The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions
01 Apr 2003-American Journal of Psychiatry (American Psychiatric Publishing)-Vol. 160, Iss: 4, pp 636-645
TL;DR: The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
Abstract: Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
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TL;DR: Evidence of a gene-by-environment interaction is provided, in which an individual's response to environmental insults is moderated by his or her genetic makeup.
Abstract: In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.
7,210 citations
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
6,809 citations
TL;DR: An examines methodologies suited to identify such symptom networks and discusses network analysis techniques that may be used to extract clinically and scientifically useful information from such networks (e.g., which symptom is most central in a person's network).
Abstract: In network approaches to psychopathology, disorders result from the causal interplay between symptoms (e.g., worry → insomnia → fatigue), possibly involving feedback loops (e.g., a person may engage in substance abuse to forget the problems that arose due to substance abuse). The present review examines methodologies suited to identify such symptom networks and discusses network analysis techniques that may be used to extract clinically and scientifically useful information from such networks (e.g., which symptom is most central in a person's network). The authors also show how network analysis techniques may be used to construct simulation models that mimic symptom dynamics. Network approaches naturally explain the limited success of traditional research strategies, which are typically based on the idea that symptoms are manifestations of some common underlying factor, while offering promising methodological alternatives. In addition, these techniques may offer possibilities to guide and evaluate therape...
1,824 citations
Cites background from "The Endophenotype Concept in Psychi..."
...Of particular interest is the analysis of endophenotypes (Cannon & Keller 2006, Gottesman & Gould 2003)....
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...In psychiatry, endophenotypes have been defined as (parts of) heritable phenotypes that are internal to the organism and that promote the development of psychiatric syndromes (Gottesman & Gould 2003)....
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Book•
01 Aug 2009
TL;DR: Mental, emotional, and behavioral (MEB) disorders—which include depression, conduct disorder, and substance abuse—affect large numbers of young people.
Abstract: This report builds on a highly valued predecessor, the 1994 Institute of Medicine (IOM) report entitled Reducing Risks for Mental Disorders: Frontiers for Preventive Intervention Research. That report provided the basis for understanding prevention science, elucidating its then-existing research base, and contemplating where it should go in the future. This report documents that an increasing number of mental, emotional, and behavioral problems in young people are in fact preventable. The proverbial ounce of prevention will indeed be worth a pound of cure: effectively applying the evidence-based prevention interventions at hand could potentially save billions of dollars in associated costs by avoiding or tempering these disorders in many individuals. Furthermore, devoting significantly greater resources to research on even more effective prevention and promotion efforts, and then reliably implementing the findings of such research, could substantially diminish the human and economic toll.
1,744 citations
Cites background from "The Endophenotype Concept in Psychi..."
...These endophenotypes can serve as a simpler, more readily identifiable focus of genetic studies (Caspi and Moffitt, 2006; Gottesman and Gould, 2003; van Belzen and Heutink, 2006)....
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TL;DR: It is proposed that the default response to uncertainty is the threat response and may be related to the well known negativity bias.
1,458 citations
Cites methods from "The Endophenotype Concept in Psychi..."
...For example in the context of psychopathology, the endophenotype concept represents an alternative to the traditional nosological categorization of disease as exemplifiedby theDiagnostic and StatisticalManual (Gottesman and Gould, 2003)....
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...as exemplifiedby theDiagnostic and StatisticalManual (Gottesman and Gould, 2003)....
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References
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TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
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22,269 citations
TL;DR: Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems are indicated.
Abstract: A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
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TL;DR: This book aims to provide a history of Chinese modern art from 17th Century to the present day through the lens of 20th Century critics, practitioners, journalists, and mediaeval and modern-day critics.
Abstract: J. Craig Venter,* Mark D. Adams, Eugene W. Myers, Peter W. Li, Richard J. Mural, Granger G. Sutton, Hamilton O. Smith, Mark Yandell, Cheryl A. Evans, Robert A. Holt, Jeannine D. Gocayne, Peter Amanatides, Richard M. Ballew, Daniel H. Huson, Jennifer Russo Wortman, Qing Zhang, Chinnappa D. Kodira, Xiangqun H. Zheng, Lin Chen, Marian Skupski, Gangadharan Subramanian, Paul D. Thomas, Jinghui Zhang, George L. Gabor Miklos, Catherine Nelson, Samuel Broder, Andrew G. Clark, Joe Nadeau, Victor A. McKusick, Norton Zinder, Arnold J. Levine, Richard J. Roberts, Mel Simon, Carolyn Slayman, Michael Hunkapiller, Randall Bolanos, Arthur Delcher, Ian Dew, Daniel Fasulo, Michael Flanigan, Liliana Florea, Aaron Halpern, Sridhar Hannenhalli, Saul Kravitz, Samuel Levy, Clark Mobarry, Knut Reinert, Karin Remington, Jane Abu-Threideh, Ellen Beasley, Kendra Biddick, Vivien Bonazzi, Rhonda Brandon, Michele Cargill, Ishwar Chandramouliswaran, Rosane Charlab, Kabir Chaturvedi, Zuoming Deng, Valentina Di Francesco, Patrick Dunn, Karen Eilbeck, Carlos Evangelista, Andrei E. Gabrielian, Weiniu Gan, Wangmao Ge, Fangcheng Gong, Zhiping Gu, Ping Guan, Thomas J. Heiman, Maureen E. Higgins, Rui-Ru Ji, Zhaoxi Ke, Karen A. Ketchum, Zhongwu Lai, Yiding Lei, Zhenya Li, Jiayin Li, Yong Liang, Xiaoying Lin, Fu Lu, Gennady V. Merkulov, Natalia Milshina, Helen M. Moore, Ashwinikumar K Naik, Vaibhav A. Narayan, Beena Neelam, Deborah Nusskern, Douglas B. Rusch, Steven Salzberg, Wei Shao, Bixiong Shue, Jingtao Sun, Zhen Yuan Wang, Aihui Wang, Xin Wang, Jian Wang, Ming-Hui Wei, Ron Wides, Chunlin Xiao, Chunhua Yan, Alison Yao, Jane Ye, Ming Zhan, Weiqing Zhang, Hongyu Zhang, Qi Zhao, Liansheng Zheng, Fei Zhong, Wenyan Zhong, Shiaoping C. Zhu, Shaying Zhao, Dennis Gilbert, Suzanna Baumhueter, Gene Spier, Christine Carter, Anibal Cravchik, Trevor Woodage, Feroze Ali, Huijin An, Aderonke Awe, Danita Baldwin, Holly Baden, Mary Barnstead, Ian Barrow, Karen Beeson, Dana Busam, Amy Carver, Angela Center, Ming Lai Cheng, Liz Curry, Steve Danaher, Lionel Davenport, Raymond Desilets, Susanne Dietz, Kristina Dodson, Lisa Doup, Steven Ferriera, Neha Garg, Andres Gluecksmann, Brit Hart, Jason Haynes, Charles Haynes, Cheryl Heiner, Suzanne Hladun, Damon Hostin, Jarrett Houck, Timothy Howland, Chinyere Ibegwam, Jeffery Johnson, Francis Kalush, Lesley Kline, Shashi Koduru, Amy Love, Felecia Mann, David May, Steven McCawley, Tina McIntosh, Ivy McMullen, Mee Moy, Linda Moy, Brian Murphy, Keith Nelson, Cynthia Pfannkoch, Eric Pratts, Vinita Puri, Hina Qureshi, Matthew Reardon, Robert Rodriguez, Yu-Hui Rogers, Deanna Romblad, Bob Ruhfel, Richard Scott, Cynthia Sitter, Michelle Smallwood, Erin Stewart, Renee Strong, Ellen Suh, Reginald Thomas, Ni Ni Tint, Sukyee Tse, Claire Vech, Gary Wang, Jeremy Wetter, Sherita Williams, Monica Williams, Sandra Windsor, Emily Winn-Deen, Keriellen Wolfe, Jayshree Zaveri, Karena Zaveri, Josep F. Abril, Roderic Guigó, Michael J. Campbell, Kimmen V. Sjolander, Brian Karlak, Anish Kejariwal, Huaiyu Mi, Betty Lazareva, Thomas Hatton, Apurva Narechania, Karen Diemer, Anushya Muruganujan, Nan Guo, Shinji Sato, Vineet Bafna, Sorin Istrail, Ross Lippert, Russell Schwartz, Brian Walenz, Shibu Yooseph, David Allen, Anand Basu, James Baxendale, Louis Blick, Marcelo Caminha, John Carnes-Stine, Parris Caulk, Yen-Hui Chiang, My Coyne, Carl Dahlke, Anne Deslattes Mays, Maria Dombroski, Michael Donnelly, Dale Ely, Shiva Esparham, Carl Fosler, Harold Gire, Stephen Glanowski, Kenneth Glasser, Anna Glodek, Mark Gorokhov, Ken Graham, Barry Gropman, Michael Harris, Jeremy Heil, Scott Henderson, Jeffrey Hoover, Donald Jennings, Catherine Jordan, James Jordan, John Kasha, Leonid Kagan, Cheryl Kraft, Alexander Levitsky, Mark Lewis, Xiangjun Liu, John Lopez, Daniel Ma, William Majoros, Joe McDaniel, Sean Murphy, Matthew Newman, Trung Nguyen, Ngoc Nguyen, Marc Nodell, Sue Pan, Jim Peck, Marshall Peterson, William Rowe, Robert Sanders, John Scott, Michael Simpson, Thomas Smith, Arlan Sprague, Timothy Stockwell, Russell Turner, Eli Venter, Mei Wang, Meiyuan Wen, David Wu, Mitchell Wu, Ashley Xia, Ali Zandieh, Xiaohong Zhu T H E H U M A N G E N O M E
5,205 citations
"The Endophenotype Concept in Psychi..." refers background in this paper
...base-pair order that represents the human genome (13, 14), and although a legion of genetic linkage and association studies have been done, psychiatry has had little success in definitively identifying “culprit” genes or gene regions in the development of diseases categorized by using the field’s diagnostic classification schemas (15–18)....
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TL;DR: The data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
Abstract: Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
2,402 citations
"The Endophenotype Concept in Psychi..." refers background in this paper
...cortex is less efficient in those subjects (123)....
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...(123) associated poorer performance on a...
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TL;DR: It is proposed that three such endophenotypes — a specific abnormality in reward-related circuitry that leads to shortened delay gradients, deficits in temporal processing that result in high intrasubject intertrial variability, and deficits in working memory — are most amenable to integrative collaborative approaches that aim to uncover the causes of ADHD.
Abstract: Research on attention-deficit/hyperactivity disorder (ADHD), a highly prevalent and controversial condition, has, for the most part, been descriptive and atheoretical. The imperative to discover the genetic and environmental risk factors for ADHD is motivating the search for quantifiable intermediate constructs, termed endophenotypes. In this selective review, we conclude that such endophenotypes should be solidly grounded in the neurosciences. We propose that three such endophenotypes — a specific abnormality in reward-related circuitry that leads to shortened delay gradients, deficits in temporal processing that result in high intrasubject intertrial variability, and deficits in working memory — are most amenable to integrative collaborative approaches that aim to uncover the causes of ADHD.
1,723 citations
"The Endophenotype Concept in Psychi..." refers background in this paper
...The hunt for candidate endophenotypes has been described in the literature on several psychiatric disorders, including schizophrenia (30, 31–33, 39, 70–73), mood disorders (28, 55, 74, 75), Alzheimer’s disease (76, 77), attention deficit hyperactivity disorder (54, 78, 79), and even personality disorders (80)....
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