A cis -eQTL in AHI1 confers risk to schizophrenia in European populations

Ren, Zhimin; Qiu, Anli; Zhang, Ai-Qi; Huang, Lijun; Rao, Shuquan

doi:10.1016/j.neulet.2016.08.050

Cited by 5 publications

(4 citation statements)

References 35 publications

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“…Study of a homogenous sample of Arab, Israeli families identified several single nucleotide polymorphisms in the 6q23.3 region that were associated with the disorder 7 . These associations were replicated in Icelandic 8 and large European samples 9 and were supported by findings in cohorts of German and Spanish 10 and North Indian patients 11 and by QTL analysis in independent European samples 12 . Studying Ahi1 expression levels in lymphoblasts from schizophrenia patients, we found reduced expression in patients with early onset of the disorder 13 , leading us to suggest that reduced Ahi1 levels may be associated with susceptibility to schizophrenia.…”

Section: Introductionsupporting

confidence: 65%

“…We suggested that altered neuronal connectivity of Ahi1 deficient mice that results in impaired integrative processing of environmental cues, leading to blunted threat detection, may underlie their stress hyporesponsiveness 18 , 19 . Thus, the low anxiety profile of Ahi1+/− mice could ostensibly reflect stress resilience while it actually derives from a cognitive-emotional deficit that may have relevance to the pathogenesis of neuropsychiatric disorders in which the gene has been implicated 6 – 10 , 12 , 14 – 16 . However, our previous studies 18 , 19 , which showed hyporesponsiveness of Ahi1+/− mice when exposed to acute stress did not directly address this important conceptual difference.…”

Section: Introductionmentioning

confidence: 99%

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Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates

et al. 2018

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The Abelson helper integration site 1 (Ahi1) gene plays a pivotal role in brain development and is associated with genetic susceptibility to schizophrenia, and other neuropsychiatric disorders. Translational research in genetically modified mice may reveal the neurobiological mechanisms of such associations. Previous studies of mice heterozygous for Ahi1 knockout (Ahi1+/−) revealed an attenuated anxiety response on various relevant paradigms, in the context of a normal glucocorticoid response to caffeine and pentylenetetrazole. Resting-state fMRI showed decreased amygdalar connectivity with various limbic brain regions and altered network topology. However, it was not clear from previous studies whether stress-hyporesponsiveness reflected resilience or, conversely, a cognitive-emotional deficit. The present studies were designed to investigate the response of Ahi1+/− mice to chronic unpredictable stress (CUS) applied over 9 weeks. Wild type (Ahi1+/+) mice were significantly affected by CUS, manifesting decreased sucrose preference (p < 0.05); reduced anxiety on the elevated plus maze and light dark box and decreased thigmotaxis in the open field (p < 0.01 0.05); decreased hyperthermic response to acute stress (p < 0.05); attenuated contextual fear conditioning (p < 0.01) and increased neurogenesis (p < 0.05). In contrast, Ahi1+/− mice were indifferent to the effects of CUS assessed with the same parameters. Our findings suggest that Ahi1 under-expression during neurodevelopment, as manifested by Ahi1+/− mice, renders these mice stress hyporesponsive. Ahi1 deficiency during development may attenuate the perception and/or integration of environmental stressors as a result of impaired corticolimbic connectivity or aberrant functional wiring. These neural mechanisms may provide initial clues as to the role Ahi1 in schizophrenia and other neuropsychiatric disorders.

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Section: Introductionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates

et al. 2018

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“…Previous studies reported the relationship between AHI1 polymorphism and psychiatric disorders, including schizophrenia, autism spectrum, major depressive disorder and bipolar disorder (Alvarez Retuerto et al 2008 ; Ingason et al 2010 ; Torri et al 2010 ; Porcelli et al 2014 ; Ren et al 2016 ). In our study, we included SNPs that previously showed association with SCZ, BD and MDD, and we found that three SNPs that previously showed association with SCZ (Ingason et al 2010 ), rs7739635, rs9494332 and rs1475069, were associated with lithium response in our group of BD patients.…”

Section: Discussionmentioning

confidence: 99%

Abelson Helper Integration Site 1 haplotypes and peripheral blood expression associates with lithium response and immunomodulation in bipolar patients

Sakrajda,

Bilska,

Czerski

et al. 2023

Psychopharmacology

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Rationale In bipolar disorder (BD), immunological factors play a role in the pathogenesis and treatment of the illness. Studies showed the potential link between Abelson Helper Integration Site 1 (AHI1) protein, behavioural changes and innate immunity regulation. An immunomodulatory effect was suggested for lithium, a mood stabilizer used in BD treatment. Objectives We hypothesized that AHI1 may be an important mediator of lithium treatment response. Our study aimed to investigate whether the AHI1 haplotypes and expression associates with lithium treatment response in BD patients. We also examined whether AHI1 expression and lithium treatment correlate with innate inflammatory response genes. Results We genotyped seven AHI1 single nucleotide polymorphisms in 97 euthymic BD patients and found that TG haplotype (rs7739635, rs9494332) was significantly associated with lithium response. We also showed significantly increased AHI1 expression in the blood of lithium responders compared to non-responders and BD patients compared to healthy controls (HC). We analyzed the expression of genes involved in the innate immune response and inflammatory response regulation (TLR4, CASP4, CASP5, NLRP3, IL1A, IL1B, IL6, IL10, IL18) in 21 lithium-treated BD patients, 20 BD patients treated with other mood stabilizer and 19 HC. We found significantly altered expression between BD patients and HC, but not between BD patients treated with different mood stabilizers. Conclusions Our study suggests the involvement of AHI1 in the lithium mode of action. Moreover, mood-stabilizing treatment associated with the innate immunity-related gene expression in BD patients and only the lithium-treated BD patients showed significantly elevated expression of anti-inflammatory IL10, suggesting lithium’s immunomodulatory potential.

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“…Neuronal primary cilia, in particular, are essential in signal processing (3,4), including cell polarity (5), axonal guidance (3,6,7), and neurogenesis in the brain (8)(9)(10). Dysfunction of neuronal primary cilia can cause numerous adverse outcomes, including neurodevelopmental disorders (11,12), cognitive impairment (13,14), and schizophrenia (15,16). These ciliopathies are at least partially attributable to structural abnormalities in the ciliary rootlets, which extend from the basal bodies and anchor the cilia to the cell membrane (17,18).…”

Section: Introductionmentioning

confidence: 99%

Label-free visualization of ciliary rootlets in mouse brain

Murakami,

Nuriya,

et al. 2024

Preprint

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Neuronal primary cilia are important role in brain development, sensory perception and neurogenesis. Rootletin, a fibrous protein composed of coiled-coil motifs, is a major structural component of ciliary rootlets and is essential for understanding ciliary functions. However, the precise mechanisms by which Rootletin influences ciliary dynamics and impacts neuronal function remain largely unknown, primarily due to the challenges in visualizing these structures. Here, we describe a label-free, rapid, and highly sensitive method to visualize Rootletin molecules in brain tissue. This platform integrates a second harmonic generation (SHG) microscope and background reduction by a one-step chemical pretreatment. Additionally, we employ coherent anti-Stokes Raman scattering imaging to simultaneously determine the cellular regions and intracellular locations of SHG signals. By applying this multimodal multiphoton imaging to mouse hippocampus, we found that neuronal ciliary rootlets were found to exhibit highly organized specific intracellular distributions. Moreover, the formation of ciliary rootlets precedes that of primary cilia. These findings highlight the utility of our label-free imaging platform in developmental and neuroscience research, providing a new tool to characterize ciliary dynamics and neuronal function.

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A cis -eQTL in AHI1 confers risk to schizophrenia in European populations

Cited by 5 publications

References 35 publications

Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates

Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates

Abelson Helper Integration Site 1 haplotypes and peripheral blood expression associates with lithium response and immunomodulation in bipolar patients

Label-free visualization of ciliary rootlets in mouse brain

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