- Email: [email protected]
RARE PATHOGENIC COPY NUMBER MUTATIONS IN MENTAL DISORDERS
140
Abstracts
check for a phenotype. Then we try to rescue the morpholinoinduced phenotype by co-injecting the wildtype (WT) human cDNA of the test gene. Finally, we test whether co-injection of morpholino and mutated human cDNA can rescue the phenotype in the fish embryos. Using these approaches, we have identified several new genes associated with these diseases (such as SHANK3, IL1RAPL1, SYNGAP1, STXBP1, and others). Interestingly, some of the identified genes show deleterious de novo mutations in patients from the 3 disease cohorts, suggesting close biological overlap in these three. A combination of high-throughput sequencing, automated SNP discovery, genetic and biological validation strategies can be used to identify SCZ and AUT genes. This approach can also be used to identify genes involved in other common diseases, especially as next-generation sequencing technologies become available to screen a larger number of candidate genes in more patient samples. However the challenge remains in robustly linking a DNA variant to a clinical phenotype. Acknowledgements: Genome Canada and Génome Québec, Université de Montréal and Canadian Foundation for Innovation & CIHR.
the implication of the genomic variability detected in 17q21 in underlying a significant proportion of illness age at expression and warrant further analyses of the genomic variability of this region. In this sense, it is interesting to note that this chromosomal region encompasses the microtubule-associated protein Tau gene (MAPT), which has been associated with neurodegenerative disorders such as Parkinson disease or Frontotemporal dementia. Additionally, chromosomal imbalances in this region have been detected in individuals with mental retardation and dysmorphic features. Moreover, this genomic interval has recently been documented to harbor a common < 900 kb inversion polymorphism, resulting in a haplotype block with two highly divergent haplotypes designated as H1 and H2. H2 is apparently under positive selection and is found at a frequency of 20% in the European population. Results of a SNP screening of this region in a larger sample of psychotic patients and their relatives will be also presented in the symposium. Acknowledgements: Narsad Foundation Research Award 2008, Fundación Alicia Koplowitz (2006), Fundació La Marató de TV3 (014430/31).
doi:10.1016/j.schres.2010.02.113 doi:10.1016/j.schres.2010.02.112 RARE PATHOGENIC COPY NUMBER MUTATIONS IN MENTAL DISORDERS CLINICAL AND COGNITIVE EXTREME PHENOTYPES AND CNVS IN ADOLESCENT AND ADULT FUNCTIONAL PSYCHOSIS Mar Fatjó-Vilas University of Barcelona, Spain Rare but with relatively high penetrance copy number variations (CNVs) have been described in adult and early onset schizophrenia but also in autistic disorders. In this sense, CNVs in genes coding for proteins that interact directly and play a role in synaptic development and function (NRXN1 and APBA2), have been interestingly identified in schizophrenic patients but also in autistic and mentally retarded patients. The above mentioned results together with the increasingly acceptance that the imprecision of categorical psychiatric diagnoses can be a limiting factor in understanding the genetic basis of mental disorders, suggest the interest of analysing CNVs in early onset psychosis, including those cases with overlapping features with autism and intelligence disabilities such as low IQ, developmental milestones and poor premorbid adjustment. The aim of the present study was to study the relationship between copy number genomic variability and extreme clinical and cognitive phenotypes of psychosis. We selected (from a sample of 150 families (quadruplets) with an affected/son daughter for functional psychosis) a subgroup of 20 Caucasian male patients with extreme phenotypes to perform a comparative genomic hybridization (CGH) analysis. Patients were selected according to their age at onset (age of first symptoms range: 13-30 years; assessed with the Symptom Onset in Schizophrenia Inventory), Intelligence Quotient (IQ range: 55-120; assessed with WISC/WAIS) and premorbid adjustment (Premorbid Adjustment Scale). Pooled DNA of 20 Caucasian healthy males, without psychiatric history in their first and second degree relatives, was used as reference in hybridizations. Array CGH analyses were performed using Agilent Human Genome Microarray 244 K (genome-wide coverage) and results were validated with RT-PCR. Significant differences were observed between early onset patients (≤ 18 years) and adult onset patients (≥ 19 years) in chromosome 17q21: p < 0.01 (Benjamini-Hochberg (adjusted)). Gains in this chromosomal region were detected in 7 early onset patients and in 1 adult onset patient while losses were observed in 8 adult onset patients. IQ did not significantly account for the observed differences in the present sample. These results suggest
David Collier Institute of Psychiatry, Kings College, London, UK Rare structural variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome- wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome- wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia. doi:10.1016/j.schres.2010.02.114
Symposium 20 FUTURE DIRECTIONS FOR THE NEUROPATHOLOGY OF SCHIZOPHRENIA Co-Chairpersons: David Cotter, Paul Harrison Tuesday, 13 April, 2010 - 3:30 pm - 5:30 pm
Overall Abstract: This symposium will summarise the value of post-mortem brain research in schizophrenia and to discuss the possible future directions of work in this area. Common themes
Abstracts
check for a phenotype. Then we try to rescue the morpholinoinduced phenotype by co-injecting the wildtype (WT) human cDNA of the test gene. Finally, we test whether co-injection of morpholino and mutated human cDNA can rescue the phenotype in the fish embryos. Using these approaches, we have identified several new genes associated with these diseases (such as SHANK3, IL1RAPL1, SYNGAP1, STXBP1, and others). Interestingly, some of the identified genes show deleterious de novo mutations in patients from the 3 disease cohorts, suggesting close biological overlap in these three. A combination of high-throughput sequencing, automated SNP discovery, genetic and biological validation strategies can be used to identify SCZ and AUT genes. This approach can also be used to identify genes involved in other common diseases, especially as next-generation sequencing technologies become available to screen a larger number of candidate genes in more patient samples. However the challenge remains in robustly linking a DNA variant to a clinical phenotype. Acknowledgements: Genome Canada and Génome Québec, Université de Montréal and Canadian Foundation for Innovation & CIHR.
the implication of the genomic variability detected in 17q21 in underlying a significant proportion of illness age at expression and warrant further analyses of the genomic variability of this region. In this sense, it is interesting to note that this chromosomal region encompasses the microtubule-associated protein Tau gene (MAPT), which has been associated with neurodegenerative disorders such as Parkinson disease or Frontotemporal dementia. Additionally, chromosomal imbalances in this region have been detected in individuals with mental retardation and dysmorphic features. Moreover, this genomic interval has recently been documented to harbor a common < 900 kb inversion polymorphism, resulting in a haplotype block with two highly divergent haplotypes designated as H1 and H2. H2 is apparently under positive selection and is found at a frequency of 20% in the European population. Results of a SNP screening of this region in a larger sample of psychotic patients and their relatives will be also presented in the symposium. Acknowledgements: Narsad Foundation Research Award 2008, Fundación Alicia Koplowitz (2006), Fundació La Marató de TV3 (014430/31).
doi:10.1016/j.schres.2010.02.113 doi:10.1016/j.schres.2010.02.112 RARE PATHOGENIC COPY NUMBER MUTATIONS IN MENTAL DISORDERS CLINICAL AND COGNITIVE EXTREME PHENOTYPES AND CNVS IN ADOLESCENT AND ADULT FUNCTIONAL PSYCHOSIS Mar Fatjó-Vilas University of Barcelona, Spain Rare but with relatively high penetrance copy number variations (CNVs) have been described in adult and early onset schizophrenia but also in autistic disorders. In this sense, CNVs in genes coding for proteins that interact directly and play a role in synaptic development and function (NRXN1 and APBA2), have been interestingly identified in schizophrenic patients but also in autistic and mentally retarded patients. The above mentioned results together with the increasingly acceptance that the imprecision of categorical psychiatric diagnoses can be a limiting factor in understanding the genetic basis of mental disorders, suggest the interest of analysing CNVs in early onset psychosis, including those cases with overlapping features with autism and intelligence disabilities such as low IQ, developmental milestones and poor premorbid adjustment. The aim of the present study was to study the relationship between copy number genomic variability and extreme clinical and cognitive phenotypes of psychosis. We selected (from a sample of 150 families (quadruplets) with an affected/son daughter for functional psychosis) a subgroup of 20 Caucasian male patients with extreme phenotypes to perform a comparative genomic hybridization (CGH) analysis. Patients were selected according to their age at onset (age of first symptoms range: 13-30 years; assessed with the Symptom Onset in Schizophrenia Inventory), Intelligence Quotient (IQ range: 55-120; assessed with WISC/WAIS) and premorbid adjustment (Premorbid Adjustment Scale). Pooled DNA of 20 Caucasian healthy males, without psychiatric history in their first and second degree relatives, was used as reference in hybridizations. Array CGH analyses were performed using Agilent Human Genome Microarray 244 K (genome-wide coverage) and results were validated with RT-PCR. Significant differences were observed between early onset patients (≤ 18 years) and adult onset patients (≥ 19 years) in chromosome 17q21: p < 0.01 (Benjamini-Hochberg (adjusted)). Gains in this chromosomal region were detected in 7 early onset patients and in 1 adult onset patient while losses were observed in 8 adult onset patients. IQ did not significantly account for the observed differences in the present sample. These results suggest
David Collier Institute of Psychiatry, Kings College, London, UK Rare structural variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome- wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome- wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia. doi:10.1016/j.schres.2010.02.114
Symposium 20 FUTURE DIRECTIONS FOR THE NEUROPATHOLOGY OF SCHIZOPHRENIA Co-Chairpersons: David Cotter, Paul Harrison Tuesday, 13 April, 2010 - 3:30 pm - 5:30 pm
Overall Abstract: This symposium will summarise the value of post-mortem brain research in schizophrenia and to discuss the possible future directions of work in this area. Common themes