Dataset Information

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

ABSTRACT:

Background

Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572.

Methods

We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date.

Results

Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572.

Conclusions

We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

SUBMITTER: Bigdeli TB

PROVIDER: S-EPMC7965063 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

Bigdeli Tim B TB Fanous Ayman H AH Li Yuli Y Rajeevan Nallakkandi N Sayward Frederick F Genovese Giulio G Gupta Rishab R Radhakrishnan Krishnan K Malhotra Anil K AK Sun Ning N Lu Qiongshi Q Hu Yiming Y Li Boyang B Chen Quan Q Mane Shrikant S Miller Perry P Cheung Kei-Hoi KH Gur Raquel E RE Greenwood Tiffany A TA Braff David L DL Achtyes Eric D ED Buckley Peter F PF Escamilla Michael A MA Lehrer Douglas D Malaspina Dolores P DP McCarroll Steven A SA Rapaport Mark H MH Vawter Marquis P MP Pato Michele T MT Pato Carlos N CN Zhao Hongyu H Kosten Thomas R TR Brophy Mary M Pyarajan Saiju S Shi Yunling Y O'Leary Timothy J TJ Gleason Theresa T Przygodzki Ronald R Muralidhar Sumitra S Gaziano J Michael JM Huang Grant D GD Concato John J Siever Larry J LJ Aslan Mihaela M Harvey Philip D PD

Schizophrenia bulletin 20210301 2

<h4>Background</h4>Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572.<h4>Methods</h4>We performed genome-wide association ...[more]

PMID: 33169155

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Project description:ObjectivesRecent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD.MethodsA total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations.ResultsAssociations of eight a priori GWAS SNPs with BD were replicated with nominal (P≤.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5'-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction.ConclusionsThese results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos. Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD.

Project description:Numerous genome-wide gene expression studies of bipolar disorder (BP) have been carried out. These studies are heterogeneous, underpowered and use overlapping samples. We conducted a systematic review of these studies to synthesize the current findings.We identified all genome-wide gene expression studies on BP in humans. We then carried out a quantitative mega-analysis of studies done with post-mortem brain tissue. We obtained raw data from each study and used standardized procedures to process and analyze the data. We then combined the data and conducted three separate mega-analyses on samples from 1) any region of the brain (9 studies); 2) the prefrontal cortex (PFC) (6 studies); and 3) the hippocampus (2 studies). To minimize heterogeneity across studies, we focused primarily on the most numerous, recent and comprehensive studies.A total of 30 genome-wide gene expression studies of BP done with blood or brain tissue were identified. We included 10 studies with data on 211 microarrays on 57 unique BP cases and 229 microarrays on 60 unique controls in the quantitative mega-analysis. A total of 382 genes were identified as significantly differentially expressed by the three analyses. Eleven genes survived correction for multiple testing with a q-value < 0.05 in the PFC. Among these were FKBP5 and WFS1, which have been previously implicated in mood disorders. Pathway analyses suggested a role for metallothionein proteins, MAP Kinase phosphotases, and neuropeptides.We provided an up-to-date summary of results from gene expression studies of the brain in BP. Our analyses focused on the highest quality data available and provided results by brain region so that similarities and differences can be examined relative to disease status. The results are available for closer inspection on-line at Metamoodics [http://metamoodics.igm.jhmi.edu/], where investigators can look up any genes of interest and view the current results in their genomic context and in relation to leading findings from other genomic experiments in bipolar disorder.

Project description:Bipolar disorder (BPD) is a complex psychiatric trait with high heritability. Despite efforts through conducting genome-wide association (GWA) studies, the success of identifying susceptibility loci for BPD has been limited, which is partially attributed to the complex nature of its pathogenesis. Pathway-based analytic strategy is a powerful tool to explore joint effects of gene sets within specific biological pathways. Additionally, to incorporate other aspects of genomic data into pathway analysis may further enhance our understanding for the underlying mechanisms for BPD. Patterns of DNA methylation play important roles in regulating gene expression and function. A commonly observed phenomenon, allele-specific methylation (ASM) describes the associations between genetic variants and DNA methylation patterns. The present study aimed to identify biological pathways that are involve in the pathogenesis of BPD while incorporating brain specific ASM information in pathway analysis using two large-scale GWA datasets in Caucasian populations. A weighting scheme was adopted to take ASM information into consideration for each pathway. After multiple testing corrections, we identified 88 and 15 enriched pathways for their biological relevance for BPD in the Genetic Association Information Network (GAIN) and the Wellcome Trust Case Control Consortium dataset, respectively. Many of these pathways were significant only when applying the weighting scheme. Three ion channel related pathways were consistently identified in both datasets. Results in the GAIN dataset also suggest for the roles of extracellular matrix in brain for BPD. Findings from Gene Ontology (GO) analysis exhibited functional enrichment among genes of non-GO pathways in activity of gated channel, transporter, and neurotransmitter receptor. We demonstrated that integrating different data sources with pathway analysis provides an avenue to identify promising and novel biological pathways for exploring the underlying molecular mechanisms for bipolar disorder. Further basic research can be conducted to target the biological mechanisms for the identified genes and pathways.

Dataset Information

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

Background

Methods

Results

Conclusions

Publications

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

Similar Datasets

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