Publications by authors named "Pablo V Gejman"

67 Publications

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Genome-wide analyses of smoking behaviors in schizophrenia: Findings from the Psychiatric Genomics Consortium.

J Psychiatr Res 2021 05 18;137:215-224. Epub 2021 Feb 18.

Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY, USA. Electronic address:

While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia are upwards of 60%. Research supports a shared etiological basis for smoking and schizophrenia, including findings from genome-wide association studies (GWAS). However, few studies have directly tested whether the same or distinct genetic variants also influence smoking behavior among schizophrenia cases. Using data from the Psychiatric Genomics Consortium (PGC) study of schizophrenia (35476 cases, 46839 controls), we estimated genetic correlations between these traits and tested whether polygenic risk scores (PRS) constructed from the results of smoking behaviors GWAS were associated with schizophrenia risk or smoking behaviors among schizophrenia cases. Results indicated significant genetic correlations of schizophrenia with smoking initiation (r = 0.159; P = 5.05 × 10), cigarettes-smoked-per-day (r = 0.094; P = 0.006), and age-of-onset of smoking (r = 0.10; P = 0.009). Comparing smoking behaviors among schizophrenia cases to the general population, we observe positive genetic correlations for smoking initiation (r = 0.624, P = 0.002) and cigarettes-smoked-per-day (r = 0.689, P = 0.120). Similarly, TAG-based PRS for smoking initiation and cigarettes-smoked-per-day were significantly associated with smoking initiation (P = 3.49 × 10) and cigarettes-smoked-per-day (P = 0.007) among schizophrenia cases. We performed the first GWAS of smoking behavior among schizophrenia cases and identified a novel association with cigarettes-smoked-per-day upstream of the TMEM106B gene on chromosome 7p21.3 (rs148253479, P = 3.18 × 10, n = 3520). Results provide evidence of a partially shared genetic basis for schizophrenia and smoking behaviors. Additionally, genetic risk factors for smoking behaviors were largely shared across schizophrenia and non-schizophrenia populations. Future research should address mechanisms underlying these associations to aid both schizophrenia and smoking treatment and prevention efforts.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096167PMC
May 2021

Allele-specific open chromatin in human iPSC neurons elucidates functional disease variants.

Science 2020 07;369(6503):561-565

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.

Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)-derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.
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http://dx.doi.org/10.1126/science.aay3983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773145PMC
July 2020

The Genetic Relevance of Human Induced Pluripotent Stem Cell-Derived Microglia to Alzheimer's Disease and Major Neuropsychiatric Disorders.

Mol Neuropsychiatry 2020 Apr 23;5(Suppl 1):85-96. Epub 2019 Jul 23.

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, Illinois, USA.

Microglia are the primary innate immune cell type in the brain that have been implicated in the pathogenesis of several neurodegenerative and neuropsychiatric disorders, most notably Alzheimer's disease (AD) and schizophrenia. Microglia generated from human induced pluripotent stem cells (hiPSCs) represent a promising in vitro cellular model for studying the neuroimmune interactions involved in these disorders. Among several methods of generating -hiPSC-derived microglia (iMG) - varying in duration and resultant purity - a recent protocol by Brownjohn et al. [Stem Cell Reports. 2018 Apr;10(4):1294-307] is particularly simple and efficient. However, the replicability of this method, transcriptomic similarity of these iMG to primary adult microglia, and their genetic relevance to disease (i.e., enrichment of disease risk loci in genes preferentially expressed in these cells) remains unclear. Using two hiPSC lines, we demonstrated that Brownjohn's protocol can rapidly generate iMG that morphologically and functionally resembled microglia. The iMG cells we generated were found to be transcriptionally similar to previously reported iMG, as well as fetal and adult microglia. Furthermore, by using cell type-specific gene expression to partition disease heritability, we showed that iMG cells are genetically relevant to AD but found no significant enrichments of risk loci of Parkinson's disease, schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorder, or body mass index. Across a range of neuronal and immune cell types, we found only iMG, primary microglia, and microglia-like cell types exhibited a significant enrichment for AD heritability. Our results thus support the use of iMG as a human cellular model for understanding AD biology and underlying genetic factors, as well as for developing and efficiently screening new therapeutics.
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http://dx.doi.org/10.1159/000501935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206606PMC
April 2020

From Schizophrenia Genetics to Disease Biology: Harnessing New Concepts and Technologies.

J Psychiatr Brain Sci 2019 19;4. Epub 2019 Sep 19.

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.

Schizophrenia (SZ) is a severe mental disorder afflicting around 1% of the population. It is highly heritable but with complex genetics. Recent research has unraveled a plethora of risk loci for SZ. Accordingly, our conceptual understanding of SZ genetics has been rapidly evolving, from oligogenic models towards polygenic or even omnigenic models. A pressing challenge to the field, however, is the translation of the many genetic findings of SZ into disease biology insights leading to more effective treatments. Bridging this gap requires the integration of genetic findings and functional genomics using appropriate cellular models. Harnessing new technologies, such as the development of human induced pluripotent stem cells (hiPSC) and the CRISPR/Cas-based genome/epigenome editing approach are expected to change our understanding of SZ disease biology to a fundamentally higher level. Here, we discuss some new developments.
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http://dx.doi.org/10.20900/jpbs.20190014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760308PMC
September 2019

From Schizophrenia Genetics to Disease Biology: Harnessing New Concepts and Technologies.

J Psychiatr Brain Sci 2019 19;4. Epub 2019 Sep 19.

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.

Schizophrenia (SZ) is a severe mental disorder afflicting around 1% of the population. It is highly heritable but with complex genetics. Recent research has unraveled a plethora of risk loci for SZ. Accordingly, our conceptual understanding of SZ genetics has been rapidly evolving, from oligogenic models towards polygenic or even omnigenic models. A pressing challenge to the field, however, is the translation of the many genetic findings of SZ into disease biology insights leading to more effective treatments. Bridging this gap requires the integration of genetic findings and functional genomics using appropriate cellular models. Harnessing new technologies, such as the development of human induced pluripotent stem cells (hiPSC) and the CRISPR/Cas-based genome/epigenome editing approach are expected to change our understanding of SZ disease biology to a fundamentally higher level. Here, we discuss some new developments.
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http://dx.doi.org/10.20900/jpbs.20190014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760308PMC
September 2019

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts.

Biol Psychiatry 2019 06 13;85(12):1065-1073. Epub 2019 Mar 13.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Background: Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings.

Methods: In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions.

Results: Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5.

Conclusions: The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.
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http://dx.doi.org/10.1016/j.biopsych.2019.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750266PMC
June 2019

Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery.

Transl Psychiatry 2018 12 13;8(1):278. Epub 2018 Dec 13.

South Texas Diabetes and Obesity Institute, Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, USA.

The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). Gene co-expression modules were identified using Weighted Gene Co-expression Network Analysis for both baseline and DA-stimulated conditions, with each module characterized for biological function and tested for association with SZ status and SNPs from a genome-wide panel. We identified seven co-expression modules under baseline, of which six were preserved in DA-stimulated data. One module shows significantly increased association with SZ after DA perturbation (baseline: P = 0.023; DA-stimulated: P = 7.8 × 10; ΔAIC = -10.5) and is highly enriched for genes related to ribosomal proteins and translation (FDR = 4 × 10), mitochondrial oxidative phosphorylation, and neurodegeneration. SNP association testing revealed tentative QTLs underlying module co-expression, notably at FASTKD2 (top P = 2.8 × 10), a gene involved in mitochondrial translation. These results substantiate the role of translational machinery in SZ pathogenesis, providing insights into a possible dopaminergic mechanism disrupting mitochondrial function, and demonstrates the utility of disease-relevant functional perturbation in the study of complex genetic etiologies.
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http://dx.doi.org/10.1038/s41398-018-0325-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293320PMC
December 2018

Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model.

Transl Psychiatry 2018 08 16;8(1):158. Epub 2018 Aug 16.

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA.

The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders.
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http://dx.doi.org/10.1038/s41398-018-0216-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095865PMC
August 2018

Clinotator: analyzing ClinVar variation reports to prioritize reclassification efforts.

F1000Res 2018 13;7:462. Epub 2018 Apr 13.

Genomic Health Initiative, NorthShore University HealthSystem, Evanston, Illinois, 60201, USA.

While ClinVar has become an indispensable resource for clinical variant interpretation, its sophisticated structure provides it with a daunting learning curve. Often the sheer depth of types of information provided can make it difficult to analyze variant information with high throughput. Clinotator is a fast and lightweight tool to extract important aspects of criteria-based clinical assertions; it uses that information to generate several metrics to assess the strength and consistency of the evidence supporting the variant clinical significance. Clinical assertions are weighted by significance type, age of submission and submitter expertise category to filter outdated or incomplete assertions that otherwise confound interpretation. This can be accomplished in batches: either lists of Variation IDs or dbSNP rsIDs, or with vcf files that are additionally annotated. Using sample sets ranging from 15,000-50,000 variants, we slice out problem variants in minutes without extensive computational effort (using only a personal computer) and corroborate recently reported trends of discordance hiding amongst the curated masses. With the rapidly growing body of variant evidence, most submitters and researchers have limited resources to devote to variant curation. Clinotator provides efficient, systematic prioritization of discordant variants in need of reclassification. The hope is that this tool can inform ClinVar curation and encourage submitters to keep their clinical assertions current by focusing their efforts. Additionally, researchers can utilize new metrics to analyze variants of interest in pursuit of new insights into pathogenicity.
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http://dx.doi.org/10.12688/f1000research.14470.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941247PMC
April 2018

Analysis of shared heritability in common disorders of the brain.

Science 2018 06;360(6395)

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
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http://dx.doi.org/10.1126/science.aap8757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097237PMC
June 2018

Open chromatin dynamics reveals stage-specific transcriptional networks in hiPSC-based neurodevelopmental model.

Stem Cell Res 2018 05 31;29:88-98. Epub 2018 Mar 31.

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, IL 60637, USA. Electronic address:

Chromatin accessibility to transcription factors (TFs) strongly influences gene transcription and cell differentiation. However, a mechanistic understanding of the transcriptional control during the neuronal differentiation of human induced pluripotent stem cells (hiPSCs), a promising cellular model for mental disorders, remains elusive. Here, we carried out additional analyses on our recently published open chromatin regions (OCRs) profiling at different stages of hiPSC neuronal differentiation. We found that the dynamic changes of OCR during neuronal differentiation highlighted cell stage-specific gene networks, and the chromatin accessibility at the core promoter region of a gene correlates with the corresponding transcript abundance. Within the cell stage-specific OCRs, we identified the binding of cell stage-specific TFs and observed a lag of a neuronal TF binding behind the mRNA expression of the corresponding TF. Interestingly, binding footprints of NEUROD1 and NEUROG2, both of which induce high efficient conversion of hiPSCs to glutamatergic neurons, were among those most enriched in the relatively mature neurons. Furthermore, TF network analysis showed that both NEUROD1 and NEUROG2 were present in the same core TF network specific to more mature neurons, suggesting a pivotal mechanism of epigenetic control of neuronal differentiation and maturation. Our study provides novel insights into the epigenetic control of glutamatergic neurogenesis in the context of TF networks, which may be instrumental to improving hiPSC modeling of neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.scr.2018.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025752PMC
May 2018

Genome-Wide Association Study of Male Sexual Orientation.

Sci Rep 2017 12 7;7(1):16950. Epub 2017 Dec 7.

Department of Human Genetics, University of Miami, Miami, Florida, 33136, United States of America.

Family and twin studies suggest that genes play a role in male sexual orientation. We conducted a genome-wide association study (GWAS) of male sexual orientation on a primarily European ancestry sample of 1,077 homosexual men and 1,231 heterosexual men using Affymetrix single nucleotide polymorphism (SNP) arrays. We identified several SNPs with p < 10, including regions of multiple supporting SNPs on chromosomes 13 (minimum p = 7.5 × 10) and 14 (p = 4.7 × 10). The genes nearest to these peaks have functions plausibly relevant to the development of sexual orientation. On chromosome 13, SLITRK6 is a neurodevelopmental gene mostly expressed in the diencephalon, which contains a region previously reported as differing in size in men by sexual orientation. On chromosome 14, TSHR genetic variants in intron 1 could conceivably help explain past findings relating familial atypical thyroid function and male homosexuality. Furthermore, skewed X chromosome inactivation has been found in the thyroid condition, Graves' disease, as well as in mothers of homosexual men. On pericentromeric chromosome 8 within our previously reported linkage peak, we found support (p = 4.1 × 10) for a SNP association previously reported (rs77013977, p = 7.1 × 10), with the combined analysis yielding p = 6.7 × 10, i.e., a genome-wide significant association.
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http://dx.doi.org/10.1038/s41598-017-15736-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721098PMC
December 2017

Open Chromatin Profiling in hiPSC-Derived Neurons Prioritizes Functional Noncoding Psychiatric Risk Variants and Highlights Neurodevelopmental Loci.

Cell Stem Cell 2017 09 10;21(3):305-318.e8. Epub 2017 Aug 10.

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA. Electronic address:

Most disease variants lie within noncoding genomic regions, making their functional interpretation challenging. Because chromatin openness strongly influences transcriptional activity, we hypothesized that cell-type-specific open chromatin regions (OCRs) might highlight disease-relevant noncoding sequences. To investigate, we mapped global OCRs in neurons differentiating from hiPSCs, a cellular model for studying neurodevelopmental disorders such as schizophrenia (SZ). We found that the OCRs are highly dynamic and can stratify GWAS-implicated SZ risk variants. Of the more than 3,500 SZ-associated variants analyzed, we prioritized ∼100 putatively functional ones located in neuronal OCRs, including rs1198588, at a leading risk locus flanking MIR137. Excitatory neurons derived from hiPSCs with CRISPR/Cas9-edited rs1198588 or a rare proximally located SZ risk variant showed altered MIR137 expression, dendrite arborization, and synapse maturation. Our study shows that noncoding disease variants in OCRs can affect neurodevelopment, and that analysis of open chromatin regions can help prioritize functionally relevant noncoding variants identified by GWAS.
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http://dx.doi.org/10.1016/j.stem.2017.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591074PMC
September 2017

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Nat Genet 2017 01 21;49(1):27-35. Epub 2016 Nov 21.

Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
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http://dx.doi.org/10.1038/ng.3725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737772PMC
January 2017

Genome-wide association study identifies 74 loci associated with educational attainment.

Nature 2016 05 11;533(7604):539-42. Epub 2016 May 11.

Department of Neurology, General Hospital and Medical University Graz, Graz 8036, Austria.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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http://dx.doi.org/10.1038/nature17671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883595PMC
May 2016

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders.

PLoS Genet 2016 05 6;12(5):e1005993. Epub 2016 May 6.

The State Diagnostic and Counselling Centre, Kópavogur, Iceland.

Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.
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http://dx.doi.org/10.1371/journal.pgen.1005993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859484PMC
May 2016

Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness.

Am J Med Genet B Neuropsychiatr Genet 2016 Mar 11;171B(2):276-89. Epub 2015 Dec 11.

Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.
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http://dx.doi.org/10.1002/ajmg.b.32402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816590PMC
March 2016

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

PLoS Genet 2015 Oct 1;11(10):e1005378. Epub 2015 Oct 1.

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
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http://dx.doi.org/10.1371/journal.pgen.1005378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591371PMC
October 2015

New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.

Int J Epidemiol 2015 Oct;44(5):1706-21

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders.

Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born.

Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090).

Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.
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http://dx.doi.org/10.1093/ije/dyv136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881824PMC
October 2015

Transcriptome outlier analysis implicates schizophrenia susceptibility genes and enriches putatively functional rare genetic variants.

Hum Mol Genet 2015 Aug 28;24(16):4674-85. Epub 2015 May 28.

Center for Psychiatric Genetics and Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.

We searched a gene expression dataset comprised of 634 schizophrenia (SZ) cases and 713 controls for expression outliers (i.e., extreme tails of the distribution of transcript expression values) with SZ cases overrepresented compared with controls. These outlier genes were enriched for brain expression and for genes known to be associated with neurodevelopmental disorders. SZ cases showed higher outlier burden (i.e., total outlier events per subject) than controls for genes within copy number variants (CNVs) associated with SZ or neurodevelopmental disorders. Outlier genes were enriched for CNVs and for rare putative regulatory variants, but this only explained a small proportion of the outlier subjects, highlighting the underlying presence of additional genetic and potentially, epigenetic mechanisms.
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http://dx.doi.org/10.1093/hmg/ddv199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512633PMC
August 2015

Genetic studies of body mass index yield new insights for obesity biology.

Nature 2015 Feb;518(7538):197-206

Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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http://dx.doi.org/10.1038/nature14177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382211PMC
February 2015

A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder.

Am J Hum Genet 2014 Dec 26;95(6):744-53. Epub 2014 Nov 26.

Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA; Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA.

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.
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http://dx.doi.org/10.1016/j.ajhg.2014.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259974PMC
December 2014

Defining the role of common variation in the genomic and biological architecture of adult human height.

Nat Genet 2014 Nov 5;46(11):1173-86. Epub 2014 Oct 5.

Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
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http://dx.doi.org/10.1038/ng.3097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250049PMC
November 2014

A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness.

Nat Commun 2014 Sep 16;5:4858. Epub 2014 Sep 16.

1] Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

Dendritic spine pathology is a key feature of several neuropsychiatric disorders. The Rac1 guanine nucleotide exchange factor kalirin-7 is critical for spine morphogenesis on cortical pyramidal neurons. Here we identify a rare coding variant in the KALRN gene region that encodes the catalytic domain, in a schizophrenia patient and his sibling with major depressive disorder. The D1338N substitution significantly diminished the protein's ability to catalyse the activation of Rac1. Contrary to wild-type kalirin-7, kalirin-7-D1338N failed to increase spine size and density. Both subjects carrying the polymorphism displayed reduced cortical volume in the superior temporal sulcus (STS), a region implicated in schizophrenia. Consistent with this, mice with reduced kalirin expression showed reduced neuropil volume in the rodent homologue of the STS. These data suggest that single amino acid changes in proteins involved in dendritic spine function can have significant effects on the structure and function of the cerebral cortex.
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http://dx.doi.org/10.1038/ncomms5858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166532PMC
September 2014

Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia.

Mol Psychiatry 2014 Sep 26;19(9):1017-1024. Epub 2013 Nov 26.

Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.
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http://dx.doi.org/10.1038/mp.2013.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033708PMC
September 2014

CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1.

Hum Mol Genet 2014 Mar 26;23(6):1669-76. Epub 2013 Oct 26.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK.

Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.
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http://dx.doi.org/10.1093/hmg/ddt540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929090PMC
March 2014

Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

Nat Genet 2013 Oct 25;45(10):1150-9. Epub 2013 Aug 25.

1] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3].

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
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http://dx.doi.org/10.1038/ng.2742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827979PMC
October 2013

Additive genetic variation in schizophrenia risk is shared by populations of African and European descent.

Am J Hum Genet 2013 Sep 15;93(3):463-70. Epub 2013 Aug 15.

Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80302, USA.

To investigate the extent to which the proportion of schizophrenia's additive genetic variation tagged by SNPs is shared by populations of European and African descent, we analyzed the largest combined African descent (AD [n = 2,142]) and European descent (ED [n = 4,990]) schizophrenia case-control genome-wide association study (GWAS) data set available, the Molecular Genetics of Schizophrenia (MGS) data set. We show how a method that uses genomic similarities at measured SNPs to estimate the additive genetic correlation (SNP correlation [SNP-rg]) between traits can be extended to estimate SNP-rg for the same trait between ethnicities. We estimated SNP-rg for schizophrenia between the MGS ED and MGS AD samples to be 0.66 (SE = 0.23), which is significantly different from 0 (p(SNP-rg = 0) = 0.0003), but not 1 (p(SNP-rg = 1) = 0.26). We re-estimated SNP-rg between an independent ED data set (n = 6,665) and the MGS AD sample to be 0.61 (SE = 0.21, p(SNP-rg = 0) = 0.0003, p(SNP-rg = 1) = 0.16). These results suggest that many schizophrenia risk alleles are shared across ethnic groups and predate African-European divergence.
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http://dx.doi.org/10.1016/j.ajhg.2013.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845872PMC
September 2013
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