Association at SYNE1 in both bipolar disorder and recurrent major depression

Green, E. K.; Grozeva, Detelina; Forty, Liz; Gordon‐Smith, Katherine; Russell, Elen; Farmer, Anne; Hamshere, Marian L.; Jones, Ian; Jones, Lisa; McGuffin, Peter; Moran, Jennifer L.; Purcell, Shaun; Sklar, Pamela; Owen, Michael John; O'Donovan, Michael Conlon; Craddock, Nick

doi:10.1038/mp.2012.48

Cited by 83 publications

(68 citation statements)

References 31 publications

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“…Because the CES-D assesses depressive symptoms in the past week, it may be that phenotypic misclassification contributed to the largely null results of this study. Other loci that appear to influence depression risk have emerged from cross-disorder genetic studies (discussed in more detail later), including SYNE1 (Green et al, 2013) (a gene associated with BPD) and CACNA1C (also associated with BPD and SCZ) (CrossDisorder Group of the Psychiatric Genomics Consortium, 2013; Green et al, 2010).…”

Section: Common Genetic Variationmentioning

confidence: 99%

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

Smoller

2015

Neuropsychopharmacol

360

243

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Research into the causes of psychopathology has largely focused on two broad etiologic factors: genetic vulnerability and environmental stressors. An important role for familial/heritable factors in the etiology of a broad range of psychiatric disorders was established well before the modern era of genomic research. This review focuses on the genetic basis of three disorder categories-posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and the anxiety disorders-for which environmental stressors and stress responses are understood to be central to pathogenesis. Each of these disorders aggregates in families and is moderately heritable. More recently, molecular genetic approaches, including genome-wide studies of genetic variation, have been applied to identify specific risk variants. In this review, I summarize evidence for genetic contributions to PTSD, MDD, and the anxiety disorders including genetic epidemiology, the role of common genetic variation, the role of rare and structural variation, and the role of gene-environment interaction. Available data suggest that stress-related disorders are highly complex and polygenic and, despite substantial progress in other areas of psychiatric genetics, few risk loci have been identified for these disorders. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. The phenotypic complexity and genetic overlap among these disorders present further challenges. The review concludes with a discussion of prospects for clinical translation of genetic findings and future directions for research.

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Section: Common Genetic Variationmentioning

confidence: 99%

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

Smoller

2015

Neuropsychopharmacol

360

243

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“…Interestingly, a meta-analysis of GWAS of bipolar disorder revealed association with SYNE1 (Sklar et al, 2011), which was recently confirmed and extended to major depression (Green et al, 2013). Furthermore, exome sequencing of sporadic autism patients identified a de novo missense mutation of predicted functional consequence in SYNE1 (O'Roak et al, 2012) and a truncating de novo mutation in DST (Iossifov et al, 2012).…”

Section: Discussionmentioning

confidence: 94%

Role of DISC1 Interacting Proteins in Schizophrenia Risk from Genome‐Wide Analysis of Missense SNPs

Costas

Suárez-Rama

Carrera

et al. 2013

Annals of Human Genetics

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SummaryA balanced translocation affecting DISC1 cosegregates with several psychiatric disorders, including schizophrenia, in a Scottish family. DISC1 is a hub protein of a network of protein-protein interactions involved in multiple developmental pathways within the brain. Gene set-based analysis has been proposed as an alternative to individual analysis of single nucleotide polymorphisms (SNPs) to get information from genome-wide association studies. In this work, we tested for an overrepresentation of the DISC1 interacting proteins within the top results of our ranked list of genes based on our previous genome-wide association study of missense SNPs in schizophrenia. Our data set consisted of 5100 common missense SNPs genotyped in 476 schizophrenic patients and 447 control subjects from Galicia, NW Spain. We used a modification of the Gene Set Enrichment Analysis adapted for SNPs, as implemented in the GenGen software. The analysis detected an overrepresentation of the DISC1 interacting proteins (permuted P-value = 0.0158), indicative of the role of this gene set in schizophrenia risk. We identified seven leading-edge genes, MACF1, UTRN, DST, DISC1, KIF3A, SYNE1, and AKAP9, responsible for the overrepresentation. These genes are involved in neuronal cytoskeleton organization and intracellular transport through the microtubule cytoskeleton, suggesting that these processes may be impaired in schizophrenia.

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“…6 These two BD risk genes also showed significant associations with MDD. 7,8 Similarly, PCLO, a candidate susceptible gene for MDD identified by GWAS, 9 has also been implicated in the genetic susceptibility of BD. 10 Similarly, CREB1 has been identified as a susceptibility gene for MDD, with lines of supporting evidence.…”

Section: Introductionmentioning

confidence: 99%

Erratum: Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

Li¹,

Luo²,

M³

et al. 2013

Mol Psychiatry

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Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64 888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P = 6.32 × 10 −5 , odds ratio (OR) = 1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10 −6 ). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.

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Association at SYNE1 in both bipolar disorder and recurrent major depression

Cited by 83 publications

References 31 publications

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

Role of DISC1 Interacting Proteins in Schizophrenia Risk from Genome‐Wide Analysis of Missense SNPs

Erratum: Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

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