Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks

Barešić, Anja; Nash, Alexander J; Dahoun, Tarik; Howes, Oliver; Lenhard, Boris

doi:10.1038/s41380-019-0518-x

Cited by 24 publications

(20 citation statements)

References 85 publications

(120 reference statements)

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“…This gene usually encodes a transcription factor (e.g., SOX9), and several transcription factors form a single regulatory network for a particular process during embryonic development and differentiation (see above). The usage of the GRB concept also contributes to a better elucidation of the biological effects of single nucleotide polymorphisms (SNPs), especially those found in non-coding gene regions (commonly in non-coding regions lay about 95% of hits obtained through whole genome-wide association studies, GWAS) [ 133 , 134 ]. Since the mid-1970s it has been known that non-coding elements have had crucial role in human evolution.…”

Section: Willams-beuren Syndrome and Schizophreniamentioning

confidence: 99%

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

et al. 2020

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The neural crest hypothesis states that the phenotypic features of the domestication syndrome are due to a reduced number or disruption of neural crest cells (NCCs) migration, as these cells differentiate at their final destinations and proliferate into different tissues whose activity is reduced by domestication. Comparing the phenotypic characteristics of modern and prehistoric man, it is clear that during their recent evolutionary past, humans also went through a process of self-domestication with a simultaneous prolongation of the period of socialization. This has led to the development of social abilities and skills, especially language, as well as neoteny. Disorders of neural crest cell development and migration lead to many different conditions such as Waardenburg syndrome, Hirschsprung disease, fetal alcohol syndrome, DiGeorge and Treacher-Collins syndrome, for which the mechanisms are already relatively well-known. However, for others, such as Williams-Beuren syndrome and schizophrenia that have the characteristics of hyperdomestication, and autism spectrum disorders, and 7dupASD syndrome that have the characteristics of hypodomestication, much less is known. Thus, deciphering the biological determinants of disordered self-domestication has great potential for elucidating the normal and disturbed ontogenesis of humans, as well as for the understanding of evolution of mammals in general.

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Section: Willams-beuren Syndrome and Schizophreniamentioning

confidence: 99%

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

et al. 2020

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“…This makes it difficult to understand how their genetic variation contributes to the etiology of these complex phenotypes. The risk SNPs are however consistently reported to be significantly enriched in regulatory regions ( 9 , 11 – 13 , 16 , 17 ) and, based on topological organization of the genome, linked to additional non-coding elements regulating not only proximal but also distant genes ( 18 , 19 ). Along this line, a recent cross-disorder GWAS of eight common psychiatric disorders identified 109 pleiotropic loci affecting more than one psychiatric disorder ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

Role of DNA Methylation in Mediating Genetic Risk of Psychiatric Disorders

Starnawska

Demontis

2021

Front. Psychiatry

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Psychiatric disorders are common, complex, and heritable conditions estimated to be the leading cause of disability worldwide. The last decade of research in genomics of psychiatry, performed by multinational, and multicenter collaborative efforts on hundreds of thousands of mental disorder cases and controls, provided invaluable insight into the genetic risk variants of these conditions. With increasing cohort sizes, more risk variants are predicted to be identified in the near future, but there appears to be a knowledge gap in understanding how these variants contribute to the pathophysiology of psychiatric disorders. Majority of the identified common risk single-nucleotide polymorphisms (SNPs) are non-coding but are enriched in regulatory regions of the genome. It is therefore of great interest to study the impact of identified psychiatric disorders' risk SNPs on DNA methylation, the best studied epigenetic modification, playing a pivotal role in the regulation of transcriptomic processes, brain development, and functioning. This work outlines the mechanisms through which risk SNPs can impact DNA methylation levels and provides a summary of current evidence on the role of DNA methylation in mediating the genetic risk of psychiatric disorders.

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“…SNPs are generally considered to affect the expression of neighboring genes and therefore the genes in close proximity tend to be regarded as risk genes. Obviously, this ignores the fact that gene expression may be influenced by long-range regulators remote from their transcription start sites [4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Prioritization of schizophrenia risk genes from GWAS results by integrating multi-omics data

Fan

et al. 2021

Transl Psychiatry

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Schizophrenia (SCZ) is a polygenic disease with a heritability approaching 80%. Over 100 SCZ-related loci have so far been identified by genome-wide association studies (GWAS). However, the risk genes associated with these loci often remain unknown. We present a new risk gene predictor, rGAT-omics, that integrates multi-omics data under a Bayesian framework by combining the Hotelling and Box–Cox transformations. The Bayesian framework was constructed using gene ontology, tissue-specific protein–protein networks, and multi-omics data including differentially expressed genes in SCZ and controls, distance from genes to the index single-nucleotide polymorphisms (SNPs), and de novo mutations. The application of rGAT-omics to the 108 loci identified by a recent GWAS study of SCZ predicted 103 high-risk genes (HRGs) that explain a high proportion of SCZ heritability (Enrichment = 43.44 and $$p = 9.30 \times 10^{ - 9}$$ p = 9.30 × 1 0 − 9 ). HRGs were shown to be significantly ($$p_{\mathrm{adj}} = 5.35 \times 10^{ - 7}$$ p adj = 5.35 × 1 0 − 7 ) enriched in genes associated with neurological activities, and more likely to be expressed in brain tissues and SCZ-associated cell types than background genes. The predicted HRGs included 16 novel genes not present in any existing databases of SCZ-associated genes or previously predicted to be SCZ risk genes by any other method. More importantly, 13 of these 16 genes were not the nearest to the index SNP markers, and them would have been difficult to identify as risk genes by conventional approaches while ten out of the 16 genes are associated with neurological functions that make them prime candidates for pathological involvement in SCZ. Therefore, rGAT-omics has revealed novel insights into the molecular mechanisms underlying SCZ and could provide potential clues to future therapies.

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Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks

Cited by 24 publications

References 85 publications

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

Role of DNA Methylation in Mediating Genetic Risk of Psychiatric Disorders

Prioritization of schizophrenia risk genes from GWAS results by integrating multi-omics data

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