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The candidate gene approach to conducting genetic association studies focuses on associations between genetic variation within pre-specified genes of interest, and phenotypes or disease states. This is in contrast to genome-wide association studies (GWAS), which is a hypothesis-free approach that scans the entire genome for associations between common genetic variants and traits of interest. Candidate genes are most often selected for study based on a priori knowledge of the gene's biological functional impact on the trait or disease in question. The rationale behind focusing on allelic variation in specific, biologically relevant regions of the genome is that certain alleles within a gene may directly impact the function of the gene in question and lead to variation in the phenotype or disease state being investigated. This approach often uses the case-control study design to try to answer the question, "Is one allele of a candidate gene more frequently seen in subjects with the disease than in subjects without the disease?" Candidate genes hypothesized to be associated with complex traits have generally not been replicated by subsequent GWASs or highly powered replication attempts. The failure of candidate gene studies to shed light on the specific genes underlying such traits has been ascribed to insufficient statistical power, low prior probability that scientists can correctly guess a specific allele within a specific gene that is related to a trait, poor methodological practices, and data dredging.
Neuropsychiatry or Organic Psychiatry is a branch of medicine that deals with psychiatry as it relates to neurology, in an effort to understand and attribute behavior to the interaction of neurobiology and social psychology factors. Within neuropsychiatry, the mind is considered "as an emergent property of the brain", whereas other behavioral and neurological specialties might consider the two as separate entities. Neuropsychiatry preceded the current disciplines of psychiatry and neurology, which previously had common training, however, those disciplines have subsequently diverged and are typically practiced separately.
The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis, although the genetics of autism are complex and it is unclear whether autism spectrum disorder (ASD) is explained more by multigene interactions or by rare mutations with major effects.
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Risk factors of schizophrenia include many genetic and environmental phenomena. The prevailing model of schizophrenia is that of a special neurodevelopmental disorder with no precise boundary or single cause. Schizophrenia is thought to develop from very complex gene–environment interactions with vulnerability factors. The interactions of these risk factors are intricate, as numerous and diverse medical insults from conception to adulthood can be involved. The combination of genetic and environmental factors leads to deficits in the neural circuits that affect sensory input and cognitive functions. Historically, this theory has been broadly accepted but impossible to prove given ethical limitations. The first definitive proof that schizophrenia arises from multiple biological changes in the brain was recently established in human tissue grown from patient stem cells, where the complexity of disease was found to be "even more complex than currently accepted" due to cell-by-cell encoding of schizophrenia-related neuropathology.
In genetic epidemiology, endophenotype is a term used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection. The concept was coined by Bernard John and Kenneth R. Lewis in a 1966 paper attempting to explain the geographic distribution of grasshoppers. They claimed that the particular geographic distribution could not be explained by the obvious and external "exophenotype" of the grasshoppers, but instead must be explained by their microscopic and internal "endophenotype".
Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene. Aralar is an integral membrane protein located in the inner mitochondrial membrane. Its primary function as an antiporter is the transport of cytoplasmic glutamate with mitochondrial aspartate across the inner mitochondrial membrane, dependent on the binding of one calcium ion. Mutations in this gene cause early infantile epileptic encephalopathy 39 (EIEE39), symptomized by global hypomyelination of the central nervous system, refractory seizures, and neurodevelopmental impairment. This gene has connections to autism.
Jeffrey H. Meyer is a scientist and professor working with mood and anxiety disorders using neuroimaging at the Department of Psychiatry, University of Toronto. He is currently the head of the Neurochemical Imaging Program in Mood and Anxiety Disorders in the Brain Health Imaging Centre at the Campbell Family Mental Health Research Institute and is working as a Senior Scientist in the General and Health Systems Psychiatry Division at the Centre for Addiction and Mental Health. He has also been awarded with the Tier 1 Canada Research Chair in the Neurochemistry of Major Depression.
5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter. Since the polymorphism was identified in the middle of the 1990s, it has been extensively investigated, e.g., in connection with neuropsychiatric disorders. A 2006 scientific article stated that "over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers" had analyzed the polymorphism. While often discussed as an example of gene-environment interaction, this contention is contested.
Scientific studies have found that different brain areas show altered activity in people with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.
Behavioural genetics, also referred to as behaviour genetics, is a field of scientific research that uses genetic methods to investigate the nature and origins of individual differences in behaviour. While the name "behavioural genetics" connotes a focus on genetic influences, the field broadly investigates the extent to which genetic and environmental factors influence individual differences, using research designs that allow removal of the confounding of genes and environment. Behavioural genetics was founded as a scientific discipline by Francis Galton in the late 19th century, only to be discredited through association with eugenics movements before and during World War II. In the latter half of the 20th century, the field saw renewed prominence with research on inheritance of behaviour and mental illness in humans, as well as research on genetically informative model organisms through selective breeding and crosses. In the late 20th and early 21st centuries, technological advances in molecular genetics made it possible to measure and modify the genome directly. This led to major advances in model organism research and in human studies, leading to new scientific discoveries.
Terrie Edith Moffitt is an American clinical psychologist who is best known for her pioneering research on the development of antisocial behavior and for her collaboration with colleague and partner Avshalom Caspi in research on gene-environment interactions in mental disorders.
The evolution of schizophrenia refers to the theory of natural selection working in favor of selecting traits that are characteristic of the disorder. Positive symptoms are features that are not present in healthy individuals but appear as a result of the disease process. These include visual and/or auditory hallucinations, delusions, paranoia, and major thought disorders. Negative symptoms refer to features that are normally present but are reduced or absent as a result of the disease process, including social withdrawal, apathy, anhedonia, alogia, and behavioral perseveration. Cognitive symptoms of schizophrenia involve disturbances in executive functions, working memory impairment, and inability to sustain attention.
Cathryn Lewis is Professor of Genetic Epidemiology and Statistics at King's College London. She is Head of Department at the Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience.
Li Tao is a Chinese academic psychiatrist. She is the dean of the Mental Health Center affiliated to Zhejiang University School of Medicine. She is a clinician, professor, and researcher, specialising in topics relating to molecular genetics and mental illness.
Hilary Patricia Blumberg is a medical doctor and the inaugural John and Hope Furth Professor of Psychiatry at the Yale School of Medicine. She is also a professor of Radiology and Biomedical Imaging, and works in the Child Study Center at Yale where she has been a faculty member since 1998. She attended Harvard University as an undergraduate, and completed medical school at Cornell University Medical College (1990). She completed her medical internship and psychiatry residency at Cornell University Medical College/New York Hospital, and her neuroimaging fellowship training at Cornell University, Weill Medical College. She has received the 2006 National Alliance for Research in Schizophrenia and Depression (NARSAD) and the Gerald L. Klerman Award for Clinical Research. Blumberg has authored a number of scientific articles that focus on bipolar disorder, neuroimaging, and effects of specific genetic variations, developmental trajectories and structure-function relationships.
Avshalom Caspi is an Israeli-American psychologist and the Edward M. Arnett Professor of Psychology and Neuroscience in the Trinity College of Arts and Sciences at Duke University, as well as Professor of Personality Development at King's College London's Institute of Psychiatry, Psychology and Neuroscience. He is known for his research on mental health and human development, much of which he has conducted with his wife and longtime research partner, Terrie Moffitt. The two first met when they presented adjacent posters at a 1987 conference in St. Louis, Missouri entitled "Deviant Pathways from Childhood to Adulthood". Among Caspi's notable discoveries was that of an association between the 5-HTTLPR polymorphism and clinical depression. This discovery, originally reported in a 2003 study, spurred a wave of subsequent research on the potential genetic roots of various psychiatric conditions. However, a 2017 meta-analysis did not support the original finding, nor did a large analysis with nearly 100% power to detect the original finding. Therefore, the general approach of candidate gene or candidate gene by environment interaction research in single small studies is no longer widely accepted.
Louise Arseneault is a Canadian psychologist and Professor of Developmental Psychology in the Social, Genetic & Developmental Psychiatry Centre in the Institute of Psychiatry, Psychology and Neuroscience at King's College London, where she has taught since 2001. She was elected a Fellow of the Academy of Medical Sciences in 2018. She is also a Mental Health Leadership Fellow at the Economic and Social Research Council. She is known for her research on mental disorders, substance abuse, and the mental health effects of childhood bullying.
In adoption studies, selective placement refers to the practice by which adoption agencies tend to deliberately match certain characteristics of an adopted child's adopted parents with those of his or her biological parents. When this occurs, it results in a correlation between environments between biological relatives raised in different homes. It has the potential to bias the conclusions of such studies, because twins who were reared in separate environments may in fact have been reared in much more similar environments than assumed. This can result in an inflated estimate of heritability. There is evidence that selective placement was a major confound in many early studies of twins reared apart. Some adoption studies report little or no evidence of selective placement. For example, a 1979 study by Ho et al. reported a generally low level of selective placement in adopted children for either physical or behavioral traits. The authors concluded that to the extent that selective placement occurred for such traits, "our data suggest that it is based largely on characteristics of the birth father," rather than those of the adoptee. Carey (2003) concluded that selective placement was "moderate" for physical characteristics and typically "small or nonexistent" for behavioral characteristics.
References
- ↑ "Matthew C Keller's Home Page". www.matthewckeller.com. Retrieved 19 February 2019.
- ↑ Duncan, Laramie E.; Keller, Matthew C. (November 2011). "A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry". American Journal of Psychiatry. 168 (10): 1041–1049. doi:10.1176/appi.ajp.2011.11020191. ISSN 0002-953X. PMC 3222234 . PMID 21890791.
- ↑ Border, Richard; Johnson, Emma C.; Evans, Luke M.; Smolen, Andrew; Berley, Noah; Sullivan, Patrick F.; Keller, Matthew C. (May 2019). "No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples". American Journal of Psychiatry. 176 (5): 376–387. doi:10.1176/appi.ajp.2018.18070881. ISSN 0002-953X. PMC 6548317 . PMID 30845820.
- ↑ Johnson, Emma C.; Border, Richard; Melroy-Greif, Whitney E.; de Leeuw, Christiaan A.; Ehringer, Marissa A.; Keller, Matthew C. (November 2017). "No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes". Biological Psychiatry. 82 (10): 702–708. doi:10.1016/j.biopsych.2017.06.033. PMC 5643230 . PMID 28823710.
- ↑ Haplotype Reference Consortium; Evans, Luke M.; Tahmasbi, Rasool; Vrieze, Scott I.; Abecasis, Gonçalo R.; Das, Sayantan; Gazal, Steven; Bjelland, Douglas W.; de Candia, Teresa R.; Goddard, Michael E.; Neale, Benjamin M. (May 2018). "Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits". Nature Genetics. 50 (5): 737–745. doi:10.1038/s41588-018-0108-x. ISSN 1061-4036. PMC 5934350 . PMID 29700474.
- ↑ Keller, Matthew C. (January 2014). "Gene × Environment Interaction Studies Have Not Properly Controlled for Potential Confounders: The Problem and the (Simple) Solution". Biological Psychiatry. 75 (1): 18–24. doi:10.1016/j.biopsych.2013.09.006. PMC 3859520 . PMID 24135711.
