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Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees.

ABSTRACT: BACKGROUND:We report on copy number variants (CNVs) found in Palauan subjects ascertained for schizophrenia and related psychotic disorders in extended pedigrees in Palau. We compare CNVs found in this Oceanic population with those seen in other samples, typically of European ancestry. Assessing CNVs in Palauan extended pedigrees yields insight into the evolution of risk CNVs, such as how they arise, are transmitted, and are lost from populations by stochastic or selective processes, none of which are easily measured from case-control samples. METHODS:DNA samples from 197 subjects affected with schizophrenia and related psychotic disorders, 185 of their relatives, and 159 control subjects were successfully characterized for CNVs using Affymetrix Genomewide Human SNP Array 5.0. RESULTS:Copy number variants thought to be associated with risk for schizophrenia and related disorders also occur in affected individuals in Palau, specifically 15q11.2 and 1q21.1 deletions, partial duplication of IL1RAPL1 (Xp21.3), and chromosome X duplications (Klinefelter's syndrome). Partial duplication within A2BP1 appears to convey an eightfold increased risk in male subjects (95% confidence interval, .8-84.4) but not female subjects (odds ratio = .4, 95% confidence interval, .03-4.9). Affected-only linkage analysis using this variant yields a logarithm of the odds score of 3.5. CONCLUSIONS:This study reveals CNVs that confer risk to schizophrenia and related psychotic disorders in Palau, most of which have been previously observed in samples of European ancestry. Only a few of these CNVs show evidence that they have existed for many generations, consistent with risk variants diminishing reproductive success.

SUBMITTER: Melhem N

PROVIDER: S-EPMC3224197 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees.

Melhem Nadine N Middleton Frank F McFadden Kathryn K Klei Lambertus L Faraone Stephen V SV Vinogradov Sophia S Tiobech Josepha J Yano Victor V Kuartei Stevenson S Roeder Kathryn K Byerley William W Devlin Bernie B Myles-Worsley Marina M

Biological psychiatry 20111007 12

<h4>Background</h4>We report on copy number variants (CNVs) found in Palauan subjects ascertained for schizophrenia and related psychotic disorders in extended pedigrees in Palau. We compare CNVs found in this Oceanic population with those seen in other samples, typically of European ancestry. Assessing CNVs in Palauan extended pedigrees yields insight into the evolution of risk CNVs, such as how they arise, are transmitted, and are lost from populations by stochastic or selective processes, non ...[more]

PMID: 21982423

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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

Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees.

Publications

Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees.

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