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POLYGENIC RISK BURDEN AND CANNABIS USE COMORBIDITY IN PATIENTS WITH SCHIZOPHRENIA AND BIPOLAR DISORDER
Abstracts
S951
1–1.5% and the heritability of CUD is estimated to 51–70%. With respect to the amount of risk explained by common variants, the SNP heritability has been estimated to 0.06– 0.2. The difference between total heritability and SNP heritability suggests that rare variants might contribute to the risk of CUD, which require sequencing to find them. Methods: We performed whole-exome sequencing of 7,366 Danish individuals identified in the Danish Newborn Screening Biobank (DNSB), including 1,236 affected with CUD, and 6,100 unaffected controls. We aligned exome sequence data against GRCh37 human genome reference with bwa and identified variants using GATK. We performed quality control of variants and individuals (including principal component analysis for exclusion of non-Europeans), annotated variants with respect to gene, functional impact and presence in the ExAC non-psych database using Hail. Subsequently various burden tests were performed. Results: Here we will present results from analysis of the impact of Ultra-Rare Variants (URVs) in CUD. We will especially focus on the burden of these variants in CUD cases compared to controls in highly evolutionary constrained genes as well as specific gene-sets relevant to CUD. Furthermore, we will assess whether CUD risk genes identified based on the common variant analysis also carry an increased burden of URVs. In addition, we will conduct gene-based association analysis to identify top-ranking genes most frequently hit by rare deleterious variants in CUD cases compared with controls. Discussion: We will discuss our comprehensive analyses of the role of URVs in CUD, which will further contribute to the understanding of the genetic architecture underlying the disorder, and help elucidating relevant biological mechanism contributing to disease risk.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.301
SU113. POLYGENIC RISK BURDEN AND CANNABIS USE COMORBIDITY IN PATIENTS WITH SCHIZOPHRENIA AND BIPOLAR DISORDER
understood so far. Previous studies have revealed that a genetic predisposition to SCZ might be associated with increased use of cannabis in healthy individuals. Given this relationship, we intended to study whether polygenic risk scores (PRS) for SCZ predict cannabis use in patients with SCZ and BD. In addition, we want to test whether BD PRS or Cannabis (CAN) PRS have an impact on cannabis use in these two subgroups. Methods: The present study included the USA GAIN/TGEN sample (1.150 BD patients) and the German KFO/PsyCourse cohort (433 SCZ and 327 BD patients) (www.kfo241.de; www.PsyCourse.de). Information on ever/never use of cannabis was available in these samples. PRS were calculated as follows: For each SNP contributing to the PRS, the number of risk variants carried by an individual was multiplied by the logarithm of the odds ratio for that particular variant. The resulting values were summed up in an additive fashion obtaining a weighted individual estimate of the SCZ genetic burden in each individual at different p-value thresholds. The most recent summary statistics on SCZ GWAS (Ripke et al., 2014), BD GWAS (Hou et al., 2016) and Cannabis use (Sherva et al., 2016) were used to ascertain risk variants, their P-values, and associated odds ratios for the respective disorders. Results: SCZ PRS were associated (Po0.05) with cannabis use in the GAIN/TGEN sample of BD patients in all P-value thresholds tested ranging from P= 0.04 until P= 1. A larger genetic burden was associated with a higher risk to use cannabis. The R2 change explained by PRS ranged from 0.5% to 1.15%. These effects of SCZ PRS were replicated in the BD patients from the KFO/PsyCourse cohort (P-value threshold 0.0001, R2 change = 1.94%, P-value = 0.020). No effects were observed in the SCZ patients from this replication cohort. Likewise, no associations were observed between BD PRS and CAN PRS in any of the subsamples in this study. Discussion: First results suggest that individuals with BD and an increased polygenic risk for SCZ are more likely to use cannabis. The association between BD and cannabis use might be not simply one of an environmental risk factor, but rather involves gene–environment interaction, as individuals choose and shape their own environment according on their own innate preferences.
Disclosure: Nothing to disclose.
n
Kristina Adorjan ,1, Sergi Papiol1, Katrin Gade1, Dörthe Malzahn1, Richard Sherva2, Monika Budde1, Fanny Aldinger1, Janos Kalman1, Urs Heilbronner1, Heike Anderson-Schmidt3, Oliver Pogarell4, Peter Falkai4, Joel Gelernter2, Thomas Schulze1 1
Institute of Psychiatric Phenomics and Genomics Yale School of Medicine 3 University Medical Centre Goettingen 4 Ludwig- Maximilian University of Munich 2
http://dx.doi.org/10.1016/j.euroneuro.2017.08.302
SU114. EARLY SEXUAL ASSAULTIVE TRAUMA, POLYGENIC RISK FOR AUD/CUD, AND NEURAL RESPONSE INHIBITION IN ADOLESCENCE AND YOUNG ADULTS: TRAJECTORIES OF FRONTAL OSCILLATIONS DURING A GO/NOGO TASK n
Background: Cannabis is the most widely used illicit drug in the world. It is well established that substance abuse comorbidity i.a. cannabis use is much higher among patients with Schizophrenia (SCZ) and Bipolar Disorders (BD) than in the general population. However, the relationship between risk of SCZ, BD and cannabis use has not been completely
Jacquelyn Meyers ,1, Vivia McCutheon2, Ashwini Pandey1, David Chorlian1, Chella Kamarajan1, Michael Seay1, Stacey Subbie1, Jian Zhang1, Arpana Agrawal2, Samuel Kuperman3, John Kramer3, Andrey Anokhin2, Victor Hesselbrock4, Kathleen Bucholz2, Bernice Porjesz1
S951
1–1.5% and the heritability of CUD is estimated to 51–70%. With respect to the amount of risk explained by common variants, the SNP heritability has been estimated to 0.06– 0.2. The difference between total heritability and SNP heritability suggests that rare variants might contribute to the risk of CUD, which require sequencing to find them. Methods: We performed whole-exome sequencing of 7,366 Danish individuals identified in the Danish Newborn Screening Biobank (DNSB), including 1,236 affected with CUD, and 6,100 unaffected controls. We aligned exome sequence data against GRCh37 human genome reference with bwa and identified variants using GATK. We performed quality control of variants and individuals (including principal component analysis for exclusion of non-Europeans), annotated variants with respect to gene, functional impact and presence in the ExAC non-psych database using Hail. Subsequently various burden tests were performed. Results: Here we will present results from analysis of the impact of Ultra-Rare Variants (URVs) in CUD. We will especially focus on the burden of these variants in CUD cases compared to controls in highly evolutionary constrained genes as well as specific gene-sets relevant to CUD. Furthermore, we will assess whether CUD risk genes identified based on the common variant analysis also carry an increased burden of URVs. In addition, we will conduct gene-based association analysis to identify top-ranking genes most frequently hit by rare deleterious variants in CUD cases compared with controls. Discussion: We will discuss our comprehensive analyses of the role of URVs in CUD, which will further contribute to the understanding of the genetic architecture underlying the disorder, and help elucidating relevant biological mechanism contributing to disease risk.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.301
SU113. POLYGENIC RISK BURDEN AND CANNABIS USE COMORBIDITY IN PATIENTS WITH SCHIZOPHRENIA AND BIPOLAR DISORDER
understood so far. Previous studies have revealed that a genetic predisposition to SCZ might be associated with increased use of cannabis in healthy individuals. Given this relationship, we intended to study whether polygenic risk scores (PRS) for SCZ predict cannabis use in patients with SCZ and BD. In addition, we want to test whether BD PRS or Cannabis (CAN) PRS have an impact on cannabis use in these two subgroups. Methods: The present study included the USA GAIN/TGEN sample (1.150 BD patients) and the German KFO/PsyCourse cohort (433 SCZ and 327 BD patients) (www.kfo241.de; www.PsyCourse.de). Information on ever/never use of cannabis was available in these samples. PRS were calculated as follows: For each SNP contributing to the PRS, the number of risk variants carried by an individual was multiplied by the logarithm of the odds ratio for that particular variant. The resulting values were summed up in an additive fashion obtaining a weighted individual estimate of the SCZ genetic burden in each individual at different p-value thresholds. The most recent summary statistics on SCZ GWAS (Ripke et al., 2014), BD GWAS (Hou et al., 2016) and Cannabis use (Sherva et al., 2016) were used to ascertain risk variants, their P-values, and associated odds ratios for the respective disorders. Results: SCZ PRS were associated (Po0.05) with cannabis use in the GAIN/TGEN sample of BD patients in all P-value thresholds tested ranging from P= 0.04 until P= 1. A larger genetic burden was associated with a higher risk to use cannabis. The R2 change explained by PRS ranged from 0.5% to 1.15%. These effects of SCZ PRS were replicated in the BD patients from the KFO/PsyCourse cohort (P-value threshold 0.0001, R2 change = 1.94%, P-value = 0.020). No effects were observed in the SCZ patients from this replication cohort. Likewise, no associations were observed between BD PRS and CAN PRS in any of the subsamples in this study. Discussion: First results suggest that individuals with BD and an increased polygenic risk for SCZ are more likely to use cannabis. The association between BD and cannabis use might be not simply one of an environmental risk factor, but rather involves gene–environment interaction, as individuals choose and shape their own environment according on their own innate preferences.
Disclosure: Nothing to disclose.
n
Kristina Adorjan ,1, Sergi Papiol1, Katrin Gade1, Dörthe Malzahn1, Richard Sherva2, Monika Budde1, Fanny Aldinger1, Janos Kalman1, Urs Heilbronner1, Heike Anderson-Schmidt3, Oliver Pogarell4, Peter Falkai4, Joel Gelernter2, Thomas Schulze1 1
Institute of Psychiatric Phenomics and Genomics Yale School of Medicine 3 University Medical Centre Goettingen 4 Ludwig- Maximilian University of Munich 2
http://dx.doi.org/10.1016/j.euroneuro.2017.08.302
SU114. EARLY SEXUAL ASSAULTIVE TRAUMA, POLYGENIC RISK FOR AUD/CUD, AND NEURAL RESPONSE INHIBITION IN ADOLESCENCE AND YOUNG ADULTS: TRAJECTORIES OF FRONTAL OSCILLATIONS DURING A GO/NOGO TASK n
Background: Cannabis is the most widely used illicit drug in the world. It is well established that substance abuse comorbidity i.a. cannabis use is much higher among patients with Schizophrenia (SCZ) and Bipolar Disorders (BD) than in the general population. However, the relationship between risk of SCZ, BD and cannabis use has not been completely
Jacquelyn Meyers ,1, Vivia McCutheon2, Ashwini Pandey1, David Chorlian1, Chella Kamarajan1, Michael Seay1, Stacey Subbie1, Jian Zhang1, Arpana Agrawal2, Samuel Kuperman3, John Kramer3, Andrey Anokhin2, Victor Hesselbrock4, Kathleen Bucholz2, Bernice Porjesz1