A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus

Abstract

Genome-wide association studies (GWASs) have reported many single nucleotide polymorphisms (SNPs) associated with psychiatric disorders, but knowledge is lacking regarding molecular mechanisms. Here we show that risk alleles spanning multiple genes across the 10q24.32 schizophrenia-related locus are associated in the human brain selectively with an increase in the expression of both BLOC-1 related complex subunit 7 (BORCS7) and a previously uncharacterized, human-specific arsenite methyltransferase (AS3MT) isoform (AS3MT(d2d3)), which lacks arsenite methyltransferase activity and is more abundant in individuals with schizophrenia than in controls. Conditional-expression analysis suggests that BORCS7 and AS3MT(d2d3) signals are largely independent. GWAS risk SNPs across this region are linked with a variable number tandem repeat (VNTR) polymorphism in the first exon of AS3MT that is associated with the expression of AS3MT(d2d3) in samples from both Caucasians and African Americans. The VNTR genotype predicts promoter activity in luciferase assays, as well as DNA methylation within the AS3MT gene. Both AS3MT(d2d3) and BORCS7 are expressed in adult human neurons and astrocytes, and they are upregulated during human stem cell differentiation toward neuronal fates. Our results provide a molecular explanation for the prominent 10q24.32 locus association, including a novel and evolutionarily recent protein that is involved in early brain development and confers risk for psychiatric illness.

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

“…The specific role of kinesin-1 in this process is likely derived from its preference for microtubules enriched in acetylated and GTP-bound tubulin (51,54,71), which are particularly abundant in the axon (51,72). Alterations in the expression of BORC and kinesin-1 subunits have been linked to psychiatric and neurological disorders (73)(74)(75)(76). In light of our findings, it would be of interest to investigate if aberrant transport of lysosomes in the axon contributes to the pathogenesis of these disorders.…”

Mechanisms and functions of lysosome positioning

“…Indeed, variations or mutations in components of the lysosome-positioning machinery cause various psychiatric and neurological disorders. For example, single nucleotide polymorphisms causing increased expression of the diaskedin (BORCS7) subunit of BORC are a major risk factor for schizophrenia (Duarte et al, 2016;Li et al, 2016a). Additional components of this machinery are mutated in several neurological diseases, including the p150-glued subunit of dynactin in ALS (Munch et al, 2004), Rab7 in Charcot-Marie-Tooth disease type 2B (Verhoeven et al, 2003), KIF1B in Charcot-Marie-Tooth disease type 2A (Zhao et al, 2001), KIF5A in hereditary spastic paraplegia type 10 (Reid et al, 2002) and KIF5C in cortical dysplasia with other brain malformations type 2 (Poirier et al, 2013).…”

[P3–102]: Genetic Risk for Schizophrenia and Psychosis in Alzheimer Disease

“…Such an effect has recently been described for the schizophrenia risk locus defined by rs55833108, and may similarly be present at loci that confer opposing risks for schizophrenia and AD+P. 78 A third scenario might result from the observation that a SNP and/or locus may be an eQTL for more than one gene. For example, the locus on chromosome 17 defined by rs8082590 was recently reported to show consistent disease and eQTL associations for two genes, TOM1L2 and DRG2, 77 encoding Target Of Myb1 Like 2 Membrane Trafficking Protein and Developmentally Regulated GTP Binding Protein 2, respectively.…”

“…[76][77][78] How these loci may lead to reduced AD+P risk cannot be asserted, but a few exemplars are worth discussion. First, a locus may alter expression of a single gene that has effects during neurodevelopment which increase schizophrenia risk, but when the same altered expression occurs in a brain with an active AD neurodegenerative process, it is protective.…”