A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia locus.
Authors:
Ming Li, Andrew E. Jaffe, Richard E. Straub, Ran Tao, Joo Heon Shin, Yanhong Wang, Qiang Chen, Chao Li, Yankai Jia, Kazutaka Ohi, Brady J. Maher, Nicholas J. Brandon, Alan Cross, Joshua G. Chenoweth, Daniel J. Hoeppner, Huijun Wei, Thomas M. Hyde, Ronald McKay, Joel E. Kleinman, Daniel R. Weinberger
Abstract
Genome-wide association studies (GWAS) have reported many 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 locus are associated in human brain selectively with increased expression of both BORCS7 and a previously uncharacterized human-specific AS3MT isoform (AS3MTd2d3) that lacks arsenic methyltransferase activity and is more abundant in individuals with schizophrenia than in controls. Conditional expression analysis suggests that the BORCS7 and AS3MTd2d3 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 which is associated with expression of AS3MTd2d3 in both Caucasian and African American samples. The VNTR genotype predicts activity in luciferase assays and DNA methylation within the AS3MT gene. Both AS3MTd2d3 and BORCS7 are expressed in adult human neurons and astrocytes and 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 involved in early brain development and risk for psychiatric illness.
Links
Nature Medicine
PubMed
