Study Report

Reference	Lencz, T., 2013 PMID: 24253340
Citation	Lencz, T., S. Guha, et al. (2013). "Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder." Nat Commun 4: 2739.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control
Study Type	Genome-wide association study and Meta-analysis
Sample Size	904 schizophrenia cases and 1,640 controls for discovery GWAS
SNP/Region/Marker Size	762,372 SNPs
Predominant Ethnicity
Population	Ashkenazi Jewish for discovery GWAS, non-Ashkenazi for replication

Sample Diagnosis	DSM-IV
Sample Status	Discovery GWAS: the inclusion criteria specified that subjects had to be diagnosed with schizophrenia or schizoaffective disorder by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), that all four grandparents of each subject were reported by the subject to be of Ashkenazi Jewish ethnic origin, and that each subject or the subjectos legal representative has signed the informed consent form. The exclusion criteria eliminated subjects diagnosed with at least one of the following disorders: psychotic disorder due to a general medical condition, substance-induced psychotic disorder, or any Cluster A (schizotypal, schizoid or paranoid) personality disorder. Replication: six independent non-Ashkenazi schizophrenia case-control cohorts and four non-Ashkenazi bipolar case-control cohorts, as well as one Ashkenazi bipolar case-control cohort, encompassing 23,191 individuals.
Replication Size	11 independent case-control cohorts of severe psychiatric disorder (comprising 5,415 schizophrenia cases, 4,785 bipolar cases and 12,991 controls)
Technique	discovery GWAS: Illumina Human-Omni1-Quad arrays; replication: genotyped (not imputed) in nine replication cohorts using the following platforms; Affymetrix 6.0, Affymetrix 500 k and Illumina Hap550
Statistical Method	The allelic association between each SNP and the risk of schizophrenia was assessed using logistic regression under the additive model, covarying for the first two components derived from genome-wide principal components analysis; These analyses were implemented in SVS7 software. The threshold for genome-wide significance was established at P<6.56E-08 based upon a strict Bonferroni correction for 762,372 tests at alpha=0.05. After pre-phasing of the original data using SHAPEIT42, genome-wide imputation was performed using IMPUTE243 using the cosmopolitan HapMap3 reference panel. Association tests were performed on imputed genotype dosages using the SNPTEST program within the IMPUTE2 framework.
Result Summary	We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 x 10(-12) (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08-1.17) across both disorders and Pmeta=2.67 x 10(-8) (OR=1.15, 95% CI: 1.08-1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.