Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents

Luo, Qiang; Chen, Qiang; Wang, Wenjia; Desrivières, Sylvane; Quinlan, Erin Burke; Jia, Tianye; Macare, Christine; Robert, Guillaume; Cui, Jing; Guedj, Mickaël; Palaniyappan, Lena; Kherif, Ferath; Banaschewski, Tobias; Bokde, Arun L.W.; Büchel, Christian; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Martinot, Jean‐Luc; Artiges, Éric; Paillère-Martinot, Marie-Laure; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Poustka, Luise; Fröhner, Juliane H.; Smolka, Michael N.; Walter, Henrik; Whelan, Robert; Callicott, Joseph H.; Mattay, Venkata S.; Pausová, Zdenka; Dartigues, Jean‐François; Tzourio, Christophe; Crivello, Fabrice; Berman, Karen F.; Li, Fēi; Paus, Tomáš; Weinberger, Daniel R.; Murray, Robin M.; Schumann, Günter; Feng, Jianfeng

doi:10.1001/jamapsychiatry.2018.4126

Cited by 56 publications

(51 citation statements)

References 72 publications

(131 reference statements)

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“…Though our sample size is smaller than prior studies (8,29), a preliminary analysis using FreeSurfer software (http://surfer.nmr.mgh.harvard.edu/) showed no detectable difference in volume between genotypes in any brain region, suggesting that MRI signal changes in A391T carriers likely result from differences in the concentrations of paramagnetic ions such as Mn (data not shown). ANOVA analyses each element showed that only Mn was statistically different between genotypes (F = 6.472, p = 0.0022, DF = 2).…”

Section: Resultsmentioning

confidence: 79%

“…Previous studies have linked the rs13107325 minor allele (T) with brain MRI changes attributed to regional volumetric differences (8,29). Given the paramagnetic properties of Mn and its known effect on MRI relaxation time (30)(31)(32), we hypothesized that the signal change resulted from changes in local concentrations of Mn and related ions.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, A391T is protective against Parkinson disorder, presumably from reduced uptake of Mn in to the pallidum or SN (10). Two recent studies associated A391T with brain MRI signal changes attributed to volumetric differences including increased gray matter in the caudate, putamen and cerebellum (8,29). MRI signal is affected by any factor influencing the magnetic field including Fe and Mn concentrations (45).…”

Section: Discussionmentioning

confidence: 99%

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The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Mealer

Jenkins

Chen

et al. 2019

Preprint

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A common missense variant (rs13107325 (C->T), A391T) in SLC39A8, a gene encoding a transporter of divalent cations including manganese (Mn), is convincingly associated with schizophrenia and has pleiotropic effects on several additional brain-related phenotypes.Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum Mn and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified Mn-related changes in human carriers of the SLC39A8 missense allele. Analysis of structural brain MRI scans from the UK Biobank showed a dose-dependent change in the ratio of T2w to T1w signal in several brain regions, presumably from altered transport of paramagnetic cations including Mn. We confirmed a specific reduction of serum Mn and showed through comprehensive profiling reduced complexity and branching of the plasma protein N-glycome in both heterozygous and homozygous minor allele carriers. N-glycome profiling of two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that hypofunction of the common missense variant exists on a spectrum with potential for reversibility.Characterizing the functional impact of this variant may enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Mealer

Jenkins

Chen

et al. 2019

Preprint

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“…Then we went on to test whether such an association was tissue specific and whether this SNP had cis-regulations on expressions of the nearby genes. For this extended exploration, we corrected for multiple comparisons between the number of nearby genes and the number of brain areas 22 . Considering the limited sample size in the UKBEC database, we also explored the Genotype Tissue Expression project (GTEx V8, including 17,382 RNA-Seq samples from 948 donors) 43,44 .…”

Section: Association Of Rs2535629 and Rs3617 With Expression Level Ofmentioning

confidence: 99%

Integrative analyses indicate an association between ITIH3 polymorphisms with autism spectrum disorder

Xie

Meng

et al. 2020

Sci Rep

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it is challenge to pinpoint the functional variants among numerous genetic variants. investigating the spatial dynamics of the human brain transcriptome for genes and exploring the expression quantitative trait loci data may provide the potential direction to identify the functional variants among autism spectrum disorders (ASD) patients. in order to explore the association of ITIH3 with ASD, the present study included three components: identifying the spatial-temporal expression of ITIH3 in the developing human brain using the expression data from the Allen institute for Brain Science; examining the cis-acting regulatory effect of SNPs on the ITIH3 expression using UK Brain expression consortium database; validating the effect of identified SNPs using a case-control study with samples of 602 cases and 604 controls. The public expression data showed that ITIH3 may have a role in the development of human brain and suggested a cis-eQTL effect for rs2535629 and rs3617 on ITIH3 in the hippocampus. Genetic analysis of the above two SNPs suggested that the over-dominant model of rs2535629 was significantly associated with decreased risk of ASD. Convergent lines of evidence supported ITIH3 rs25352629 as a susceptibility variant for ASD. Autism spectrum disorder (ASD) depicts a complex series of neurodevelopmental phenotypes resulting in a substantial burden for individuals, family and society 1-5. Epidemiological surveys show that the prevalence of ASD is about 1 in 59 children aged 8 years in America 6 and 1 in 100 children aged 6-10 years in Jilin, a city in northern China 7. The key part of ASD susceptibility is estimated to be caused by common variants 8. The application of genome-wide association studies (GWAS) in recent years has made rapid progress in the identification of genes whose variants significantly increase the susceptibility of ASD 9-14. However, due to the issue of false-positives that results from massive number of statistical tests in GWAS 15,16 , many ASD-risk genetic variants were not successfully validated across different samples 17-19. With the available public datasets, it is now possible to investigate the spatial dynamics of the human brain transcriptome for candidate genes described in previous GWAS and incorporate the expression quantitative trait loci (eQTL) derived from brain tissues, which may provide the potential direction to identify the functional variants. Such comprehensive researches have made achievements in many kinds of psychiatric disorders 20 , schizophrenia(SCZ) 21,22 , attention-deficit hyperactivity disorder(ADHD) 23 , and bipolar disorder(BP) 24 to name a few. Among the ASD susceptibility genes (TRIM33, CDH9, CNTN4, etc.) 9,10,13,14,25,26 found by GWAS, ITIH3 (inter-alpha-trypsin inhibitor heavy chain 3, containing 24 exons and spanning 14.2 kb in the genome, located in 3p21.1) was the suspicious risk gene for ASD. The single nucleotide polymorphism (SNP) rs2535629 in ITIH3 was associated with the combination of five traits, including ASD, ADHD, BP, SCZ and major depressi...

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“…This irreproducibility can significantly hamper the reliability of the identified disease signature and restrict the clinical application of the discovered DEGs . Moreover, this may be the reason why there is no objective molecular marker available for the diagnosis or treatment of SZ, and why the cause of SZ remains a profound mystery in the community of biomedical researches …”

Section: Introductionmentioning

confidence: 99%

Identification of the gene signature reflecting schizophrenia’s etiology by constructing artificial intelligence‐based method of enhanced reproducibility

Yang

Wang

et al. 2019

CNS Neurosci Ther

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Aims As one of the most fundamental questions in modern science, “what causes schizophrenia (SZ)” remains a profound mystery due to the absence of objective gene markers. The reproducibility of the gene signatures identified by independent studies is found to be extremely low due to the incapability of available feature selection methods and the lack of measurement on validating signatures’ robustness. These irreproducible results have significantly limited our understanding of the etiology of SZ. Methods In this study, a new feature selection strategy was developed, and a comprehensive analysis was then conducted to ensure a reliable signature discovery. Particularly, the new strategy (a) combined multiple randomized sampling with consensus scoring and (b) assessed gene ranking consistency among different datasets, and a comprehensive analysis among nine independent studies was conducted. Results Based on a first‐ever evaluation of methods’ reproducibility that was cross‐validated by nine independent studies, the newly developed strategy was found to be superior to the traditional ones. As a result, 33 genes were consistently identified from multiple datasets by the new strategy as differentially expressed, which might facilitate our understanding of the mechanism underlying the etiology of SZ. Conclusion A new strategy capable of enhancing the reproducibility of feature selection in current SZ research was successfully constructed and validated. A group of candidate genes identified in this study should be considered as great potential for revealing the etiology of SZ.

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Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents

Cited by 56 publications

References 72 publications

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Integrative analyses indicate an association between ITIH3 polymorphisms with autism spectrum disorder

Identification of the gene signature reflecting schizophrenia’s etiology by constructing artificial intelligence‐based method of enhanced reproducibility

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