Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia.
Copy number variations (CNVs) account for a substantial proportion of human genomic variation, and have been shown to cause neurodevelopmental disorders. We sought to determine the relevance of CNVs to the aetiology of schizophrenia (SZ). Whole-genome, high-resolution, tiling path BAC array comparative genomic hybridization (array CGH) was employed to test DNA from 93 individuals with DSM-IV SZ. Common DNA copy number changes that are unlikely to be directly pathogenic in SZ were filtered out by comparison to a reference dataset of 372 control individuals analyzed in our laboratory, and a screen against the Database of Genomic Variants. The remaining aberrations were validated with Affymetrix 250K SNP arrays or 244K Agilent oligo-arrays and tested for inheritance from the parents. A total of 13 aberrations satisfied our criteria. Two of them are very likely to be pathogenic. The first one is a deletion at 2p16.3 that was present in an affected sibling and disrupts NRXN1. The second one is a de novo duplication at 15q13.1 spanning APBA2. The proteins of these two genes interact directly and play a role in synaptic development and function. Both genes have been affected by CNVs in patients with autism and mental retardation, but neither has been previously implicated in SZ.
Kirov
George
G
Department of Psychological Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK.
Gumus
Dilihan
D
Chen
Wei
W
Norton
Nadine
N
Georgieva
Lyudmila
L
Sari
Murat
M
O'Donovan
Michael C
MC
Erdogan
Fikret
F
Owen
Michael J
MJ
Ropers
Hans-Hilger
HH
Ullmann
Reinhard
R
D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics; D015820:Cadherins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics*
C491636:APBA2 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C112162:neurexophilin