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POTENTIAL ALTERATIONS IN LEUKOCYTE MITOCHONDRIAL DNA COPY NUMBER FROM PATIENTS WITH BIPOLAR DISORDER TYPE I
S900
Abstracts
disorders and may contribute to understanding the underlying biology of disorders and identification of new targets for treatment.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.212
SU24. POTENTIAL ALTERATIONS IN LEUKOCYTE MITOCHONDRIAL DNA COPY NUMBER FROM PATIENTS WITH BIPOLAR DISORDER TYPE I n
Euijung Ryu ,1, Gregory Jenkins1, Jared Evans1, Ana Andreazza2, Marquis Vawter3, Susan McElroy4, Mark Frye1, Joanna Biernacka1
99.6) in BDI and 88.7 (77.6 – 100.6) in controls, respectively. Adjusting for age and sex, the mtDNA copy number was marginally lower in BDI patients compared to controls (P=0.055). The total number of heteroplasmic SNVs was similar between cases and controls (median: 21 for both groups). Discussion: This small study potentially supports recent findings on a slight decrease in mtDNA copies among BDI and more copies in females. This study also shows that mtDNA copy number decreases with age, while the degree of heteroplasmy increases. Although the underlying mechanism for this observation is not clear, it may reflect mitochondrial DNA replication and degradation due to mitochondrial dysfunction and premature cellular senescence in BD.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.213
1
Mayo Clinic University of Toronto 3 University of California, Irvine 4 Lindner Center of HOPE 2
Background: Mitochondrial dysfunction has been well documented in patients with Bipolar Disorder (BD). Studies demonstrated that alternations in mtDNA copy number have been associated with mitochondrial dysfunction and increased oxidative stress. However, association between mtDNA copy number and BD compared to controls has been inconclusive so far. In this study, we aimed to assess whether mtDNA copy number is altered in BD type I (BDI) compared to controls. We also explored whether the total number of heteroplasmic Single Nucleotide Variants (SNVs) for a given subject, another marker for oxidative stress, is altered in BDI. Methods: One hundred BDI patients were selected for Whole Genome Sequencing (WGS) experiment using leukocyte DNA from the Mayo Clinic Bipolar Disorder Biobank. In addition, 1000 patients from the Mayo Clinic Biobank, a control biobank, were also selected for the experiment. After applying basic quality control filtering (e.g., low sequencing coverage and sample contamination) to nuclear DNA sequencing data, this study used 99 BD1 patients and 961 controls. MtDNA copy number was defined as the relative quantity of mtDNA compared to nuclear DNA. For each SNV, likelihood functions were estimated under two models (heteroplasmy and homoplasmy) taking into account sequencing error, and log-likelihood ratio (LLR) was calculated. The total number of heteroplasmic SNVs for a given subject was calculated by counting the sites with LLR Z 5. Adjusting for age and sex, regression models were used to test the association between BD status and mtDNA copy number and the total number of heteroplasmic SNVs after log-transformation. Results: BDI patients were younger compared to controls (median age at the biobank enrollment: 45 in BDI vs 61 in controls) with more females in cases (60% vs 50%). Overall, older age and male sex were associated with lower mtDNA copy number (P o 10-4). The total number of heteroplasmic SNVs was slightly higher with older age (P=0.041). The median mtDNA copy number was 84.7 (25th – 75th percentile: 75.2 –
SU25. TARGETED NEXT GENERATION SEQUENCING OF 187 GENES IN A BULGARIAN PSYCHOSIS SAMPLE n
Radka Kaneva ,1, Ivan Popov2, Olga Beltcheva1, Mladen Penchev3, Gyulnas Dzebir2, Elliot Rees4, Radosveta Bozhilova2, Vesela Stoyanova3, Vanyo Mitev2, Michael Owen5, Michael O'Donovan5, George Kirov5, Vihra Milanova3 1
Medical University of Sofia Molecular Medicine Center, Medical University of Sofia 3 Alexandrovska University Hospital, Medical University of Sofia 4 Cardiff University 5 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University 2
Background: There is strong evidence for partial overlap of genetic influence on Schizophrenia (SCZ), Schizoaffective Disorder (SAD) and Bipolar Affective Disorder (BAD). Part of this is due to common genetic variants, detected by GWAS, with a small individual effect on risk. Recent studies using next generation sequencing reveal growing evidence of the role of rare genetic variants in both diseases. We performed targeted NGS on 187 candidate genes to further investigate the genetic architecture of Bulgarian patients with bipolar disorder and schizophrenia. Methods: A total of 300 individuals with BAD, 151 with SCZ, 15 SAD according to DSMIV and ICD-10, as well as 85 healthy population controls and 40 healthy relatives were recruited. The samples were sequenced on the Ion PROTON platform. The sequencing panel comprised of 187 preselected strong candidate genes, based on the results from GWAS and previous NGS studies. Only samples with coverage of at least 95% of the target region at 20x were included in the analyses. Case-control association testing was done using PLINK. The rare variants have been evaluated and divided into groups based on their functional relevance: LOF variants (frameshift and nonsense); with potentially damaging effect on protein function (splice site, missense
Abstracts
disorders and may contribute to understanding the underlying biology of disorders and identification of new targets for treatment.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.212
SU24. POTENTIAL ALTERATIONS IN LEUKOCYTE MITOCHONDRIAL DNA COPY NUMBER FROM PATIENTS WITH BIPOLAR DISORDER TYPE I n
Euijung Ryu ,1, Gregory Jenkins1, Jared Evans1, Ana Andreazza2, Marquis Vawter3, Susan McElroy4, Mark Frye1, Joanna Biernacka1
99.6) in BDI and 88.7 (77.6 – 100.6) in controls, respectively. Adjusting for age and sex, the mtDNA copy number was marginally lower in BDI patients compared to controls (P=0.055). The total number of heteroplasmic SNVs was similar between cases and controls (median: 21 for both groups). Discussion: This small study potentially supports recent findings on a slight decrease in mtDNA copies among BDI and more copies in females. This study also shows that mtDNA copy number decreases with age, while the degree of heteroplasmy increases. Although the underlying mechanism for this observation is not clear, it may reflect mitochondrial DNA replication and degradation due to mitochondrial dysfunction and premature cellular senescence in BD.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.213
1
Mayo Clinic University of Toronto 3 University of California, Irvine 4 Lindner Center of HOPE 2
Background: Mitochondrial dysfunction has been well documented in patients with Bipolar Disorder (BD). Studies demonstrated that alternations in mtDNA copy number have been associated with mitochondrial dysfunction and increased oxidative stress. However, association between mtDNA copy number and BD compared to controls has been inconclusive so far. In this study, we aimed to assess whether mtDNA copy number is altered in BD type I (BDI) compared to controls. We also explored whether the total number of heteroplasmic Single Nucleotide Variants (SNVs) for a given subject, another marker for oxidative stress, is altered in BDI. Methods: One hundred BDI patients were selected for Whole Genome Sequencing (WGS) experiment using leukocyte DNA from the Mayo Clinic Bipolar Disorder Biobank. In addition, 1000 patients from the Mayo Clinic Biobank, a control biobank, were also selected for the experiment. After applying basic quality control filtering (e.g., low sequencing coverage and sample contamination) to nuclear DNA sequencing data, this study used 99 BD1 patients and 961 controls. MtDNA copy number was defined as the relative quantity of mtDNA compared to nuclear DNA. For each SNV, likelihood functions were estimated under two models (heteroplasmy and homoplasmy) taking into account sequencing error, and log-likelihood ratio (LLR) was calculated. The total number of heteroplasmic SNVs for a given subject was calculated by counting the sites with LLR Z 5. Adjusting for age and sex, regression models were used to test the association between BD status and mtDNA copy number and the total number of heteroplasmic SNVs after log-transformation. Results: BDI patients were younger compared to controls (median age at the biobank enrollment: 45 in BDI vs 61 in controls) with more females in cases (60% vs 50%). Overall, older age and male sex were associated with lower mtDNA copy number (P o 10-4). The total number of heteroplasmic SNVs was slightly higher with older age (P=0.041). The median mtDNA copy number was 84.7 (25th – 75th percentile: 75.2 –
SU25. TARGETED NEXT GENERATION SEQUENCING OF 187 GENES IN A BULGARIAN PSYCHOSIS SAMPLE n
Radka Kaneva ,1, Ivan Popov2, Olga Beltcheva1, Mladen Penchev3, Gyulnas Dzebir2, Elliot Rees4, Radosveta Bozhilova2, Vesela Stoyanova3, Vanyo Mitev2, Michael Owen5, Michael O'Donovan5, George Kirov5, Vihra Milanova3 1
Medical University of Sofia Molecular Medicine Center, Medical University of Sofia 3 Alexandrovska University Hospital, Medical University of Sofia 4 Cardiff University 5 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University 2
Background: There is strong evidence for partial overlap of genetic influence on Schizophrenia (SCZ), Schizoaffective Disorder (SAD) and Bipolar Affective Disorder (BAD). Part of this is due to common genetic variants, detected by GWAS, with a small individual effect on risk. Recent studies using next generation sequencing reveal growing evidence of the role of rare genetic variants in both diseases. We performed targeted NGS on 187 candidate genes to further investigate the genetic architecture of Bulgarian patients with bipolar disorder and schizophrenia. Methods: A total of 300 individuals with BAD, 151 with SCZ, 15 SAD according to DSMIV and ICD-10, as well as 85 healthy population controls and 40 healthy relatives were recruited. The samples were sequenced on the Ion PROTON platform. The sequencing panel comprised of 187 preselected strong candidate genes, based on the results from GWAS and previous NGS studies. Only samples with coverage of at least 95% of the target region at 20x were included in the analyses. Case-control association testing was done using PLINK. The rare variants have been evaluated and divided into groups based on their functional relevance: LOF variants (frameshift and nonsense); with potentially damaging effect on protein function (splice site, missense