Large genomic copy number variations (CNVs) have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication.
To detect novel CNVs increasing susceptibility to schizophrenia, utilizing two ethnically homogeneous discovery cohorts and replication in large samples.
Genetic association study of microarray data.
DNA samples were collected at nine sites from different countries.
Two discovery cohorts were comprised of: a) 790 cases (schizophrenia and schizoaffective disorder) and 1347 controls of Ashkenazi Jewish descent; and b) 662 trios (offspring affected with schizophrenia or schizoaffective disorder) from Bulgaria. Replication datasets consisted of 12,398 cases and 17,945 controls.
Main outcome measure
Statistically increased rate of specific CNVs in cases versus controls.
One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 out of 13,850 cases (0.094%) and in 3 out of 19,954 controls (0.015%), Fisher Exact p = 0.0014; OR = 6.25 (95%CI = 1.78 – 21.93).
Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains nine genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional eight genes. Our findings add a new locus to the list of CNVs that increase risk to develop schizophrenia.