Reelin gene variants and risk of autism spectrum disorders: An integrated meta‐analysis

Wang, Zhenling; Yuan, Hong; Zou, Li; Zhong, Rong; Zhu, Beibei; Shen, Na; Chen, Wei; Lou, Jiao; Ke, Juntao; Zhang, Ti; Wang, Weipeng; Miao, Xiaoping

doi:10.1002/ajmg.b.32222

Cited by 86 publications

(63 citation statements)

References 29 publications

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“…When the P value of Q statistic test was B0.10, or I 2 statistic C50 %, indicating a high degree of heterogeneity among these studies, random-effect model (DerSimonian-Laird) was used to estimate the summary ORs. Otherwise, P value of Q statistic test was [0.10, or I 2 statistic \50 %, suggesting no heterogeneity among these studies, and the fixed-effects model (Mantel-Haenszel) was performed [25,26]. Sensitivity analysis was performed by recalculating ORs after omitting each study in turn to study whether the overall ORs were influenced by a specific study.…”

Section: Discussionmentioning

confidence: 99%

TREM2 variants and risk of Alzheimer’s disease: a meta-analysis

Liu

Wang

2015

Neurol Sci

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Recent studies show that heterozygous variant of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of Alzheimer's disease (AD) but with inconclusive results. Here, we conducted a meta-analysis to summarize and clarify the association between TREM2 variants and AD, and examined the relationship between TREM2 genetic variant and the etiology of AD. Relevant case-control studies were retrieved and collected according to established inclusion criteria. Odds ratio (OR) and 95% confidence interval (95% CI) were used to estimate the associations between three TREM2 variants (rs75932628, rs104894002, and rs143332484) and AD. In overall meta-analysis, the summary ORs for rs75932628, rs104894002, and rs143332484 were 2.70 [95% CI: 2.24, 3.24; P < 0.001], 7.21 (95% CI: 1.28, 40.78; P = 0.025), and 1.65 (95% CI: 1.24, 2.21; P = 0.001), respectively, indicating that the TREM2 rs75932628, rs104894002, and rs143332484 may contribute to AD risk. However, sensitivity analysis showed that the results of rs104894002 and rs143332484 should be interpreted with caution, and larger sample size, particularly in different ethnicities, are needed to validate the two variants. The current meta-analysis demonstrates that TREM2 is a candidate gene for AD susceptibility, and TREM2 variant rs75932628 may be a risk factor for AD.

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Section: Discussionmentioning

confidence: 99%

TREM2 variants and risk of Alzheimer’s disease: a meta-analysis

Liu

Wang

2015

Neurol Sci

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“…Moreover, recent data suggest that a defect in reelin signaling pathway confers greater susceptibility to autism (20–25, 27). …”

Section: Discussionmentioning

confidence: 99%

“…Genetic variants in RELN have been investigated as risk factors of ASD in numerous epidemiologic studies but with inconclusive results (13–19). However, recent data collected on much larger samples and with more advanced genetic approaches indicated a relationship between reelin gene mutation and increase risk of autism, suggesting that reelin deficiency may be a vulnerability factor in the etiology of this neurodevelopmental disorder (20–27). …”

Section: Introductionmentioning

confidence: 99%

Mapping Pathological Phenotypes in Reelin Mutant Mice

et al. 2014

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Autism Spectrum Disorders (ASD) are neurodevelopmental disorders with multifactorial origin characterized by social communication deficits and the presence of repetitive behaviors/interests. Several studies showed an association between the reelin gene mutation and increased risk of ASD and a reduced reelin expression in some brain regions of ASD subjects, suggesting a role for reelin deficiency in ASD etiology. Reelin is a large extracellular matrix glycoprotein playing important roles during development of the central nervous system. To deeply investigate the role of reelin dysfunction as vulnerability factor in ASD, we assessed the behavioral, neurochemical, and brain morphological features of reeler male mice. We recently reported a genotype-dependent deviation in the ultrasonic vocal repertoire and a general delay in motor development of reeler pups. We now report that adult male heterozygous (Het) reeler mice did not show social behavior and communication deficits during male–female social interactions. Wildtype and Het mice showed a typical light/dark locomotor activity profile, with a peak during the central interval of the dark phase. However, when faced with a mild stressful stimulus (a saline injection) only Het mice showed an over response to stress. In addition to the behavioral studies, we conducted high performance liquid chromatography and magnetic resonance imaging and spectroscopy to investigate whether reelin mutation influences brain monoamine and metabolites levels in regions involved in ASD. Low levels of dopamine in cortex and high levels of glutamate and taurine in hippocampus were detected in Het mice, in line with clinical data collected on ASD children. Altogether, our data detected subtle but relevant neurochemical abnormalities in reeler mice supporting this mutant line, particularly male subjects, as a valid experimental model to estimate the contribution played by reelin deficiency in the global ASD neurobehavioral phenotype.

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“…TBR1 has established roles in patterning of the central nervous system, including regulation of neuronal identities during cortical development 14 . It is striking that among the small number of known TBR1 targets, three— RELN , GRIN2B and AUTS2 —have been implicated in ASD 3,7,8,15–18 . Of particular interest, GRIN2B is one of the six genes mutated recurrently in ASD.…”

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confidence: 99%

De novo TBR1 mutations in sporadic autism disrupt protein functions

et al. 2014

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Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

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Reelin gene variants and risk of autism spectrum disorders: An integrated meta‐analysis

Cited by 86 publications

References 29 publications

TREM2 variants and risk of Alzheimer’s disease: a meta-analysis

TREM2 variants and risk of Alzheimer’s disease: a meta-analysis

Mapping Pathological Phenotypes in Reelin Mutant Mice

De novo TBR1 mutations in sporadic autism disrupt protein functions

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