Microdeletions of 3q29 Confer High Risk for Schizophrenia

• Published in: American journal of human genetics Vol. 87; no. 2; pp. 229 - 236
• Main Authors: Mulle, Jennifer Gladys, Dodd, Anne F., McGrath, John A., Wolyniec, Paula S., Mitchell, Adele A., Shetty, Amol C., Sobreira, Nara L., Valle, David, Rudd, M. Katharine, Satten, Glen, Cutler, David J., Pulver, Ann E., Warren, Stephen T.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.08.2010; Cell Press; Elsevier
• Subjects: Adult and adolescent clinical studies; Base Pairing - genetics; Biological and medical sciences; Case-Control Studies; Chromosomes, Human, Pair 3 - genetics; Classical genetics, quantitative genetics, hybrids; DNA Copy Number Variations - genetics; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic Loci - genetics; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Human; Humans; Medical genetics; Medical sciences; Molecular and cellular biology; Physical Chromosome Mapping; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Reproducibility of Results; Risk assessment; Schizophrenia; Schizophrenia - genetics; Sequence Deletion - genetics; Young Adult; Psychosis; Genetic mapping; Human; High risk; Microdeletion; Schizophrenia; Genetics
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2010.07.013

Schizophrenia (SZ) is a severe psychiatric illness that affects ∼1% of the population and has a strong genetic underpinning. Recently, genome-wide analysis of copy-number variation (CNV) has implicated rare and de novo events as important in SZ. Here, we report a genome-wide analysis of 245 SZ cases and 490 controls, all of Ashkenazi Jewish descent. Because many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases, with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3–1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, because increasing evidence suggests an overlap of specific rare copy-number variants (CNVs) between autism and SZ. By combining our data with prior CNV studies of SZ and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with SZ (p = 0.02) and an odds ratio estimate of 17 (95% confidence interval: 1.36–1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior SZ family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for SZ susceptibility.