The neurobiology of APOE in schizophrenia and mood disorders

Gibbons, Andrew S.; Udawela, Madhara; Jeon, Wonjin; Seo, Mi Hae; Brooks, Lucy; Dean, Brian

doi:10.2741/3729

Cited by 24 publications

(18 citation statements)

References 186 publications

(178 reference statements)

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“…In particular, LRP8 directly interacts with proteins encoded by RELN and apolipoprotein E (APOE) (Fig. 6b), in which the latter genes have been repeatedly reported conferring risk for psychosis in distinct samples [15,16,68].…”

Section: Lrp8 Participates In a Highly Interconnected Ppi Network Formentioning

confidence: 99%

Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis

Huang

Grigoroiu‐Serbanescu

et al. 2015

Mol Neurobiol

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Reelin (RELN) is identified as a risk gene for major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). However, the role of its downstream signaling molecule, the low-density lipoprotein receptor-related protein 8 (LRP8) in these illnesses is still unclear. To detect whether LRP8 is a susceptibility gene for SCZ and BPD, we analyzed the associations of single nucleotide polymorphisms (SNPs) in LRP8 in a total of 47,187 subjects (including 9379 SCZ patients; 6990 BPD patients; and 12,556 controls in a screening sample, and 1397 SCZ families, 3947 BPD patients, and 8387 controls in independent replications), and identified a non-synonymous SNP rs5174 in LRP8 significantly Ming Li and Liang Huang contributed equally to this work. Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9559-6) contains supplementary material, which is available to authorized users. , odds ratio (OR)=1.066, 95 % confidence interval (CI)=1.035-1.098). The risk SNP rs5174 was also associated with LRP8 messenger RNA (mRNA) expression in multiple brain tissues across independent samples (lowest P=0.00005). Further exploratory analysis revealed that LRP8 was preferentially expressed in fetal brain tissues. Protein-protein interaction (PPI) analysis demonstrated that LRP8 significantly participated in a highly interconnected PPI network build by top risk genes for SCZ and BPD (P=7.0×10 −4). Collectively, we confirmed that LRP8 is a risk gene for psychosis, and our results provide useful information toward a better understanding of genetic mechanism involving LRP8 underlying risk of complex psychiatric disorders.

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Section: Lrp8 Participates In a Highly Interconnected Ppi Network Formentioning

confidence: 99%

Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis

Huang

Grigoroiu‐Serbanescu

et al. 2015

Mol Neurobiol

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“…In contrast, average allelic summary odds ratios for non- APOE -related variants are ∼1.25 (Bertram and Tanzi, 2008). APOE has also been implicated in the pathophysiology of schizophrenia and mood disorders (Gibbons et al, 2011). …”

Section: The Genetics Of Human Brain Network Connectivitymentioning

confidence: 99%

Connectomic Intermediate Phenotypes for Psychiatric Disorders

Fornito¹,

Bullmore²

2012

Front. Psychiatry

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Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes (IPs) that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI) is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA, ZNF804A, and APOE, may be higher for IPs characterized at the level of distributed neural systems than at the level of spatially localized brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of the human connectome.

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“…Many of these genes encode proteins that influence cellular differentiation, cell‐fate determination, and synapse formation. One such widely examined gene is apolipoprotein E ( APOE ), which regulates axon extension and biogenesis of the cytoskeleton and has a role in synaptic plasticity [Gibbons et al, 2011]. The most recent meta‐analysis of this gene suggests the presence of a risk‐conferring variant with significant association to schizophrenia, although further studies are required to determine if the association is universal or population‐specific [Schurhoff et al, 2003; Xu et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

A re‐review of the association between the NOTCH4 locus and schizophrenia

Shayevitz

Cohen

Faraone

et al. 2012

American J of Med Genetics Pt B

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NOTCH4 has long been identified as a candidate susceptibility gene for schizophrenia, but the collective body of genetic association studies of this gene has been less than conclusive. Recently a variant in NOTCH4 was implicated as one of the most reliably associated polymorphisms observed in a genome-wide association scan of the disorder, and the collective evidence for this polymorphism now surpasses criteria for genome-wide significance. To place these developments in context, we now summarize the initial work identifying NOTCH4 as a candidate gene for schizophrenia. The results of the genome-wide association studies that have confirmed this as a risk gene, and novel bioinformatics analyses that reveal potential functional profiles of the most likely risk-conferring polymorphisms. These analyses suggest that the NOTCH4 polymorphisms most strongly associated with schizophrenia exert their effects on susceptibility by altering the efficiency and/or alternative splicing of Notch4 transcripts. Further experimental evidence should be pursued to clarify the NOTCH4-regulated molecular and cellular phenotypes of relevance to the disorder, and the functional consequences of the implicated polymorphisms in the gene.

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The neurobiology of APOE in schizophrenia and mood disorders

Cited by 24 publications

References 186 publications

Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis

Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis

Connectomic Intermediate Phenotypes for Psychiatric Disorders

A re‐review of the association between the NOTCH4 locus and schizophrenia

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