ADAMTSL3 as a candidate gene for schizophrenia: Gene sequencing and ultra-high density association analysis by imputation

Abstract

We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifslike-3) could illuminate a novel disease mechanism and a potentially specific target, we have used complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants that could potentially cause the association, and to identify additional possible pathogenic rare variants, we sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by resequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations.

Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia

“…Second, during adulthood, PNNs may undergo degradation, and/or lack stability, as a consequence of disregulation of ECM remodeling processes. Our findings, together with recent findings from genetic studies showing that several vulnerability genes for SZ encode PNN components and enzymes involved in ECM remodeling (Buxbaum et al, 2008; Cichon et al, 2011; Dow et al, 2011; Groszewska et al, 2011; Ripke and Consortium, 2011; Ripke et al, 2013; Ripke and Schizophrenia Working Group of the Psychiatric Genomics, 2014; Rybakowski et al, 2009). …”

C. elegans Punctin Clusters GABAA Receptors via Neuroligin Binding and UNC-40/DCC Recruitment

“…Localization and morphology of the positive cells support an exclusive neuronal expression of the mRNA. In addition, mutations in punctin-2 (ADAMTSL3), neuroligins, and DCC are directly or indirectly implicated in neuropsychiatric disorders (Dow et al, 2011;Grant et al, 2012;Jamain et al, 2003;Sü dhof, 2008). Whether Punctin-2 (ADAMTSL3) also interacts with DCC and neuroligins to control postsynaptic organization in the mammalian nervous system is therefore a tantalizing hypothesis.…”

Are There Schizophrenia Genetic Markers and Mutations? A Systematic Review and Meta-Analyses

“…(2011) [6] Whole blood samples were randomly selected from 92 schizophrenia patients from both the Munich and Aberdeen subjects.…”

“…ADAMTSL3 is a member of the ADAMTS superfamily of proteins, encompassing the 19 human ADAMTS metalloproteases and the seven non-proteolytic ADAMTS-like proteins [6].…”

“…Supporting evidence has linked the high heritability of schizophrenia (SCZ) to a combination of relatively common alleles of small effect and to a few rare alleles with relatively large effects [3] [4]. Genes like GRIK2, GRIA2, [5] ADAMTSL3 [6] and polymorphism present in the MAOA promoter region was associated with schizophrenia [7]. Due to its complex genetic architecture and joint effects among these genes, the overall effect of a gene network is expected to have a greater effect than the sum of individual effect of each gene [8].…”