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Resequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders.

ABSTRACT: BACKGROUND: The PTPRA gene, which encodes the protein RPTP-?, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks. METHODS: We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3'UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls. RESULTS: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element. MAJOR CONCLUSIONS: No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.

SUBMITTER: Xing J

PROVIDER: S-EPMC4231042 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Resequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders.

Xing Jingrui J Wang Chenyao C Kimura Hiroki H Takasaki Yuto Y Kunimoto Shohko S Yoshimi Akira A Nakamura Yukako Y Koide Takayoshi T Banno Masahiro M Kushima Itaru I Uno Yota Y Okada Takashi T Aleksic Branko B Ikeda Masashi M Iwata Nakao N Ozaki Norio N

PloS one 20141113 11

<h4>Background</h4>The PTPRA gene, which encodes the protein RPTP-α, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks.<h4>Methods</h4>We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 38 ...[more]

PMID: 25393624

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Project description:BackgroundAutism spectrum disorders and schizophrenia have been associated with an overlapping set of copy number variant loci, but the nature and degree of overlap in copy number variants (deletions compared to duplications) between these two disorders remains unclear.MethodsWe systematically evaluated three lines of evidence: (1) the statistical bases for associations of autism spectrum disorders and schizophrenia with a set of the primary CNVs thus far investigated, from previous studies; (2) data from case series studies on the occurrence of these CNVs in autism spectrum disorders, especially among children, and (3) data on the extent to which the CNVs were associated with intellectual disability and developmental, speech, or language delays. We also conducted new analyses of existing data on these CNVs in autism by pooling data from seven case control studies.ResultsFour of the CNVs considered, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, showed clear statistical evidence as autism risk factors, whereas eight CNVs, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup 16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, were strongly statistically supported as risk factors for schizophrenia. Three of the CNVs, dup 1q21.1, dup 16p11.2, and dup 16p13.1, exhibited statistical support as risk factors for both autism and schizophrenia, although for each of these CNVs statistical significance was nominal for tests involving one of the two disorders. For the CNVs that were statistically associated with schizophrenia but were not statistically associated with autism, a notable number of children with the CNVs have been diagnosed with autism or ASD; children with these CNVs also demonstrate a high incidence of intellectual disability and developmental, speech, or language delays.ConclusionsThese findings suggest that although CNV loci notably overlap between autism and schizophrenia, the degree of strongly statistically supported overlap in specific CNVs at these loci remains limited. These analyses also suggest that relatively severe premorbidity to CNV-associated schizophrenia in children may sometimes be diagnosed as autism spectrum disorder.

Dataset Information

Resequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders.

Publications

Resequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders.

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