Genetic Copy Number Variants in Sib Pairs Both Affected with Schizophrenia

Genome-wide screening for DNA copy-number variations (CNVs) was conducted for ten pairs, a total of 20 cases, of affected siblings using oligonucleotide array-based CGH. We found negative symptoms were significantly more severe (p < 0.05) in the subgroup that harboring more genetic imbalance (n ≧ 13, n = number of CNV-disrupted genes) as compared with the subgroup with fewer CNVs (n ≦ 6), indicating the degree of genetic imbalance may influence the severity of schizophrenia negative symptoms. Four central nervous system (CNS) related genes including CCAAT/enhancer binding protein, delta (CEBPD, 8q11.21), retinoid X receptor, alpha (RXRA, 9q34.2), LIM homeobox protein 5 (LHX5, 12q24.13) and serine/threonine kinase 11 (STK11, 19p13.3) are recurrently (incidence ≧16.7%) disrupted by CNVs. Two genes, PVR (poliovirus receptor) and BU678720, are concordant deleted in one and two, respectively, pairs of co-affected siblings. However, we did not find significant association of this BU678720 and schizophrenia in a large case-control sample. We conclude that the high genetic loading of CNVs may as the underlying cause of schizophrenia negative symptoms, and the CNS-related genes revealed by this study warrants further investigation. Ten pairs, a total of 20 cases, of schizophrenia affected siblings were analyzed. The reference genomic DNA pools used for this study were constructed by pooling equal amounts of DNA extracted from ten healthy men or ten healthy women who live in Taiwan. Each array hybridization experiment was performed with differentially labeled gender-matched samples, one from the affected individual, and the other from the DNA control pool. To rule out probable CNPs in our ethnic group, two array hybridization experiments were performed using the male or female pooled control and the same-gender commercialized normal Caucasian samples (Promega, Madison, WI, USA).