To identify susceptibility loci for schizophrenia, we performed a two-stage genome-wide association study (GWAS) of schizophrenia in the Han Chinese population (GWAS: 746 individuals with schizophrenia and 1,599 healthy controls; validation: 4,027 individuals with schizophrenia and 5,603 healthy controls). We identified two susceptibility loci for schizophrenia at 6p21-p22.1 (rs1233710 in an intron of ZKSCAN4, P(combined) = 4.76 × 10(-11), odds ratio (OR) = 0.79; rs1635 in an exon of NKAPL, P(combined) = 6.91 × 10(-12), OR = 0.78; rs2142731 in an intron of PGBD1, P(combined) = 5.14 × 10(-10), OR = 0.79) and 11p11.2 (rs11038167 near the 5' UTR of TSPAN18, P(combined) = 1.09 × 10(-11), OR = 1.29; rs11038172, P(combined) = 7.21 × 10(-10), OR = 1.25; rs835784, P(combined) = 2.73 × 10(-11), OR = 1.27). These results add to previous evidence of susceptibility loci for schizophrenia at 6p21-p22.1 in the Han Chinese population. We found that NKAPL and ZKSCAN4 were expressed in postnatal day 0 (P0) mouse brain. These findings may lead to new insights into the pathogenesis of schizophrenia.

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Enzyme replacement therapy (ERT) effectively reverses storage in several lysosomal storage diseases. However, improvement in brain is limited by the blood-brain barrier except in the newborn period. In this study, we asked whether this barrier could be overcome by higher doses of enzyme than are used in conventional trials. We measured the distribution of recombinant human ␤-glucuronidase (hGUS) and reduction in storage by weekly doses of 0.3-40 mg͞kg administered i.v. over 1-13 weeks to mucopolysaccharidosis type VII mice immunotolerant to recombinant hGUS. Mice given up to 5 mg͞kg enzyme weekly over 3 weeks had moderate reduction in meningeal storage but no change in neocortical neurons. Mice given 20 -40 mg͞kg three times over 1 week showed no reduction in storage in any area of the CNS except the meninges. In contrast, mice receiving 4 mg͞kg per week for 13 weeks showed clearance not only in meninges but also in parietal neocortical and hippocampal neurons and glia. Mice given 20 mg͞kg once weekly for 4 weeks also had decreased neuronal, glial, and meningeal storage and averaged 2.5% of wild-type hGUS activity in brain. These results indicate that therapeutic enzyme can be delivered across the blood-brain barrier in the adult mucopolysaccharidosis type VII mouse if administered at higher doses than are used in conventional ERT trials and if the larger dose of enzyme is administered over a sufficient period. These results may have important implications for ERT for lysosomal storage diseases with CNS involvement.␤-glucuronidase deficiency ͉ immune tolerance ͉ lysosomal storage disease ͉ mannose-6-phosphate receptor T he mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases (LSD) caused by the deficiency of enzymes needed for the stepwise degradation of glycosaminoglycans (GAGs). The widespread lysosomal accumulation of undegraded GAGs leads to progressive cellular and organ dysfunction (1). Current treatments for patients with MPSs include hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) (2, 3). MPS type VII (also known as Sly disease) results from deficiency of ␤-D-glucuronoside glucuronosohydrolase (GUS; EC 3.2.1.31) and is inherited as an autosomal recessive trait. Affected patients share many clinical features with patients with other MPSs, including shortened life span, mental retardation, organomegaly, and bone and joint abnormalities, that are collectively referred to as dysostosis multiplex (4). The murine model of MPS VII has proven valuable for the evaluation of novel therapies for LSDs, including bone marrow transplantation, neural progenitor cell transplantation, somatic cell gene replacement therapy, and ERT (5).Previous studies have shown that i.v. injection of a fixed-dose of recombinant murine ␤-glucuronidase (mGUS) initiated at birth reduced pathological evidence of disease and prevented some of the learning, memory, and hearing deficits in the MPS VII mouse (6). However, recombinant mGUS reduced lysosomal storage in the neurons of the brain only i...