Abstract
Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer's disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. A chromosome 16p11.2 duplication CNV (chr16: 29,554,843-30,105,652) was identified in 2 of 440 AD+P subjects, but not in 136 AD subjects without psychosis, or in 593 AD subjects with intermediate psychosis status, or in 855 non-AD individuals. The frequency of this duplication CNV in AD+P (0.46%) was similar to that reported previously in schizophrenia (0.46%). This duplication CNV was further validated using the NanoString nCounter CNV Custom CodeSets. The 16p11.2 duplication has been associated with developmental delay, intellectual disability, behavioral problems, autism, schizophrenia (SCZ), and bipolar disorder. These two AD+P patients had no personal of, nor any identified family history of, SCZ, bipolar disorder and autism. To the best of our knowledge, our case report is the first suggestion that 16p11.2 duplication is also linked to AD+P. Although rare, this CNV may have an important role in the development of psychosis.
Highlights
About 40–60% of patients with late-onset Alzheimer’s disease (AD), defined by an onset after age 60 years, develop psychosis (AD+P) [1,2]
Recent large scale genome-wide association study (GWAS) of Alzheimer’s disease with psychotic symptoms [3] found several single nucleotide polymorphisms (SNPs) that were tentatively associated with AD+P when compared to AD-P, but none of them were genome-wide significant
Several other studies reported some susceptibility loci and candidate genes for AD+P which increased the risk of schizophrenia (SCZ) and other psychiatric disorders, the specific genetic determinants remain to be identified [1,4,5,6]
Summary
About 40–60% of patients with late-onset Alzheimer’s disease (AD), defined by an onset after age 60 years, develop psychosis (AD+P) [1,2]. Recent large scale genome-wide association study (GWAS) of Alzheimer’s disease with psychotic symptoms [3] found several single nucleotide polymorphisms (SNPs) that were tentatively associated with AD+P when compared to AD-P, but none of them were genome-wide significant. Some of these associations were overlapped with other psychiatric disorders with psychotic features such as schizophrenia (SCZ). Recent studies have shown that autism and SCZ share several rare copy number variants (CNVs) [10,11] Some of these CNVs are shared with various intellectual disability syndromes [12]. Moreno-De-Luca et al [13] summarized CNV studies in autism and SCZ, and reported 7 recurrent CNVs across autism and SCZ, which included a deletion on chromosome 1q21.1 (position in human genome build 36/hg18: 144,963,732-145,864,377), a deletion on chromosome 3q29 (197,244,288-198,830,238), a deletion on chromosome 15q13.3 (28,698,632-30,234,007), a duplication on chromosome 16p11.2 (29,557,553-30,107,434), a duplication on chromosome 16p13.11 (15,421,876-16,200,195), a deletion on chromosome 17q12 (31,893,783-33,277,865) and a PLOS ONE | www.plosone.org
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