Convergence of linkage, association and GWAS findings for a candidate region for bipolar disorder and schizophrenia on chromosome 4p

Christoforou, Andrea; McGhee, Kevin A.; Morris, Stewart W.; Thomson, Pippa A.; Anderson, Susan M.; McLean, Alan W.; Torrance, Helen S.; Hellard, Stéphanie Le; Pickard, Ben; StClair, David; Muir, Walter; Blackwood, Douglas; Porteous, David J.; Evans, Kathryn

doi:10.1038/mp.2010.25

Cited by 48 publications

(35 citation statements)

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“…Comparison with other published GWA studies for bipolar disorder, excluding those with partial overlap of subjects, appears to corroborate several loci and candidate genes, including CNTNAP5 [50,61], ZNF804A [62], ZNF659 [37], SORCS2 [50,63,64], and ZNF536 [61]. A full list is provided in the Additional file 1: Table S2).…”

Section: Discussionsupporting

confidence: 65%

Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1

et al. 2014

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BackgroundRecently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).MethodsHere we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.ResultsAlthough no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.ConclusionsThe findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.

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Section: Discussionsupporting

confidence: 65%

Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1

et al. 2014

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“…These observations are in line with the notion that knockdown of these genes using short hairpin RNAs in HEK293 cells causes a significant increase in APP processing. (Reitz et al 2013) Variation in SORCS2 has also been associated with changes in temporal brain structure, (Kohannim et al 2012) bipolar disorder and schizophrenia (Christoforou et al 2011) and body mass index, (Wei et al 2012) and variation in SorCS3 is associated with ADHD. (Lionel et al 2011)…”

Section: The Vps10 Receptor Familymentioning

confidence: 99%

The role of the retromer complex in aging-related neurodegeneration: a molecular and genomic review

Reitz

2014

Mol Genet Genomics

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The retromer coat complex is a vital component of the intracellular trafficking mechanism sorting cargo from the endosomes to the trans-Golgi network or to the cell surface. In recent years, genes encoding components of the retromer coat complex and members of the vacuolar protein sorting 10 (Vps10) family of receptors which play pleiotropic functions in protein trafficking and intracellular/intercellularsignaling in neuronal and non-neuronal cells and are primary cargos of the retromer complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and frontotemporal lobar degeneration. In addition to their functions in protein trafficking, the members of the Vps10 receptor family (sortilin, SorL1, SorCS1, SorCS2, and SorCS3) modulate neurotrophic signaling pathways. Both sortilin and SorCS2 act as cell surface receptors to mediate acute responses to proneurotrophins. In addition, sortilin can modulate the intracellular response to brain-derived neurotrophic factor (BDNF) by direct control of BDNF levels and regulating anterograde trafficking of Trk receptors to the synapse. This review article summarizes the emerging data from this rapidly growing field of intracellular trafficking signaling in the pathogenesis of neurodegeneration.

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“…SORCS genes have been associated with a range of synaptopathies, including Alzheimer's disease and autism (Christoforou et al, 2011; Grupe et al, 2006; Laumet et al, 2010; Li et al, 2008; Liang et al, 2009; Lionel et al, 2011; Ollila et al, 2009; Reitz et al, 2011; Sanders et al, 2012). Impaired neuronal receptor trafficking resulting from SORCS1 mutations could contribute to defects in synaptic proteome composition and function underlying synaptopathies.…”

Section: Discussionmentioning

confidence: 99%

“…Less is known about the sorting function and endogenous cargo of the three remaining mammalian VPS10P receptors, SorCS (sortilin-related CNS expressed) 1, -2, and -3 (Hermey et al, 2004; Hermey et al, 1999; Rezgaoui et al, 2001). The three SorCS genes are expressed in complementary patterns in the brain (Hermey et al, 2004; Oetjen et al, 2014), SorCS3 localizes to synapses (Breiderhoff et al, 2013), and SORCS genes have been associated with autism, schizophrenia, bipolar disorder, ADHD, and late-onset Alzheimer's disease (Christoforou et al, 2011; Grupe et al, 2006; Laumet et al, 2010; Li et al, 2008; Liang et al, 2009; Lionel et al, 2011; Ollila et al, 2009; Reitz et al, 2011; Sanders et al, 2012). Their prominent association with synaptopathies suggests that SorCS receptors might play a role in the trafficking of synaptic components.…”

Section: Introductionmentioning

confidence: 99%

The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

Savas

Ribeiro

Wierda

et al. 2015

Neuron

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The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1 knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1–deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer's disease, suggesting that perturbed receptor trafficking contributes to defects in synaptic composition and function underlying synaptopathies.

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Convergence of linkage, association and GWAS findings for a candidate region for bipolar disorder and schizophrenia on chromosome 4p

Cited by 48 publications

References 10 publications

Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1

Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1

The role of the retromer complex in aging-related neurodegeneration: a molecular and genomic review

The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

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