Abstract Background There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity. Methods Here, we test ...the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: COGEND (ascertained for nicotine dependence n=918 cases, 988 controls), COGA (ascertained for alcohol dependence n=643 cases, 384 controls), and FSCD (ascertained for cocaine dependence n=210 cases, 317 controls). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to 1000 Genomes reference panel. Results In each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo R2 range 0.8%-3.7%, minimum p=4x10-23 ). Conclusions These results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.
Abstract Nicotine dependence is highly comorbid with schizophrenia, and the etiology of the comorbidity is unknown. To determine whether there is a genetic correlation of smoking behavior with ...schizophrenia, genome-wide association study (GWAS) meta-analysis results from five smoking phenotypes (ever/never smoker (N = 74,035), age of onset of smoking (N = 28,647), cigarettes smoked per day (CPD, N = 38,860), nicotine dependence (N = 10,666), and current/former smoker (N = 40,562)) were compared to GWAS meta-analysis results from schizophrenia (N = 79,845) using linkage disequilibrium (LD) score regression. First, the SNP heritability ( h2 g ) of each of the smoking phenotypes was computed using LD score regression (ever/never smoker h2 g = 0.08, age of onset of smoking h2 g = 0.06, CPD h2 g = 0.06, nicotine dependence h2 g = 0.15, current/former smoker h2 g = 0.07, p < 0.001 for all phenotypes). The SNP heritability for nicotine dependence was statistically higher than the SNP heritability for the other smoking phenotypes (p < 0.0005 for all two-way comparisons). Next, a statistically significant (p < 0.05) genetic correlation was observed between schizophrenia and three of the five smoking phenotypes (nicotine dependence r g = 0.14, CPD r g = 0.12, and ever/never smoking r g = 0.10). These results suggest that there is a component of common genetic variation that is shared between smoking behaviors and schizophrenia.
Objective:The authors sought to demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes.Method:In ...a large genome-wide association study of cases with schizophrenia and controls, the authors first identified sets of interacting single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (SNP sets) regardless of clinical status. Second, they examined the risk of schizophrenia for each SNP set and tested replicability in two independent samples. Third, they identified genotypic networks composed of SNP sets sharing SNPs or subjects. Fourth, they identified sets of distinct clinical features that cluster in particular cases (phenotypic sets or clinical syndromes) without regard for their genetic background. Fifth, they tested whether SNP sets were associated with distinct phenotypic sets in a replicable manner across the three studies.Results:The authors identified 42 SNP sets associated with a 70% or greater risk of schizophrenia, and confirmed 34 (81%) or more with similar high risk of schizophrenia in two independent samples. Seventeen networks of SNP sets did not share any SNP or subject. These disjoint genotypic networks were associated with distinct gene products and clinical syndromes (i.e., the schizophrenias) varying in symptoms and severity. Associations between genotypic networks and clinical syndromes were complex, showing multifinality and equifinality. The interactive networks explained the risk of schizophrenia more than the average effects of all SNPs (24%).Conclusions:Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.
IMPORTANCE Although early mortality in severe psychiatric illness is linked to smoking and alcohol, to our knowledge, no studies have comprehensively characterized substance use behavior in severe ...psychotic illness. In particular, recent assessments of substance use in individuals with mental illness are based on population surveys that do not include individuals with severe psychotic illness. OBJECTIVE To compare substance use in individuals with severe psychotic illness with substance use in the general population. DESIGN, SETTING, AND PARTICIPANTS We assessed comorbidity between substance use and severe psychotic disorders in the Genomic Psychiatry Cohort. The Genomic Psychiatry Cohort is a clinically assessed, multiethnic sample consisting of 9142 individuals with the diagnosis of schizophrenia, bipolar disorder with psychotic features, or schizoaffective disorder, and 10 195 population control individuals. MAIN OUTCOMES AND MEASURES Smoking (smoked >100 cigarettes in a lifetime), heavy alcohol use (>4 drinks/day), heavy marijuana use (>21 times of marijuana use/year), and recreational drug use. RESULTS Relative to the general population, individuals with severe psychotic disorders have increased risks for smoking (odds ratio, 4.6; 95% CI, 4.3-4.9), heavy alcohol use (odds ratio, 4.0; 95% CI, 3.6-4.4), heavy marijuana use (odds ratio, 3.5; 95% CI, 3.2-3.7), and recreational drug use (odds ratio, 4.6; 95% CI, 4.3-5.0). All races/ethnicities (African American, Asian, European American, and Hispanic) and both sexes have greatly elevated risks for smoking and alcohol, marijuana, and drug use. Of specific concern, recent public health efforts that have successfully decreased smoking among individuals younger than age 30 years appear to have been ineffective among individuals with severe psychotic illness (interaction effect between age and severe mental illness on smoking initiation, P = 4.5 × 105). CONCLUSIONS AND RELEVANCE In the largest assessment of substance use among individuals with severe psychotic illness to date, we found the odds of smoking and alcohol and other substance use to be dramatically higher than recent estimates of substance use in mild mental illness.
IMPORTANCE Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease ...understanding and address the urgent need for new drug targets. OBJECTIVE To identify SCZ susceptibility genes. DESIGN We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. SETTING Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. PATIENTS We included 11 185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. MAIN OUTCOMES AND MEASURES Case-control status for SCZ. RESULTS Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P <. 01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 × 10−16) and 93% in subjects of European ancestry only (P < 2.20 × 10−16). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 × 10−10) and NOTCH4 (P = 3.16 × 10−7) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 × 10−7), AS3MT (P = 9.01 × 10−7), CNNM2 (P = 6.07 × 10−7), and NT5C2 (P = 4.09 × 10−7). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). CONCLUSIONS AND RELEVANCE We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.
•Individuals with BD reported having experienced more childhood and lifetime adverse events.•Individuals with BD had a higher prevalence of PTSD.•Among all the ACE questions, parental psychopathology ...has the highest OR.•Physical abuse, emotional abuse and emotional neglect also had relatively high OR.
We examined the presence of adverse events in both childhood and adulthood and the prevalence of PTSD in individuals with Bipolar Disorder (BD). There were 191 adults diagnosed with BD Type I and 924 controls, of predominantly African Ancestry (AA). All were administered the GPC-Screening Tool and the BD group the DIPAD. In addition Childhood adversities were measured using the ACE (from 0 to 10), about traumatic events before age 18 and lifetime adversities were measured with 15 questions adapted from the Study of Addiction: Genetics and Environment (A-SAGE (from 0 to 15) for all cases and controls. Probable PTSD (pPTSD) was measured with 4 questions on the GPC screener. Sum scores were calculated for the ACE and A-SAGE by tallying positive responses. Odd Ratios (OR) were used to measure the association between BD and Controls exposure to adversity. BD was associated with a significantly higher mean ACE score and A-SAGE score compared to controls. There was a significantly higher prevalence of pPTSD in the BD (54.5%) versus Controls (6.6%) as well. Greater OR's were seen in the BD compared to Controls for each ACE question (p<0.05). Results were similar for A-SAGE. Limitations include possible recall bias, and missing data.
The study of neurodevelopmental molecular mechanisms in schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously ...utilized cell lines with neural progenitor properties (CNON) derived from the superior or middle turbinates of patients with schizophrenia and control groups to study schizophrenia-specific gene expression. In this study, we analyzed single-cell RNA seq data from two CNON cell lines (one derived from an individual with schizophrenia (SCZ) and the other from a control group) and two biopsy samples from the middle turbinate (MT) (also from an individual with SCZ and a control). We compared our data with previously published data regarding the olfactory neuroepithelium and demonstrated that CNON originated from a single cell type present both in middle turbinate and the olfactory neuroepithelium and expressed in multiple markers of mesenchymal cells. To define the relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data derived from an embryonic brain and found that the expression profile of the CNON closely matched the expression profile one of the cell types in the embryonic brain. Finally, we evaluated the differences between SCZ and control samples to assess the utility and potential benefits of using CNON single-cell RNA seq to study the etiology of schizophrenia.
IMPORTANCE: DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. OBJECTIVE: To scan genome-wide DNA methylation ...data to identify differentially methylated CpGs between SZ cases and controls. DESIGN, SETTING, AND PARTICIPANTS: Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases and 250 controls (n = 497) from the Genomic Psychiatry Cohort. MAIN OUTCOMES AND MEASURES: Identification of differentially methylated positions across the genome in SZ cases compared with controls. RESULTS: Of the 689 case participants in the discovery set, 477 (69%) were men and 258 (37%) were non–African American; of the 645 controls, 273 (42%) were men and 419 (65%) were non–African American. In our replication set, cases/controls were 76% male and 100% non–African American. We identified SZ-associated methylation differences at 923 CpGs in the discovery set (false discovery rate, <0.2). Of these, 625 showed changes in the same direction including 172 with P < .05 in the replication set. Some replicated differentially methylated positions are located in a top-ranked SZ region from genome-wide association study analyses. CONCLUSIONS AND RELEVANCE: This analysis identified 172 replicated new associations with SZ after careful correction for cell type heterogeneity and other potential confounders. The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for SZ.
Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely ...unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10−4). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.
A detailed understanding of the genome-wide variability of single-nucleotide germline mutation rates is essential to studying human genome evolution. Here, we use ~36 million singleton variants from ...3560 whole-genome sequences to infer fine-scale patterns of mutation rate heterogeneity. Mutability is jointly affected by adjacent nucleotide context and diverse genomic features of the surrounding region, including histone modifications, replication timing, and recombination rate, sometimes suggesting specific mutagenic mechanisms. Remarkably, GC content, DNase hypersensitivity, CpG islands, and H3K36 trimethylation are associated with both increased and decreased mutation rates depending on nucleotide context. We validate these estimated effects in an independent dataset of ~46,000 de novo mutations, and confirm our estimates are more accurate than previously published results based on ancestrally older variants without considering genomic features. Our results thus provide the most refined portrait to date of the factors contributing to genome-wide variability of the human germline mutation rate.
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