- Email: [email protected]
Association Between Polygenic Risk Score for Schizophrenia and Neurocognitive Measures in the Western Australian Family Study of Schizophrenia (Wafss)
Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016 This work represents a step forwards in the psychiatric genetic research on borderline personality disorder. While we will need larger sample sizes to reach genome-wide significance and clinical samples will be very valuable for the interpretation of results, the new insights in the causality of this trait open new paths for research and intervention.
Disclosure Nothing to Disclose http://dx.doi.org/10.1016/j.euroneuro.2016.09.609
GENOME-WIDE POLYGENIC ATLAS OF THE PHENOME IN EMERGING ADULTHOOD: PREDICTION OF BEHAVIORAL AND HEALTH OUTCOMES
Arden Moscati1, Anna Docherty1, Jeanne Savage2, Jessica Salvatore2, Megan Cooke1, Fazil Aliev3, Ashlee Moore1, Roseann Peterson2, Alexis Edwards1, Brien Riley2, Daniel Adkins2, Bradley Webb1, Danielle Dick2, Silviu Bacanu2, Kenneth Kendler2 1
Virginia Institute for Psychiatric and Behavioral Genetics 2 Virginia Commonwealth University 3 Virginia Commonwealth University and Karabuk University Background: Identifying genetic relationships between complex traits in emerging adulthood can provide useful etiological insights into risk for psychopathology and other adverse outcomes. This study examined genomic data from a large sample of emerging adults (N = 5,947) to construct an atlas of polygenic risk that indexes diverse psychiatric, behavioral and health outcomes. Methods: Genome-wide association studies of 34 diverse psychiatric phenotypes and health factors were used as discovery samples to calculate genome-wide polygenic scores (GPS), which were then used to predict 55 phenotypes in the emerging adults. Special emphasis was placed on replicating previously published phenotypic and genetic relationships. All analyses were tested separately in each ancestry group (based on 1000 Genomes super-populations) and corrected for multiple testing within group. Results: The analyses resulted in over 1,800 associations between GPS and phenotype, with over 80 reaching significance. The majority of previously published hypotheses were replicated. A number of notable findings emerged beyond the expected within-trait prediction (GPS for height and body mass index predicted phenotypic height and BMI, respectively). The GPS for schizophrenia predicted depressive symptoms, anxiety symptoms, and nicotine use, as well as experiences of interpersonal trauma and family history of
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mental health problems. The neuroticism GPS significantly predicted general anxiety, phobia, insomnia, phenotypic neuroticism, and depressive symptoms. Conversely, the subjective well-being GPS predicted fewer depressive symptoms, fewer anxiety symptoms, decreased family history of mental health problems, as well as increased social support and relationship satisfaction. Many of these associations were consistent across ancestry groups. Discussion: These results highlight the utility of a comprehensive polygenic modeling framework, and provide potential avenues for prediction of risk and resilience in emerging adulthood. While the variance explained by any of these GPSs is small, they provide easily accessible information to guide future prediction, prevention, and intervention efforts to improve health and quality of life outcomes. Furthermore, many distinct GPS displayed significant prediction of the same phenotypes, indicating that more crosstrait research is needed to better understand the complex pattern of relationships between psychiatric outcomes.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.610
ASSOCIATION BETWEEN POLYGENIC RISK SCORE FOR SCHIZOPHRENIA AND NEUROCOGNITIVE MEASURES IN THE WESTERN AUSTRALIAN FAMILY STUDY OF SCHIZOPHRENIA (WAFSS)
Nina McCarthy1, Melanie Clark1, Gemma Cadby1, John Blangero2, Milan Dragovic1, Phillip Melton1, Eric Moses3, Johanna Badcock1, Assen Jablensky1 1
The University of Western Australia University of Texas Rio Grande 3 University of Western Australia and Curtin University 2
Background: Schizophrenia (SZ) is a clinically heterogeneous disorder with multifactorial causes including a significant genetic contribution. Recent, large scale GWAS have described a polygenic risk score (PRS) for SZ which accounts for 7% of variation on the liability scale (BulikSullivan et al, 2015). The aim of this study was to ascertain whether the PRS also contributed to a range of psychological measures which are associated with SZ. Methods: Our cohort comprised a set of 127 multiplex families recruited through a proband with SZ (n= 536 including 161 SZ cases) and a control group of 30 unaffected families (n = 121). We examined neurocognitive measures across 6 domains: General cognitive ability (National Adult Reading Test & Shipley Institute of Living Scale IQ); verbal learning and memory (Rey Auditory Verbal Learning Test); sustained attention (Continuous Performance Task, degraded stimulus and identical pairs); speed of information processing (inspection time); executive function (Controlled
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Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016
Oral Word Association Task) and personality factors (Schizotypal Personality Questionnaire & Temperament and Character Inventory) (Hallmayer et al, 2005). Whole genome sequence (WGS) data (Illumina 10X platform, 15X coverage) were available for a subset of the multiplex families (n = 320). We mapped all 102,636 PRS SNPs to the called WGS data by rsID; 97,507 passed QC and were used to calculate a PRS for each individual (Purcell et al, 2009). Correlation between PRS and each neurocognitive measure was conducted in SOLAR adjusting for the relationship matrix, age, sex and educational attainment. Results: In the multiplex families, all psychological measures were associated with SZ in the expected direction (FDR corrected at α 0.05). Comparison with the control families showed that the Shipley measure of current IQ, and the identical pairs measure of sustained attention were significantly impaired in unaffected relatives of those with SZ compared the healthy control cohort (FDR-corrected at α 0.05) indicating a shared genetic component with SZ. PRS was significantly correlated with the identical pairs task, both inspection time tasks, and personality measures after FDR correction with the expected direction of effect. Discussion: Recent studies have shown associations between PRS and neurocognitive measures in healthy populations, including IQ measures in a population based sample of children (Hubbard et al 2016) and working memory in young adults (Hatzimanolis et al 2015). Our findings add to these data and support the presence of shared common genetic factors between SZ and measures of sustained attention, speed of information processing and personality factors in a familial cohort with SZ. This information may help to inform the selection of endophenotypes for SZ.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.611
diseases. However, access to brain tissues to assess DNAm is essentially limited to post-mortem samples. The use of surrogate tissues, such as blood and saliva, has become common in identifying methylation changes associated with psychiatric disease. However, there is no literature showing direct association of DNAm between brain and peripheral tissues within individuals to support the validity of such surrogate tissues. In this study, we determined the extent to which these peripheral tissues can be used as surrogates for DNAm in the brain. Methods: DNA from blood, saliva, and live brain tissue samples from 12 treatment refractory epilepsy patients undergoing brain resection were collected. Genome-wide methylation was assessed with the Infinium HumanMethylation450 BeadChip array. Data were processed and analyzed with the R package RnBeads. Tissue relatedness was analyzed with Pearson correlation. Subsets of CpGs within different genomic regions, including promoter, genic, and intergenic regions, were evaluated for their degree of DNAm similarity. Results: Blood and saliva showed a high degree of correlation for DNAm (r2= 0.97), and saliva DNAm was revealed to be more similar to brain DNAm (r2 = 0.86) than was blood (r2 =0.82; po1x10-4). This pattern held true when analyzing the correlation within brain regions, including the frontal cortex, hippocampus, and amygdala, with saliva and blood, and within each individual. Analysis of DNAm correlation between peripheral tissues and brain in genomic regions showed that correlations within promoter (saliva r2= 0.91, blood r2 = 0.88) and genic regions (saliva r2= 0.88, blood r2 = 0.85) were higher than intergenic regions (saliva r2= 0.77, blood r2 = 0.73). Discussion: Genome-wide analysis of DNAm from both saliva and blood revealed a high degree of correlation with live brain DNAm within individuals, but saliva was more highly correlated. This indicates that saliva is a suitable surrogate for DNAm in the brain.
Disclosure Nothing to Disclose.
13:30 - 14:30 Oral Session: Methylation Studies GENOME-WIDE DNA METHYLATION COMPARISON BETWEEN LIVE HUMAN BRAIN AND PERIPHERAL TISSUES WITHIN INDIVIDUALS
Patricia Braun, Marie Hafner, Yasunori Nagahama, Benjamin Hing, Melissa McKane, Andrew Grossbach, Matthew Howard, Hiroto Kawasaki, James Potash, Gen Shinozaki
http://dx.doi.org/10.1016/j.euroneuro.2016.09.612
SEXUALLY DIMORPHIC DNA METHYLATION IN HUMAN BRAIN AND RELEVANCE TO PSYCHIATRIC DISORDERS
Yan Xia1, Chunyu Liu2, Chao Chen3, Kangli Wang3, Rujia Dai3, Chuan Jiao3, WeiKun Jia3 1
The University of Iowa Carver College of Medicine
The State Key Laboratory of Medical Genetics, Central South University 2 University of Illinois at Chicago 3 Central South University
Background: DNA methylation (DNAm) is a critical epigenetic mark impacting gene expression, and differential DNAm in the brain is associated with a number of psychiatric
Background: The prevalence of many psychiatric disorders, including autism spectrum disorders (ASDs), depression, intellectual disability (ID), has presented clear sex
Disclosure Nothing to Disclose http://dx.doi.org/10.1016/j.euroneuro.2016.09.609
GENOME-WIDE POLYGENIC ATLAS OF THE PHENOME IN EMERGING ADULTHOOD: PREDICTION OF BEHAVIORAL AND HEALTH OUTCOMES
Arden Moscati1, Anna Docherty1, Jeanne Savage2, Jessica Salvatore2, Megan Cooke1, Fazil Aliev3, Ashlee Moore1, Roseann Peterson2, Alexis Edwards1, Brien Riley2, Daniel Adkins2, Bradley Webb1, Danielle Dick2, Silviu Bacanu2, Kenneth Kendler2 1
Virginia Institute for Psychiatric and Behavioral Genetics 2 Virginia Commonwealth University 3 Virginia Commonwealth University and Karabuk University Background: Identifying genetic relationships between complex traits in emerging adulthood can provide useful etiological insights into risk for psychopathology and other adverse outcomes. This study examined genomic data from a large sample of emerging adults (N = 5,947) to construct an atlas of polygenic risk that indexes diverse psychiatric, behavioral and health outcomes. Methods: Genome-wide association studies of 34 diverse psychiatric phenotypes and health factors were used as discovery samples to calculate genome-wide polygenic scores (GPS), which were then used to predict 55 phenotypes in the emerging adults. Special emphasis was placed on replicating previously published phenotypic and genetic relationships. All analyses were tested separately in each ancestry group (based on 1000 Genomes super-populations) and corrected for multiple testing within group. Results: The analyses resulted in over 1,800 associations between GPS and phenotype, with over 80 reaching significance. The majority of previously published hypotheses were replicated. A number of notable findings emerged beyond the expected within-trait prediction (GPS for height and body mass index predicted phenotypic height and BMI, respectively). The GPS for schizophrenia predicted depressive symptoms, anxiety symptoms, and nicotine use, as well as experiences of interpersonal trauma and family history of
S505
mental health problems. The neuroticism GPS significantly predicted general anxiety, phobia, insomnia, phenotypic neuroticism, and depressive symptoms. Conversely, the subjective well-being GPS predicted fewer depressive symptoms, fewer anxiety symptoms, decreased family history of mental health problems, as well as increased social support and relationship satisfaction. Many of these associations were consistent across ancestry groups. Discussion: These results highlight the utility of a comprehensive polygenic modeling framework, and provide potential avenues for prediction of risk and resilience in emerging adulthood. While the variance explained by any of these GPSs is small, they provide easily accessible information to guide future prediction, prevention, and intervention efforts to improve health and quality of life outcomes. Furthermore, many distinct GPS displayed significant prediction of the same phenotypes, indicating that more crosstrait research is needed to better understand the complex pattern of relationships between psychiatric outcomes.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.610
ASSOCIATION BETWEEN POLYGENIC RISK SCORE FOR SCHIZOPHRENIA AND NEUROCOGNITIVE MEASURES IN THE WESTERN AUSTRALIAN FAMILY STUDY OF SCHIZOPHRENIA (WAFSS)
Nina McCarthy1, Melanie Clark1, Gemma Cadby1, John Blangero2, Milan Dragovic1, Phillip Melton1, Eric Moses3, Johanna Badcock1, Assen Jablensky1 1
The University of Western Australia University of Texas Rio Grande 3 University of Western Australia and Curtin University 2
Background: Schizophrenia (SZ) is a clinically heterogeneous disorder with multifactorial causes including a significant genetic contribution. Recent, large scale GWAS have described a polygenic risk score (PRS) for SZ which accounts for 7% of variation on the liability scale (BulikSullivan et al, 2015). The aim of this study was to ascertain whether the PRS also contributed to a range of psychological measures which are associated with SZ. Methods: Our cohort comprised a set of 127 multiplex families recruited through a proband with SZ (n= 536 including 161 SZ cases) and a control group of 30 unaffected families (n = 121). We examined neurocognitive measures across 6 domains: General cognitive ability (National Adult Reading Test & Shipley Institute of Living Scale IQ); verbal learning and memory (Rey Auditory Verbal Learning Test); sustained attention (Continuous Performance Task, degraded stimulus and identical pairs); speed of information processing (inspection time); executive function (Controlled
S506
Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016
Oral Word Association Task) and personality factors (Schizotypal Personality Questionnaire & Temperament and Character Inventory) (Hallmayer et al, 2005). Whole genome sequence (WGS) data (Illumina 10X platform, 15X coverage) were available for a subset of the multiplex families (n = 320). We mapped all 102,636 PRS SNPs to the called WGS data by rsID; 97,507 passed QC and were used to calculate a PRS for each individual (Purcell et al, 2009). Correlation between PRS and each neurocognitive measure was conducted in SOLAR adjusting for the relationship matrix, age, sex and educational attainment. Results: In the multiplex families, all psychological measures were associated with SZ in the expected direction (FDR corrected at α 0.05). Comparison with the control families showed that the Shipley measure of current IQ, and the identical pairs measure of sustained attention were significantly impaired in unaffected relatives of those with SZ compared the healthy control cohort (FDR-corrected at α 0.05) indicating a shared genetic component with SZ. PRS was significantly correlated with the identical pairs task, both inspection time tasks, and personality measures after FDR correction with the expected direction of effect. Discussion: Recent studies have shown associations between PRS and neurocognitive measures in healthy populations, including IQ measures in a population based sample of children (Hubbard et al 2016) and working memory in young adults (Hatzimanolis et al 2015). Our findings add to these data and support the presence of shared common genetic factors between SZ and measures of sustained attention, speed of information processing and personality factors in a familial cohort with SZ. This information may help to inform the selection of endophenotypes for SZ.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.611
diseases. However, access to brain tissues to assess DNAm is essentially limited to post-mortem samples. The use of surrogate tissues, such as blood and saliva, has become common in identifying methylation changes associated with psychiatric disease. However, there is no literature showing direct association of DNAm between brain and peripheral tissues within individuals to support the validity of such surrogate tissues. In this study, we determined the extent to which these peripheral tissues can be used as surrogates for DNAm in the brain. Methods: DNA from blood, saliva, and live brain tissue samples from 12 treatment refractory epilepsy patients undergoing brain resection were collected. Genome-wide methylation was assessed with the Infinium HumanMethylation450 BeadChip array. Data were processed and analyzed with the R package RnBeads. Tissue relatedness was analyzed with Pearson correlation. Subsets of CpGs within different genomic regions, including promoter, genic, and intergenic regions, were evaluated for their degree of DNAm similarity. Results: Blood and saliva showed a high degree of correlation for DNAm (r2= 0.97), and saliva DNAm was revealed to be more similar to brain DNAm (r2 = 0.86) than was blood (r2 =0.82; po1x10-4). This pattern held true when analyzing the correlation within brain regions, including the frontal cortex, hippocampus, and amygdala, with saliva and blood, and within each individual. Analysis of DNAm correlation between peripheral tissues and brain in genomic regions showed that correlations within promoter (saliva r2= 0.91, blood r2 = 0.88) and genic regions (saliva r2= 0.88, blood r2 = 0.85) were higher than intergenic regions (saliva r2= 0.77, blood r2 = 0.73). Discussion: Genome-wide analysis of DNAm from both saliva and blood revealed a high degree of correlation with live brain DNAm within individuals, but saliva was more highly correlated. This indicates that saliva is a suitable surrogate for DNAm in the brain.
Disclosure Nothing to Disclose.
13:30 - 14:30 Oral Session: Methylation Studies GENOME-WIDE DNA METHYLATION COMPARISON BETWEEN LIVE HUMAN BRAIN AND PERIPHERAL TISSUES WITHIN INDIVIDUALS
Patricia Braun, Marie Hafner, Yasunori Nagahama, Benjamin Hing, Melissa McKane, Andrew Grossbach, Matthew Howard, Hiroto Kawasaki, James Potash, Gen Shinozaki
http://dx.doi.org/10.1016/j.euroneuro.2016.09.612
SEXUALLY DIMORPHIC DNA METHYLATION IN HUMAN BRAIN AND RELEVANCE TO PSYCHIATRIC DISORDERS
Yan Xia1, Chunyu Liu2, Chao Chen3, Kangli Wang3, Rujia Dai3, Chuan Jiao3, WeiKun Jia3 1
The University of Iowa Carver College of Medicine
The State Key Laboratory of Medical Genetics, Central South University 2 University of Illinois at Chicago 3 Central South University
Background: DNA methylation (DNAm) is a critical epigenetic mark impacting gene expression, and differential DNAm in the brain is associated with a number of psychiatric
Background: The prevalence of many psychiatric disorders, including autism spectrum disorders (ASDs), depression, intellectual disability (ID), has presented clear sex