Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies

Arnedo, Javier; Švrakić, Dragan M.; Val, Coral del; Romero-Záliz, Rocío; Hernández-Cuervo, Helena; Fanous, Ayman H.; Pato, Michele T.; Pato, Carlos N.; Erausquin, Gabriel A. de; Cloninger, C. Robert; Zwir, Igor

doi:10.1176/appi.ajp.2014.14040435

Cited by 222 publications

(160 citation statements)

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“…Third, as to the underlying neurobiology and possible treatment interventions of TMS in patients with schizophrenia, the clinical diagnostic issue of the heterogeneity of the disorder, which is a typical characteristic of schizophrenia, is not taken into account [6] . Although the symptoms may be common, schizophrenia may have many different causes that are influenced by genetic and environmental factors, resulting in a very heterogenic population of patients [7] .…”

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confidence: 99%

Transcranial magnetic stimulation for schizophrenia: potential and risks

Bosch¹,

Yeo²,

Staudte³

et al. 2017

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Section: For Reprints Contact: Service@oaepublishcommentioning

confidence: 99%

Transcranial magnetic stimulation for schizophrenia: potential and risks

Bosch¹,

Yeo²,

Staudte³

et al. 2017

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“…In addition, if each gene had a tenuous connection with the development of the disease, a cluster association increased the risk by 70%-100%. [21] Regarding the combination of genes that have a limited number of variations, it was stated that there is the simultaneous presence of a predisposition to the schizoid state with characteristic changes of thinking and of creativity. It should be noted that the average life expectancy (26-32.3 years) [6] in this historical period at lowprogredient forms of endogenous diseases (debuting in 20-25 years) reduced the probability, because of high-risk habitats, of reaching the final or even psychotic deployed stages.…”

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confidence: 99%

Creativity as a Determinant of the Development of Homo Sapiens

Kruglov¹

2016

Int J Biomed

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This work was undertaken to determine the genesis and role of creativity (Cr) in the formation of mental qualities that gave Homo sapiens (HS) the evolutionary advantages in intra-and interspecific competition during the period of the intraspecific bifurcation of hominids on the border of the Middle and Upper Paleolithic. Creativity allowed HS to design the adaptive forms of purposeful behavior corresponding to the conditions and the degree of uncertainty, and create stable mental constructs, in the absence of perceptual sources, that do not require reactive behavior. Visualization of a target image, which originally had an applied and instructional value in the process of semantic filling, was transformed into a symbol, which, getting the qualities of the perceptual source, loses its connection to the primary value and initiates the creation of qualitatively new needs for hominids: bilateral (direct and inverse) relations in the system "subject-symbol." The ability to produce the prognostic hypothesis with expansion of the operating range of the HS mind allowed the ability to search and change the tactics of an adaptive behavior, which gave the results: improvements in quality of life and an increase in life expectancy (genetically fixed); domination in intraand interspecific competition; the emergence of new operating systems of the psyche, including the emergence and development of symbolic thought. As a criterion of creativity, with the potential ability for quantitative measurement, we propose the value of deviation of creative oscillations ("proposal" of a creative individual) from the boundaries between stereotypes: for the cognition sphere, a deviation from the border between recognizable and unrecognizable; for the social sphere, between acceptable and unacceptable. (Int J Biomed. 2016; 6(4):298-302.)

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“…Given that the genetic architecture of psychiatric disorders is such that very many small effect loci, but not many large effect loci have been found to contribute to risk [58,109], it appears unlikely that clustering approaches based on genetic data will be very informative, and suggests that claims to the opposite [159] may need to be reconsidered.…”

Section: Discussionmentioning

confidence: 99%

“…Reports of the successful detection of schizophrenia subtypes based on genetic data have been met with great interest as well as with skepticism [159], but to date no such genotype based sub-classification has withstood the test of time and replication. Motivated by preliminary positive results based on simulated, unstructured genotype data, we set out to explore the conditions under which genotype based clustering can achieve reasonable separation between simulated case subtypes.…”

Section: Genetic Heterogeneitymentioning

confidence: 99%

“…Some merely aimed at identifying the presence of genetic heterogeneity in a population [158], while others had the more ambitious goal of identifying genetic subtypes and grouping individuals accordingly [159]. However, while Arnedo et al [159] reported to find evidence for distinct schizophrenia subtypes, this claim has been heavily disputed on a number of grounds (see PubMed discussion at http://www.ncbi.nlm.nih.gov/pubmed/25219520). While the potential benefit of identifying genetic clusters is large, it is not clear whether clustering methods are powerful enough to achieve this feat.…”

Section: Introductionmentioning

confidence: 99%

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The genetic architecture of psychiatric disorders

Maier¹

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The genetic nature of psychiatric disorders was observed by clinicians long before DNA had been identified as the molecule of inheritance. The greatest identified risk factor of many psychiatric disorders still is a positive family history. Until recently this knowledge has not contributed substantially to treatment efforts or to a better understanding of the disease processes because we lacked the necessary genetic data. Advances in genotyping technologies have brought an end to this data shortage which is leading to a better understanding of the genetic architecture of psychiatric disorders. Two patterns started to emerge which were uncommon in earlier studied Mendelian disorders. (i) most of the genetic part of disease risk is conferred by a large number of genetic loci of small effect, and (ii) genetic loci often influence a large number of traits at the same time. While this is true of many traits ("complex" traits), these two phenomena (polygenicity and pleiotropy) are particularly pronounced in psychiatric disorders. This has wide-reaching consequences for the analysis and interpretation of genetic data and provides challenges as well as opportunities. This thesis focuses on two areas in particular: genetic heterogeneity and genetic risk prediction.Genetic heterogeneity in a phenotypically homogenous group describes a situation where different and distinct genetic risk profiles are causing similar symptoms in different people.This can be easily identified under a Mendelian inheritance pattern, but proves to be challenging under polygenicity. The presence of genetic heterogeneity can limit the accuracy of genetic risk prediction.The aim of genetic risk prediction is to use the information that has been gathered on the effects of genetic loci to estimate the genetic liability of an individual to develop a disease.Here, pleiotropy offers an opportunity to increase the accuracy of genetic prediction by leveraging information from multiple diseases at the same time.The aim in this thesis is to describe several projects which center around the two concepts of genetic risk prediction based on multiple traits and of genetic heterogeneity. Chapter 1 sets the scene with an overview of recently developed polygenic methods. Chapter 2 deals with the effects of genetic heterogeneity on heritability estimates and demonstrates how genetic heterogeneity might contribute to the phenomenon of missing heritability, which is 3 the discrepancy between twin study heritability estimates and the variance explained by the sum of individual genetic loci. Chapter 3 addresses the question of whether genotype clustering can detect groups with different genetic risk profiles. Chapter 4 describes the implementation of a multivariate extension to the univariate Best Linear Unbiased Prediction (BLUP) method and its application to five psychiatric traits. Chapters 4 and 5 investigate whether this multivariate BLUP model can be approximated when only summary statistics, not individual level genotype data, are available for the predi...

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Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies

Abstract: Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.

Cited by 222 publications

References 42 publications

Transcranial magnetic stimulation for schizophrenia: potential and risks

Transcranial magnetic stimulation for schizophrenia: potential and risks

Creativity as a Determinant of the Development of Homo Sapiens

The genetic architecture of psychiatric disorders

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