title: Genome-wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis-regulation of BORCS7, AS3MT, and NT5C2 in the human brain.
abstract: Chromosome 10q24.32-q24.33 is one of the most robustly supported risk loci to emerge from genome-wide association studies (GWAS) of schizophrenia. However, extensive linkage disequilibrium makes it difficult to distinguish the actual susceptibility gene(s) at the locus, limiting its value for improving biological understanding of the condition. In the absence of coding changes that can account for the association, risk is likely conferred by altered regulation of one or more genes in the region. We, therefore, used highly sensitive measures of allele-specific expression to assess cis-regulatory effects associated with the two best-supported schizophrenia risk variants (SNP rs11191419 and indel ch10_104957618_I/rs202213518) on the primary positional candidates BORCS7, AS3MT, CNNM2, and NT5C2 in the human brain. Heterozygosity at rs11191419 was associated with increased allelic expression of BORCS7 and AS3MT in the fetal and adult brain, and with reduced allelic expression of NT5C2 in the adult brain. Heterozygosity at ch10_104957618_I was associated with reduced allelic expression of NT5C2 in both the fetal and adult brain. Comparisons between cDNA ratios in heterozygotes and homozygotes for the risk alleles indicated that cis-effects on NT5C2 expression in the adult dorsolateral prefrontal cortex could be largely accounted for by genotype at these two risk variants. While not excluding effects on other genes in the region, this study implicates altered neural expression of BORCS7, AS3MT, and NT5C2 in susceptibility to schizophrenia arising from genetic variation at the chromosome 10q24 locus. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Rodrigo R R
authors.initials: RRR
authors.lastname: Duarte
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Nolan
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Deepak P
authors.initials: DP
authors.lastname: Srivastava
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Murray
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.|MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bray
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins; D015870:Gene Expression / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics
chemical_list: C000619378:BORCS7 protein, human; C558175:CNNM2 protein, human; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D016213:Cyclins; D003598:Cytoskeletal Proteins; D008780:Methyltransferases; C505756:AS3MT protein, human; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human
keywords: GWAS; allele-specific expression; functional genetics; gene expression