SPOCK3, a risk gene for adult ADHD and personality disorders

Weber, Heike; Scholz, Claus‐Jürgen; Jacob, Christian; Heupel, Julia; Kittel‐Schneider, Sarah; Erhardt, Angelika; Hempel, Susanne; Schmidt, Brigitte; Kiel, Tilman; Gessner, Alexandra; Lesch, Klaus‐Peter; Reif, Andreas

doi:10.1007/s00406-013-0476-2

Cited by 22 publications

(13 citation statements)

References 55 publications

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“…Genome‐wide association studies (GWAS) [Neale et al, ; Lasky‐Su et al, ,; Lesch et al, ; Mick et al, ; Neale et al, ; Hinney et al, ; Stergiakouli et al, ; Ebejer et al, ; Yang et al, ; Weber et al, ; Sánchez‐Mora et al, ; Zayats et al, ] have revealed additional candidate genes (e.g., CDH13, SPOCK3, KCNC1, KCNIP1, KCNIP4), although these variants have not achieved genome‐wide significance [Franke et al, ; Neale et al, ; Hinney et al, ; Sánchez‐Mora et al, ]. The most consistent finding is the CDH13 gene, which has been implicated in two family‐based GWAS [Lasky‐Su et al, ; Neale et al, ] and two case‐control GWAS [Lesch et al, ; Neale et al, ].…”

Section: Introductionmentioning

confidence: 99%

Pathway analysis in attention deficit hyperactivity disorder: An ensemble approach

Mooney

McWeeney

Faraone

et al. 2016

American J of Med Genetics Pt B

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Despite a wealth of evidence for the role of genetics in attention deficit hyperactivity disorder (ADHD), specific and definitive genetic mechanisms have not been identified. Pathway analyses, a subset of gene-set analyses, extend the knowledge gained from genome-wide association studies (GWAS) by providing functional context for genetic associations. However, there are numerous methods for association testing of gene sets and no real consensus regarding the best approach. The present study applied six pathway analysis methods to identify pathways associated with ADHD in two GWAS datasets from the Psychiatric Genomics Consortium. Methods that utilize genotypes to model pathway-level effects identified more replicable pathway associations than methods using summary statistics. In addition, pathways implicated by more than one method were significantly more likely to replicate. A number of brain-relevant pathways, such as RhoA signaling, glycosaminoglycan biosynthesis, fibroblast growth factor receptor activity, and pathways containing potassium channel genes, were nominally significant by multiple methods in both datasets. These results support previous hypotheses about the role of regulation of neurotransmitter release, neurite outgrowth and axon guidance in contributing to the ADHD phenotype and suggest the value of cross-method convergence in evaluating pathway analysis results.

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Section: Introductionmentioning

confidence: 99%

Pathway analysis in attention deficit hyperactivity disorder: An ensemble approach

Mooney

McWeeney

Faraone

et al. 2016

American J of Med Genetics Pt B

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“…In our Spock3 -deficient mice, the corticostriatal information processing might also be altered, because their corticostriatal neuronal circuits were moderately impaired during brain development. Furthermore, a recent genome-wide association study raises the possibility that Spock3 might be an ADHD-related gene [41]. Because the Spock3- mutant mice exhibited no hyperactivity, these results together suggest that Spock3- mutant mice might be an animal model of attention deficit disorder, included in ADHD, in which carelessness but not hyperactivity is dominant [42].…”

Section: Discussionmentioning

confidence: 87%

Structural Abnormalities of Corpus Callosum and Cortical Axonal Tracts Accompanied by Decreased Anxiety-Like Behavior and Lowered Sociability in Spock3-Mutant Mice

Yamamoto

Uchiyama²,

Nara³

et al. 2014

Dev Neurosci

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Spock3/Testican-3 is a nervous system-expressed heparan sulfate proteoglycan belonging to a subgroup of the BM-40/SPARC/osteonectin family, the role of which in brain development is unclear. Because Spock1, a member of the Spock family, inhibits their attachment to substrates and the neurite outgrowth of cultured neuronal cells, Spock3 is also thought to be similarly involved in the neuronal development. In the present study, we established a Spock3-mutant mouse harboring a deletion extending from the presumptive upstream regulatory region to exon 4 of the Spock3 locus and performed histological and behavioral studies on these mutant mice. In wild-type (WT) mice, all Spock members were clearly expressed during brain development. In adults, intense Spock1 and Spock2 expressions were observed throughout the entire brain; whereas, Spock3 expression was no longer visible except in the thalamic nuclei. Thus, Spock3 expression is mostly confined to the developmental stage of the brain. In adult mutant mice, the cells of all cortical layers were swollen. The corpus callosum was narrowed around the central region along the rostral-caudal axis and many small spaces were observed without myelin sheaths throughout the entire corpus callosum. In addition, the cortical input and output fibers did not form into thick bundled fibers as well as the WT counterparts did. Moreover, a subpopulation of corticospinal axonal fibers penetrated into the dorsal striatum with moderately altered orientations. Consistent with these modifications of brain structures, the mutant mice exhibited decreased anxiety-like behavior and lowered sociability. Together, these results demonstrate that Spock3 plays an important role in the formation or maintenance of major neuronal structures in the brain.

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“…One of these SNPs (rs10983304) associated with NEO-PI-R-neuroticism leads to alternative splicing (https://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm). Functional genetic variants resulting in post-transcriptional alternative splicing have been implicated for other aADHD, Bipolar Disorder, Autism-Spectrum-Disorder, and personality traits related genes (Sharp et al 2014;Waltes et al 2014;Weber et al 2014). These findings may indicate small pleiotropic effects of single ASTN2 variants conferring overlapping, respective contrasting risks for ADHD, comorbid disorders, and ADHD related adult personality traits.…”

Section: Discussionmentioning

confidence: 98%

The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits

et al. 2016

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Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N = 592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p = 0.025). This was not observed in the adult case-control sample alone, but retained in the combined sample (nominal p = 0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits.

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SPOCK3, a risk gene for adult ADHD and personality disorders

Cited by 22 publications

References 55 publications

Pathway analysis in attention deficit hyperactivity disorder: An ensemble approach

Pathway analysis in attention deficit hyperactivity disorder: An ensemble approach

Structural Abnormalities of Corpus Callosum and Cortical Axonal Tracts Accompanied by Decreased Anxiety-Like Behavior and Lowered Sociability in Spock3-Mutant Mice

The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits

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