Progress in the Genetics of Polygenic Brain Disorders: Significant New Challenges for Neurobiology

McCarroll, Steven A.; Hyman, Steven E.

doi:10.1016/j.neuron.2013.10.046

Cited by 80 publications

(70 citation statements)

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“…Genetic studies have the potential to identify molecular mechanisms of MDD vulnerability (53), but even mega-and meta-analyses of large genome-wide association studies (GWAS) have not identified genetic variants associated with MDD that survive genome-wide statistical correction (54,55). Nominally significant associations will include many false-positives.…”

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confidence: 99%

Brain galanin system genes interact with life stresses in depression-related phenotypes

Juhász

Hullám

Eszlári

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.galanin receptors | mood disorders | network-based analysis | neurogenesis | transmitter coexistence M ajor depressive disorder (MDD) is a common and serious disease afflicting more women than men, and a leading cause of disability worldwide, associated with much suffering and major costs for society (1, 2). Environmental psychosocial stressors are important in pathogenesis, because episodes are usually preceded by adverse life events, and early childhood experiences of physical and emotional abuse and parental neglect are important vulnerability factors (3, 4). Genetic vulnerability is significant with a heritability of about 35% (5). We remain ignorant about the brain processes that translate these genetic and environmental influences into depressive symptoms or risk. A major clue is that effective antidepressant drugs act directly or indirectly to enhance neurotransmission in serotonin (5-HT) and norepinephrine monoamine pathways, proving the monoamine hypothesis of depression (6-8). Many other candidate mechanisms have been identified in anatomical, pharmacological, and behavioral studies of stress in rodents. However, the demonstration of stateor trait-related abnormalities in human monoamine or other neural systems remains frustratingly elusive, despite modern brain-imaging methods. To determine whether the neuropeptide galanin has a role in depression, we used a unique Bayesian systems-based analysis to dissect out the influ...

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confidence: 99%

Brain galanin system genes interact with life stresses in depression-related phenotypes

Juhász

Hullám

Eszlári

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Epidemiologic, clinical and experimental data indicates that a majority of brain disorders are multifactorial disorders with strong and complex genetic component [1][2][3]. Among those disorders are schizophrenia (SCZ) [4], posttraumatic stress disorder (PTSD) [5], and ischemic stroke (IS) [6].…”

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confidence: 99%

Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke

Boyajyan¹

2014

IJGG

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Abstract:Epidemiologic, clinical and experimental data indicates that a majority of brain disorders including schizophrenia (SCZ), posttraumatic stress disorder (PTSD), and ischemic stroke (IS) are multifactorial disorders with strong and complex genetic component. Identification of all genetic variations associated with these disorders may sufficiently contribute to understanding of their basic pathomechanisms and encourage development of new innovative approaches to their early diagnosis and treatment. The aim of this review article is to provide overview of our recent studies on evaluation of potential association of SCZ, PTSD and IS with functional single nucleotide polymorphisms (SNPs) of synaptic plasticity and apoptosis regulatory genes in Armenian population. Here, our attention was focused on genes encoding netrin G1 (NTNG1), brain-derived neurotrophic factor (BDNF), complexin-2 (CPLX2), nerve growth factor (NGF) and its receptor (NGFR), annexin family proteins -annexin A5 and annexin A11 (ANXAV, ANXA11), and B-cell lymphoma 2 (Bcl-2) family proteins -Bcl-2 proper and Bcl-2-associated X protein (BCL2, BAX). Genomic DNA samples of diseased and healthy individuals were genotyped for a number of SNPs of the mentioned genes using polymerase chain reaction with sequence-specific primers (PCR-SSP). The significance of differences in genotype and allele frequencies and minor allele carriage between patients and healthy control subjects was determined using Pearson's Chi-square test. P-values less than 0.05 were considered statistically significant. Significant associations were found between: (1) SCZ and BDNF rs6265, CPLX2 rs1366116, rs3892909, NGF rs6330, rs4839435, NGFR rs734194, rs11466155, rs2072446, ANXAV rs11575945, BAX rs1057369 SNPs; (2) PTSD and CPLX2 rs1366116, BCL2 rs956572 SNPs; (3) IS and NTNG1 rs628117, CPLX2 rs1366116, ANXAV rs11575945 SNPs. The obtained results indicated the involvement of genetically determined alterations in synaptic plasticity and apoptosis in pathomechanisms of SCZ, PTSD and IS. The minor T allele of the CPLX2 gene rs1366116 polymorphism represents risk factor for all studied diseased conditions indicating important functional significance of this genetic variation in maintenance of synaptic plasticity. Another important conclusion of these studies is that minor alleles of some polymorphic variants of genes, encoding synaptic plasticity and apoptosis regulatory proteins, may play a protective role relative to SCZ decreasing the risk for development of this disorder. In summary, our studies emphasize the important contribution of changes in synaptic plasticity and apoptosis regulation to pathomechanisms of SCZ, PTSD, and IS as well as significant input of genetic factors to these changes.

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“…Schizophrenia is highly heritable, but unlike diseases caused by a single, highly penetrant mutation (causing a phenotype with high probability), in schizophrenia the large aggregate risk attributable to genes is seen to have a polygenic basis. Disease liability is being mapped to hundreds, perhaps ultimately more than a thousand, genetic loci, each contributing a small increment of risk 1,2,4 . Further, many of the risk-associated genetic variants (risk alleles) for schizophrenia also contribute to the risk of bipolar disorder, autism, depression and other psychiatric disorders 5 .…”

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confidence: 99%

“…The ability to study these networks is more likely than studying individual genes to yield insight into schizophrenia mechanisms and to suggest drug targets. For example, a possible protein network arising from the schizophrenia genetic data is involved in the postsynaptic specialization of excitatory neurons [2][3][4] . Despite a wealth of genetic findings, further investment in gene discovery is needed.…”

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confidence: 99%

“…Despite a wealth of genetic findings, further investment in gene discovery is needed. Each risk allele discovered identifies a gene with some role in pathogenesis, and provides a new piece in the jigsaw puzzle from which important networks and pathways emerge 4 . A more difficult question concerns the selection of living systems, cells or animal models for the functional analysis of alleles and pathways.…”

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Perspective: Revealing molecular secrets

Hyman

2014

Nature

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Progress in the Genetics of Polygenic Brain Disorders: Significant New Challenges for Neurobiology

Cited by 80 publications

References 70 publications

Brain galanin system genes interact with life stresses in depression-related phenotypes

Brain galanin system genes interact with life stresses in depression-related phenotypes

Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke

Perspective: Revealing molecular secrets

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