
Journal Article
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by
GRIA1-4
genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca
2+
-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous
de novo GRIA2
mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most
GRIA2
mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that
de-novo
variants in
GRIA2
can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous
de novo
mutations in the
GRIA2
gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca
2+
transport and AMPAR currents.”
Journal Article
A perfect life : a novel
Jane Weiss is obsessed with finding the genetic marker for Valentine's Disease, a neurodegenerative disorder. Her pursuit is deeply personal. Valentine killed her mother, and she and her freewheeling sister, Laurel, could be genetic carriers; each has a fifty percent chance of developing the disease.
Book
Genetic architectures of psychiatric disorders: the emerging picture and its implications
Key Points
Psychiatric disorders cause enormous morbidity, mortality and personal and societal costs.
Despite considerable investigation, little is known for certain about aetiologies. Genetic approaches are a major avenue of investigation.
In the past 5 years, a considerable number of new findings have been discovered that meet community standards for robustness and replication.
Where sample sizes are sufficiently large, genome-wide association has yielded several dozen findings that suggest novel biological mechanisms.
Studies of rare variation (generally using genome-wide association study chips) have yielded over ten copy number variants that confer markedly increased risk. However, these tend to be nonspecific and increase risk for multiple different neuropsychiatric conditions.
Studies of exonic variation have yielded new findings for autism. However, for autism and schizophrenia, these findings are not abundant, and their genetic architectures do not appear to consist of a series of Mendelian traits, making the 'many Mendelian model' very unlikely.
Looking at the psychiatric disorders for which there are sufficient genetics data, it seems that these disorders are fairly typical complex traits with genetic variation scattered across the allelic spectrum.
For the first time, a fairly complete enumeration of the 'parts list' for these disorders is attainable using established methods. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings.
This Review considers recent findings — from genome-wide association studies, structural variant studies and exome sequencing — about the genetics of nine psychiatric disorders. The authors evaluate the implications of our current picture of the genetic architectures of these conditions for future research strategies.
Psychiatric disorders are among the most intractable enigmas in medicine. In the past 5 years, there has been unprecedented progress on the genetics of many of these conditions. In this Review, we discuss the genetics of nine cardinal psychiatric disorders (namely, Alzheimer's disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence and schizophrenia). Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings.
Journal Article
Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs
Naomi Wray and colleagues report an analysis of genome-wide association data sets from the Psychiatric Genomics Consortium for five psychiatric disorders. They find that common variation explains 17–29% of the variance in liability and provide further support for a shared genetic etiology for these related psychiatric disorders.
Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Journal Article