Intermediate phenotypes in schizophrenia genetics redux: is it a no brainer?

H, Tan; Callicott, Joseph H.; Dr, Weinberger

doi:10.1038/sj.mp.4002145

Cited by 98 publications

(70 citation statements)

References 56 publications

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“…What we are beginning to see across GWAS of complex disorders are not necessarily the same genes showing the strongest signal, but rather consistency at the level of gene families or biological pathways. The distance from genotype to phenotype may be a bridge too far for genetic-only approaches, given the intervening complex layers of epigenetics, gene expression regulation and endophenotypes [Tan et al, 2008]. Using GWAS data in conjunction with gene expression data as part of CFG or integrative genomics [Degnan et al, 2008] approaches, followed by pathway-level analysis of the prioritized candidate genes, can serve as the necessary Rosetta Stone for unraveling the genetic code of complex disorders such as bipolar disorder.…”

Section: Discussionmentioning

confidence: 99%

Convergent functional genomics of genome‐wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms

Le-Niculescu

Patel

Bhat

et al. 2008

American J of Med Genetics Pt B

180

165

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Given the mounting convergent evidence implicating many more genes in complex disorders such as bipolar disorder than the small number identified unambiguously by the firstgeneration Genome-Wide Association studies (GWAS) to date, there is a strong need for improvements in methodology. One strategy is to include in the next generation GWAS larger numbers of subjects, and/or to pool independent studies into meta-analyses. We propose and provide proof of principle for the use of a complementary approach, convergent functional genomics (CFG), as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach. With the CFG approach, the integration of genetics with genomics, of human and animal model data, and of multiple independent lines of evidence converging on the same genes offers a way of extracting signal from noise and prioritizing candidates. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder, yielding a series of novel (such as Klf12, Aldh1a1, A2bp1, Ak3l1, Rorb, Rora) and previously known (such as Bdnf, Arntl, Gsk3b, Disc1, Nrg1, Htr2a) candidate genes, blood biomarkers, as well as a comprehensive identification of pathways and mechanisms. These become prime targets for hypothesis driven follow-up studies, new drug development and personalized medicine approaches.

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Section: Discussionmentioning

confidence: 99%

Convergent functional genomics of genome‐wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms

Le-Niculescu

Patel

Bhat

et al. 2008

American J of Med Genetics Pt B

180

165

View full text Add to dashboard Cite

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“…Finally, the substantial shared genetic liability for neuropsychiatric disorders such as schizophrenia, major depressive disorder, ASD, attention deficit-hyperactivity disorder and bipolar disorder (e.g., Craddock et al, 2006a;Crespi et al, 2010;Purcell et al, 2009; Cross-Disorder Group of the Psychiatric Genomics et al, 2013), reinforces that our present diagnostic categories and symptom definitions do not map onto distinct underlying genetic etiologies. To the extent that genes cause psychiatric disorders and their signs and symptoms, they do so via their effects on brain function (Tan et al, 2008). Given the heterogeneity of present diagnostic categories, alternate phenotyping strategies are needed to understand the genetic origins and mechanisms of psychiatric disorders and to facilitate the development of more valid psychiatric nosology and more effective interventions.…”

Section: Rationale For the Use Of Neuroimaging-based Cognitive Endophmentioning

confidence: 99%

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

Manoach¹,

Agam²

2016

Innovations in Cognitive Neuroscience

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Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive-compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromallyunaffected family members, and evidence of genetic mediation. Understanding the mechanisms of error processing deficits in neuropsychiatric disorders may provide novel neural and behavioral targets for treatment and sensitive surrogate markers of treatment response. Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments. Given the dearth of effective interventions for cognitive deficits in neuropsychiatric disorders, this represents a potentially promising approach.

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“…Intermediate phenotypes, for example, have been used as clinical symptoms to reflect the underlying genetic mechanism. 11 The Positive and Negative Syndrome Scale (PANSS) can assess the intermediate phenotype of SCZ. 12 Thus, we investigated the association between locus rs11191580 and intermediate phenotypes of SCZ as evaluated by the PANSS in this study.…”

Section: Introductionmentioning

confidence: 99%

The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS

Li¹,

Jiang

Long

et al. 2016

Rev. Bras. Psiquiatr.

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Objective: Recent genome-wide association studies have identified a significant relationship between the NT5C2 variant rs11191580 and schizophrenia (SCZ) in European populations. This study aimed to validate the association of rs11191580 polymorphism with SCZ risk in a South Chinese Han population. The relationship of this polymorphism with the severity of SCZ clinical symptoms was also explored. Methods: A case-control study was performed in 462 patients with SCZ and 598 healthy controls. rs11191580 was genotyped by the Sequenom MassARRAY iPLEX platform. A total of 459 SCZ patients completed the Positive and Negative Syndrome Scale (PANSS) evaluation. Data were analyzed by PLINK software. Results: We confirmed an association of the rs11191580 polymorphism with SCZ risk in South Chinese Han under a dominant genetic model (OR adj = 0.769; 95%CI adj = 0.600-0.984; p adj = 0.037). PANSS scores showed a significant association between variant rs11191580 and total score (p adj = 0.032), lack of response scale score (p adj = 0.022), and negative scale score (additive: p adj = 0.004; dominant: p adj = 0.016; recessive: p adj = 0.021) after data were adjusted for age and sex. Conclusion: NT5C2 variant rs11191580 conferred susceptibility to SCZ and affected the clinical symptoms of SCZ in a South Chinese Han population.

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Intermediate phenotypes in schizophrenia genetics redux: is it a no brainer?

Cited by 98 publications

References 56 publications

Convergent functional genomics of genome‐wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms

Convergent functional genomics of genome‐wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS

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