A Positional Cloning Study on Schizophrenia

This Group of Genomic Research in Psychiatric Disorders (GENOP) located at the Department of Psychiatry, College of Medicine and National Taiwan University Hospital (NTUH) had completed a serial psychopathological study of schizophrenia (SCH) defined by DSM-IV criteria. The results of this GENOP included: (1) delineating 2 to 3 subtypes of schizophrenia with prospective follow-up validity; (2) finding a trait marker of impaired attention measured by continuous performance test (CPT); (3) impaired executive function assess by Wisconsin Card Sorting Test (WCST) and impaired inhibition of P50 evoked potential; (4) five dinucleotide repeat polymorphism (DRP) markers in 5 different chromosomes with significant linkage scores, including D1S251 at 1q42.1, D6S296 at 6p22 , D8S1222 at 8p14, and D15S976 at 15q14, and D22S278 at 22q12; (5) finding a significant linkage of polymorphism marker located in a neurodevelopmental gene NOTCH4 ( 6p22); and neurophysiological function related gene CHNRA7 (15q14); (6) successfully collected 700 multiplex families, collected by the collaboration between of NTUH, Taiwan - NIMH, USA in the Taiwan Schizophrenia Genetic Linkage Study (TSLS) project, with at least two siblings affected with schizophrenia in Taiwan. A genome-wide scan on this big sample will be completed recently in the laboratory of NIMH, U.S.A.. Around 300 families had also CPT data in the whole family. This is probably the biggest number of multiplex families of a single ethnicity all over the world; (7) successfully setting up DNA and cell banks as well as clinical data bank. This substantial long track of this GENOP provided convincing background for this Positional Cloning Study on Schizophrenia (POCOS). Understanding the controversial results of current linkage study on SCH world-wide, this POCOS was designed to make a break through design in the study for locating and identifying the vulnerability genes of SCH by using (1) phenomenological subtypes; (2) endophenotype defined by impaired attention (CPT) and/or impaired executive function (WCST); (3) using large enough size of samples of a single ethnicity of Taiwanese family pedigrees. Major research tasks include (1) Linkage analysis and quantitative trait loci analysis, in collaboration with the team of Harvard Medical School, on the endophenotype defined by impaired attention and impaired executive function in 300 families with at least two siblings affected with SCH; (2) Two stages of genotyping, using High Throughput technology, of dense SNP markers, around DRP markers with significant linkage scores in the NTUH and TSLS studies, with average marker interval of 30kb in 3000 subjects of 700 multiplex families (a total of 300 markers) for linkage and quantitative trait loci analysis; (3) Two stages of study on the polymorphisms and/or mutations of candidate genes using association study and TDT test. Each stage with 10 Candidate Genes in the NTUH and TSLS project, respectively. In the first stage, these are: (a) Neurodevelopmental related genes: DISC1, TRAX (1q42.1), NOTCH4 and TNF(6p21.3) and NT-3; (b) Neurotransmitter receptor genes of CHNRA7 (15q14) and NMDA related to attention impairment; (c) Neurotransmitter metabolizing enzyme gene COMT (22q11.2) related to impaired frontal lobe function; and (d) Pharmacology related genes of DRD3 and 5HTA2.