Genetic identification of brain cell types underlying schizophrenia

Skene, Nathan G.; Bryois, Julien; Bakken, Trygve E.; Breen, Gerome; Crowley, James J.; Gaspar, Héléna A.; Giusti‐Rodríguez, Paola; Hodge, Rebecca D.; Miller, Jeremy A.; Muñoz-Manchado, Ana B.; O’Donovan, Michael; Pardiñas, Antonio F.; Ryge, Jesper; Walters, James; Linnarsson, Sten; Lein, Ed; Sullivan, Patrick F.; Hjerling-Leffler, Jens

doi:10.1038/s41588-018-0129-5

Cited by 558 publications

(796 citation statements)

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“…These results, shown in Table 9, are Bonferroni corrected and were found in a single category that showed a significant association. This analysis supports a recent study showing involvement preferentially of projection neurons as altered in SZ transcriptomic wide association study involvement [82]. As shown above for BD epistatic analysis, mitochondrial genes were not overenriched in the 530 genes analyzed.…”

Section: Interaction Analysis Of Mitochondrial and Nuclear-encoded Genessupporting

confidence: 77%

“…These interactions may ultimately transform the genetic landscape of these disorders far better than single SNP associations. Analysis of epistatic interactions when stratifying a relatively small GWAS of SZ by mtDNA SNPs produced a projection neuron single cell category that was also found in 2 much larger SZ GWAS of PGC and CLOZUK ( n > 250,000 subjects), which was highly significant [82]. With large volumes of data being generated from the sequencing of mtDNA, further effort is required to compile and evaluate these studies to completely understand the role of rare and common mitochondrial variants in psychiatric disorders.…”

Section: Resultsmentioning

confidence: 99%

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Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

et al. 2019

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Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondrial DNA (mtDNA) SNPs, T16519C and T195C, both showed an association with SZ and BD. A review of 4 studies of A15218G located in the cytochrome B oxidase gene (CYTB, SZ = 11,311, control = 35,735) shows a moderate association with SZ (p = 2.15E-03). Another mtDNA allele A12308G was nominally associated with psychosis in BD type I subjects and SZ. The first published study testing the epistatic interaction between nuclear-encoded and mitochondria-encoded genes demonstrated evidence for potential interactions between mtDNA and the nuclear genome for BD. A similar analysis for the risk of SZ revealed significant joint effects (34 nuclear-mitochondria SNP pairs with joint effect p ≤ 5E-07) and significant enrichment of projection neurons. The mitochondria-encoded gene CYTB was found in both the epistatic interactions for SZ and BD and the single SNP association of SZ. Future efforts considering population stratification and polygenic risk scores will test the role of mitochondrial variants in psychiatric disorders.

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Section: Interaction Analysis Of Mitochondrial and Nuclear-encoded Genessupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

et al. 2019

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“…The expression 8 specificity of associated genes in mouse brain cell types differed between bipolar 9 disorder and major depressive disorder analyses. Cell-types more associated with 10 bipolar disorder (pyramidal neurons and striatal interneurons) were also enriched in 11 analyses of schizophrenia (38). Cell-types more associated in major depressive 12 disorder (neuroblasts, adult dopaminergic neurons, embryonic GABAergic neurons) 13 had weaker enrichments in schizophrenia, but were enriched in analyses of 14 neuroticism (57).…”

Section: Snp-based Heritability and Genetic Correlationsmentioning

confidence: 99%

“…Gene set analysis was 9 performed in MAGMA (Supplementary Methods and Results). Further analyses were 10 performed to assess the enrichment of associated genes with expression-specificity 11 profiles from tissues (Genotype-Tissue Expression project, version 7) and broadly-12 defined ("level 1") and narrowly-defined ("level 2") mouse brain cell-types (38,39). 13 Analyses were performed in MAGMA following previously described methods with 14 minor modifications, with Bonferroni-correction for significance (Supplementary 15 Methods) (38).…”

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confidence: 99%

“…Further analyses were 10 performed to assess the enrichment of associated genes with expression-specificity 11 profiles from tissues (Genotype-Tissue Expression project, version 7) and broadly-12 defined ("level 1") and narrowly-defined ("level 2") mouse brain cell-types (38,39). 13 Analyses were performed in MAGMA following previously described methods with 14 minor modifications, with Bonferroni-correction for significance (Supplementary 15 Methods) (38). Similar analyses can be performed in LDSC-SEG -we report 16 MAGMA results, which reflect specificity of expression across the range, whereas 17 LDSC-SEG compares the top 10% of the range with the remainder (40).…”

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confidence: 99%

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The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls

Coleman

Breen

2018

Preprint

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Mood disorders affect 10-20% of the population, ranging from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Multiple approaches have shown considerable sharing of genetic risk factors between unipolar and bipolar mood disorders. We use data from the largest genome-wide association studies of major depression (MD) and bipolar disorder (BD) to investigate the molecular basis of the shared genetic liability to mood disorders. We meta-analysed we implicate pathways and neuronal subtypes which highlight similarities but also potential differences between MD and BD. Our results reflected MD more than BD, perhaps due to the larger sample size for MD, but also perhaps because depression is their predominant common feature. Overall, these results provide evidence for a genetic mood disorders spectrum.

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Schizophrenia—An Overview

2020

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he Clinical Challenge 1 in this issue of JAMA Psychiatry describes a patient who clinicians will be familiar with: a young woman who develops auditory hallucinations, unusual beliefs, and a deterioration in cognitive abilities and social function and is diagnosed with schizophrenia in early adulthood. The diagnosis of schizophrenia is based on a clinical assessment. In response to concerns regarding diagnostic reliability, early narrative descriptions of the disorder have been replaced with codified criteria (Box). Positive symptoms, such as delusions and hallucinations, are often the reason the patient presents to the clinician. However, the disorder is also associated with negative symptoms, such as amotivation and social withdrawal, and cognitive symptoms, including deficits in working memory, executive function, and processing speed. While more recent descriptions emphasize positive symptoms (Box), earlier conceptualizations saw negative symptoms as core features of the disorder, 2 and negative and cognitive symptoms contribute substantially to the long-term burden associated with the disorder. 3 The disorder typically appears in early adulthood, and a prodromal period frequently precedes the first psychotic episode (Figure 1).Schizophrenia has a lifetime prevalence of about 1% 4 and accounts for a huge health care burden, with annual associated costs in the United States estimated to be more than $150 billion. 5 The fact that a disorder affecting around 1% of the population is associated with such costs is attributable to the fact that typical onset is in early adulthood and the long-term impairments in social and occupational function associated with the disease (Figure 1). 6 The disorder is also associated with reduced life expectancy: someone with schizophrenia has a mean life expectancy about 15 years shorter than the general population and a 5% to 10% lifetime risk of death by suicide. 7 In this review, we discuss findings from epidemiological, genetic, neuroimaging, and preclinical research to provide an overview of schizophrenia and consider the gaps in knowledge that remain. Theme 1: Convergence of Genetic and Early Environmental Risk Factors on NeurodevelopmentThe patient in the Clinical Challenge 1 case has a history of perinatal complications. Although schizophrenia typically appears in early adulthood, multiple strands of evidence indicate that its pathogenesis begins early in neurodevelopment. 8 This evidence includes increased rates of in utero adversity, such as maternal infections and starvation during pregnancy, and obstetric complications, including preterm birth and preeclampsia. [9][10][11] There is also evidence consistent with disrupted early neurodevelopment, such as skin markers of altered ectodermal development and mild cognitive and motor impairments in childhood. 9,12 Such impairments may manifest as IMPORTANCE Schizophrenia is a common, severe mental illness that most clinicians will encounter regularly during their practice. This report provides an overview of the clinical...

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Genetic identification of brain cell types underlying schizophrenia

Cited by 558 publications

References 60 publications

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls

Schizophrenia—An Overview

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