BDNF Val66Met variant and age of onset in schizophrenia

Chao, Helen M.; Kao, Hung‐Teh; Porton, Barbara

doi:10.1002/ajmg.b.30619

Cited by 52 publications

(32 citation statements)

References 14 publications

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“…2 and Table III). BDNF has been previously implicated in a variety of neuropsychiatric disorders, by both animal model and human studies: depression [Pezawas et al, 2008;Sen et al, 2008], bipolar disorder [Ogden et al, 2004], anxiety, alcoholism [Rodd et al, 2007], and schizophrenia [Le- Niculescu et al, 2007a;Chao et al, 2008]. Notably, there are several candidate gene association studies to date implicating BDNF in bipolar disorder Liu et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

Patel

Le-Niculescu

Koller

et al. 2010

American J of Med Genetics Pt B

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We previously proposed and provided proof of principle for the use of a complementary approach, convergent functional genomics (CFG), combining gene expression and genetic data, from human and animal model studies, 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 [Le-Niculescu et al., 2009b]. CFG provides a fit-to-disease prioritization of genes that leads to generalizability in independent cohorts, and counterbalances the fit-to-cohort prioritization inherent in classic genetic-only approaches, which have been plagued by poor reproducibility across cohorts. We have now extended our previous work to include more datasets of GWAS, and more recent evidence from other lines of work. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder. Biological pathway analyses identified top canonical pathways, and epistatic interaction testing inside these pathways has identified genes that merit future follow-up as direct interactors (intra-pathway epistasis, INPEP). Moreover, we have put together a panel of best P-value single nucleotide polymorphisms (SNPs), based on the top candidate genes we identified. We have developed a genetic risk prediction score (GRPS) based on our panel, and demonstrate how in two independent test cohorts the GRPS differentiates between subjects with bipolar disorder and normal controls, in both European-American and African-American populations. Lastly, we describe a prototype of how such testing could be used to categorize disease risk in individuals and aid personalized medicine approaches, in psychiatry and beyond.

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Section: Discussionmentioning

confidence: 99%

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

Patel

Le-Niculescu

Koller

et al. 2010

American J of Med Genetics Pt B

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“…One meta-analysis found an elevated risk for schizophrenia in homozygous Met carriers (Gratacos et al, 2007), but another did not (Kanazawa et al, 2007). The Met allele has been associated with earlier onset of schizophrenia (Chao et al, 2008) and reductions of ERN amplitude and post-error slowing in healthy individuals (Beste et al, 2012).…”

Section: Bdnf Val 66 Metmentioning

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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“…2, and Tables I and III). Bdnf has been previously implicated in a variety of neuropsychiatric disorders, by both animal model and human studies: depression [Pezawas et al, 2008;Sen et al, 2008], bipolar disorder [Ogden et al, 2004], anxiety, alcoholism [Rodd et al, 2007], and schizophrenia [Le-Niculescu et al, 2007a;Chao et al, 2008]. Notably, there are several candidate gene association studies to date implicating Bdnf in bipolar disorder Liu et al, in press].…”

Section: Ncam1mentioning

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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BDNF Val66Met variant and age of onset in schizophrenia

Cited by 52 publications

References 14 publications

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

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

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